Cancer cells prevent you from sleeping at night in order to survive

Cancer Overrides the Circadian Clock to Survive

Source: Medical University of South Carolina.

Tumor cells use the unfolded protein response to alter circadian rhythm, which contributes to more tumor growth, Hollings Cancer Center researchers at the Medical University of South Carolina (MUSC) find. A key part of the circadian clock opposes this process, according to a paper published online Dec. 11 in Nature Cell Biology.

For tumors to grow and spread, cancer cells must make larger than normal amounts of nucleic acids and protein, so they can replicate themselves. Yet in both normal and cancer cells that increase their synthesis of protein, a small percent of those proteins do not fold properly. When that happens, the cell activates its unfolded protein response (UPR), which slows down the making of new proteins while the misfolded proteins are refolded. Eventually, the buildup of misfolded proteins becomes toxic and leads to cell death. However, cancer cells have learned to use the UPR to slow protein synthesis when needed, in order to handle the backlog of misfolded proteins. This helps them survive in conditions that would kill normal cells.

This pattern of adaptation is often seen in tumor cells, according to J. Alan Diehl, Ph.D., the SmartState Endowed Chair in Lipidomics, Pathobiology and Therapy at the MUSC Hollings Cancer Center and senior researcher on the project. “What a tumor cell is doing is taking a pathway that’s already in the cell and using it to its advantage,” said Diehl.

Yet it was not clear exactly how cancer cells were able to use UPR activity to influence circadian rhythm. Diehl’s group found that the UPR and circadian rhythm are linked together to lead the clockwork of the cell and also that cancer cells use the UPR to manipulate the circadian clock in ways that allow them to survive conditions that are toxic to normal cells.

To start, Diehl and his fellow researchers formulated a new idea based on what was known about protein synthesis in the cell. First, as they knew, the UPR is altered in tumors, and second, cells establish a circadian rhythm to regulate metabolism by producing levels of certain proteins that rise and fall in coordination with natural cycles of light and dark. Third, other scientists had observed that circadian rhythm is altered in tumor cells. Since protein production is tied to circadian rhythm, Diehl’s group asked if misfolded proteins might change circadian rhythm in cancer cells.

In their first set of experiments, Diehl’s research team used chemicals to activate the UPR in osteosarcoma cells. They found that, when activated, the UPR changes levels of an important protein called Bmal1, which is a transcription factor that rises and falls with cycles of light and dark. As it does, it regulates the expression of major circadian rhythm genes. When cells were exposed to cycles of light and dark, Bmal1 levels peaked during dark hours. But when the UPR was chemically activated, Bmal1 stayed low during both light and dark phases, which caused a phase shift in the expression of circadian genes. When one of the main parts of the UPR machinery was absent in cells, the phase shift did not happen.

Next, the group found that the UPR functions much like a “middleman” between light-dark cycles and the ability of cells to establish a circadian rhythm from those cycles. Levels of the circadian protein Bmal1 continued to decrease, as the UPR was increasingly activated. In rodents that had their light-dark cycles suddenly reversed, Bmal1 stopped rising and falling – a clear sign that their circadian rhythms were disrupted. Shifts in light exposure activated the UPR in those rodents’ cells.

But what does that mean for the development of cancer? The team found that patients with breast, gastric or lung cancers survived longer when they had higher levels of Bmal1 protein. In myc-driven cancers, the UPR was causing the loss of Bmal1 protein, which caused the tumors to grow. Myc-driven tumors lost circadian rhythm, whereas normal cells maintained it. Conversely, high levels of Bmal1 overtook the UPR, thereby allowing protein synthesis to continue, which was toxic to tumor cells. In this way, Bmal1 directly encourages protein synthesis.

This is the first study showing that human cancer suppresses circadian rhythm by controlling protein synthesis through Bmal1. Cancer cells survived longer by using the UPR to suppress Bmal1 and short-circuit their circadian rhythms. These results are important for human biology, according to Yiwen Bu, Ph.D., a postdoctoral scholar in Diehl’s laboratory and first author on the paper. “Every single normal cell in our body has circadian oscillation,” said Bu. “We showed that resetting the circadian rhythms in cancer cells slows down their proliferation.”

Image shows a DNA strand.

Still, do changes in light-dark cycles contribute to the development of cancer in humans? It is not yet clear in patients if circadian shifts contribute to changes in the UPR and if that, in turn, contributes to the development of cancer. But these results could help clinicians boost the effectiveness of current cancer treatments, Diehl said.

“Physicians are beginning to think about timing delivery of therapies in such a way that, say, if we deliver a drug at a certain time of day, we’ll get better on-target effects on the cancer and less toxicity in the normal cells,” he said.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Source: Heather Woolwine – Medical University of South Carolina
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “A PERK–miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival” by Yiwen Bu, Akihiro Yoshida, Nilesh Chitnis, Brian J. Altman, Feven Tameire, Amanda Oran, Victoria Gennaro, Kent E. Armeson, Steven B. McMahon, Gerald B. Wertheim, Chi V. Dang, Davide Ruggero, Constantinos Koumenis, Serge Y. Fuchs & J. Alan Diehl in Nature Cell Biology. Published online December 11 2017 doi:10.1038/s41556-017-0006-y

CITE THIS NEUROSCIENCENEWS.COM ARTICLE
Medical University of South Carolina “Cancer Overrides the Circadian Clock to Survive.” NeuroscienceNews. NeuroscienceNews, 28 December 2017.
<http://neurosciencenews.com/cancer-circadian-clock-8241/&gt;.

Abstract

A PERK–miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival

The unfolded protein response (UPR) is a stress-activated signalling pathway that regulates cell proliferation, metabolism and survival. The circadian clock coordinates metabolism and signal transduction with light/dark cycles. We explore how UPR signalling interfaces with the circadian clock. UPR activation induces a 10 h phase shift in circadian oscillations through induction of miR-211, a PERK-inducible microRNA that transiently suppresses both Bmal1 and Clock, core circadian regulators. Molecular investigation reveals that miR-211 directly regulates Bmal1 and Clock via distinct mechanisms. Suppression of Bmal1 and Clock has the anticipated impact on expression of select circadian genes, but we also find that repression of Bmal1 is essential for UPR-dependent inhibition of protein synthesis and cell adaptation to stresses that disrupt endoplasmic reticulum homeostasis. Our data demonstrate that c-Myc-dependent activation of the UPR inhibits Bmal1 in Burkitt’s lymphoma, thereby suppressing both circadian oscillation and ongoing protein synthesis to facilitate tumour progression.

“A PERK–miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival” by Yiwen Bu, Akihiro Yoshida, Nilesh Chitnis, Brian J. Altman, Feven Tameire, Amanda Oran, Victoria Gennaro, Kent E. Armeson, Steven B. McMahon, Gerald B. Wertheim, Chi V. Dang, Davide Ruggero, Constantinos Koumenis, Serge Y. Fuchs & J. Alan Diehl in Nature Cell Biology. Published online December 11 2017 doi:10.1038/s41556-017-0006-y

Night owls have higher risk of dying sooner

 

EMF and Diabetes

During the last 3 Sundays, I have been jogging and walking bare feet in Santa Cruz beach, California. I believe in nature’s help in grounding, releasing negative charges in our bodies. Email motherhealth@gmail.com if you have any research related to EMF, Diabetes and other health issues to find the root cause and empower others to a healthy body.

Connie

Dr. Magda Havas, PhD » Diabetes and Electrosensitivity

March 2010. If you have difficulty regulating your blood sugar and you are electrically sensitive you may have type 3 diabetes according to research published in the Journal Electromagnetic Biology and Medicine in 2008. Unlike Type 1 diabetes (juvenile diabetes) that is largely genetically controlled, and Type 2 diabetes …

Diabetes and EMFs | Cause of Diabetes | Type 3 Diabetes – EarthCalm

exposure to electromagnetic fields (EMFs). … Dr. Havas’s study concludes that many diabetics may be electrically-sensitive, a condition which may cause increased blood sugar in their tests. … No matter what type of Diabetes you have, you will benefit from EMF protection.

Could EMFs Cause Diabetes? – ElectricSense

Jan 13, 2011 – Studies show that diabetes can be triggered by exposure to electromagnetic fields (EMFs). It causes Type 3 diabetes. Learn the principal causes and solutions.

[PDF]Diabetes and ElectroMagnetic Fields: the evidence – Next-up

a connection between the increase in diabetes and EMF exposure, but also the effectiveness of filters on ELF electrical equipment that help to reduce the suffering and the symptoms of diabetics. “We can take a diabetic person and put them in an environment polluted by EMR and measure their sugar levels,” she explained …

Electromagnetic Fields Can Worsen Diabetes – Real Diabetes Truth …

Aug 29, 2013 – There is mounting evidence that electromagnetic fields (EMF) from the electronic equipment that constantly surrounds us are bad for our health.

EMF and Diabetes | eatgenius

eatgenius.com › Bites

Mar 17, 2017 – EMF is a risk factor for diabetes and affects diabetes management.

DoH: EMF and Diabetes / Cell Phone Radiation Standards – Institute …

geopathology-za.wikidot.com › … › Department of Health

Please WAKE-UP !!! Minister of Health and Minister of Environment !!! – Please WAKE-UP, now !!!**. Electromagnetic Fields lead to Diabetic Disasters – and not only THAT !!! See: http://www.naturalnews.com/029328_diabetes_electromagnetic_pollution.html. Talking about certain PROBLEMS does not help much, unless you …

EMF / EMR and type 3 Diabetes | Life Energy Designs

Diabetes can be caused by EMF / EMR exposure. This is the conclusion of the latest peer-reviewed research by Dr. Magda Havas PhD. In sensitive people, which she classifies as having type 3 diabetesor environmentally triggered diabetes, exposure to dirty electricity (EMF/EMR) is enough to send their blood sugar high.

Dirty electricity elevates blood sugar among electrically sensitive …

by M Havas – ‎2008 – ‎Cited by 54 – ‎Related articles

Electromagn Biol Med. 2008;27(2):135-46. doi: 10.1080/15368370802072075. Dirty electricity elevates blood sugar among electrically sensitive diabetics and may explain brittle diabetes. Havas M(1). Author information: (1)Environmental & Resource Studies, Trent University, Peterborough, Ontario, Canada.

Electromagnetic Fields Lead to Diabetic Disasters – NaturalNews.com

Jul 31, 2010 – (NewsTarget) In recent years, many of us have grown increasingly aware of the possible dangers posed by Electromagnetic Fields (EMFs) [1]. As electrical and wireless applications continue to become more ubiquitous in society, so our exposure to EMFs continues to climb. Although low levels of natural …

Potassium rich foods in the afternoon and sodium rich foods in the morning for sleep

Mechanism that Controls When We Sleep and When We Wake Discovered

Simple 2-cycle mechanism turns key brain neurons on or off during 24-hour day.

Fifteen years ago, an odd mutant fruit fly caught the attention and curiosity of Dr. Ravi Allada, a circadian rhythms expert at Northwestern University, leading the neuroscientist to recently discover how an animal’s biological clock wakes it up in the morning and puts it to sleep at night.

The clock’s mechanism, it turns out, is much like a light switch. In a study of brain circadian neurons that govern the daily sleep-wake cycle’s timing, Allada and his research team found that high sodium channel activity in these neurons during the day turn the cells on and ultimately awaken an animal, and high potassium channel activity at night turn them off, allowing the animal to sleep. Investigating further, the researchers were surprised to discover the same sleep-wake switch in both flies and mice.

“This suggests the underlying mechanism controlling our sleep-wake cycle is ancient,” said Allada, professor and chair of neurobiology in the Weinberg College of Arts and Sciences. He is the senior author of the study. “This oscillation mechanism appears to be conserved across several hundred million years of evolution. And if it’s in the mouse, it is likely in humans, too.”

Better understanding of this mechanism could lead to new drug targets to address sleep-wake trouble related to jet lag, shift work and other clock-induced problems. Eventually, it might be possible to reset a person’s internal clock to suit his or her situation.

The researchers call this a “bicycle” mechanism: two pedals that go up and down across a 24-hour day, conveying important time information to the neurons. That the researchers found the two pedals — a sodium current and potassium currents — active in both the simple fruit fly and the more complex mouse was unexpected.

The findings were published today in the Aug. 13 issue of the journal Cell.

“What is amazing is finding the same mechanism for sleep-wake cycle control in an insect and a mammal,” said Matthieu Flourakis, the lead author of the study. “Mice are nocturnal, and flies are diurnal, or active during the day, but their sleep-wake cycles are controlled in the same way.”

When he joined Allada’s team, Flourakis had wondered if the activity of the fruit fly’s circadian neurons changed with the time of day. With the help of Indira M. Raman, the Bill and Gayle Cook Professor in the department of neurobiology, he found very strong rhythms: The neurons fired a lot in the morning and very little in the evening.

The researchers next wanted to learn why. That’s when they discovered that when sodium current is high, the neurons fire more, awakening the animal, and when potassium current is high, the neurons quiet down, causing the animal to slumber. The balance between sodium and potassium currents controls the animal’s circadian rhythms.

This image shows how light affects the suprachiasmatic nucleus in the circadian cycle.

Flourakis, Allada and their colleagues then wondered if such a process was present in an animal closer to humans. They studied a small region of the mouse brain that controls the animal’s circadian rhythms — the suprachiasmatic nucleus, made up of 20,000 neurons — and found the same mechanism there.

“Our starting point for this research was mutant flies missing a sodium channel who walked in a halting manner and had poor circadian rhythms,” Allada said. “It took a long time, but we were able to pull everything — genomics, genetics, behavior studies and electrical measurements of neuron activity — together in this paper, in a study of two species.

“Now, of course, we have more questions about what’s regulating this sleep-wake pathway, so there is more work to be done,” he said.

ABOUT THIS CIRCADIAN RHYTHM RESEARCH

In addition to Allada and Flourakis, other authors of the paper are Elzbieta Kula-Eversole, Tae Hee Han and Indira M. Raman, of Northwestern; Alan L. Hutchison, Aaron R. Dinner and Kevin P. White, of the University of Chicago; Kimberly Aranda and Dejian Ren, of the University of Pennsylvania; Devon L. Moose and Bridget C. Lear, of the University of Iowa; and Casey O. Diekman, of the New Jersey Institute of Technology.

Funding: The study was funded by the National Institutes of Health and Defense Advanced Research Projects Agency.

Source: Megan Fellman – Northwestern University
Image Source: The image is in the public domain
Original Research: Abstract for “A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability” by Matthieu Flourakis, Elzbieta Kula-Eversole, Alan L. Hutchison, Tae Hee Han, Kimberly Aranda, Devon L. Moose, Kevin P. White, Aaron R. Dinner, Bridget C. Lear, Dejian Ren, Casey O. Diekman, Indira M. Raman, and Ravi Alladac in Cell. Published online August 13 2015 doi:10.1016/j.cell.2015.07.036


Abstract

A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability

Highlights
•Rhythmic sodium leak conductance depolarizes Drosophila circadian pacemaker neurons
•NCA localization factor 1 links the molecular clock to sodium leak channel activity
•Antiphase cycles in resting K+ and Na+ conductances drive membrane potential rhythms
•This “bicycle” mechanism is conserved in master clock neurons between flies and mice

Summary
Circadian clocks regulate membrane excitability in master pacemaker neurons to control daily rhythms of sleep and wake. Here, we find that two distinctly timed electrical drives collaborate to impose rhythmicity on Drosophila clock neurons. In the morning, a voltage-independent sodium conductance via the NA/NALCN ion channel depolarizes these neurons. This current is driven by the rhythmic expression of NCA localization factor-1, linking the molecular clock to ion channel function. In the evening, basal potassium currents peak to silence clock neurons. Remarkably, daily antiphase cycles of sodium and potassium currents also drive mouse clock neuron rhythms. Thus, we reveal an evolutionarily ancient strategy for the neural mechanisms that govern daily sleep and wake.

“A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability” by Matthieu Flourakis, Elzbieta Kula-Eversole, Alan L. Hutchison, Tae Hee Han, Kimberly Aranda, Devon L. Moose, Kevin P. White, Aaron R. Dinner, Bridget C. Lear, Dejian Ren, Casey O. Diekman, Indira M. Raman, and Ravi Alladac in Cell. Published online August 13 2015 doi:10.1016/j.cell.2015.07.036

Simple EKG Can Determine Whether Patient Has Depression or Bipolar Disorder

Simple EKG Can Determine Whether Patient Has Depression or Bipolar Disorder

Summary: Heart rate variability can indicate whether a person has bipolar disorder or major depression, a new study reports.

Source: Loyola University Health System.

A groundbreaking Loyola Medicine study suggests that a simple 15-minute electrocardiogram could help a physician determine whether a patient has major depression or bipolar disorder.

Bipolar disorder often is misdiagnosed as major depression. But while the symptoms of the depressive phase of bipolar disorder are similar to that of major depression, the treatments are different and often challenging for the physician.

In bipolar disorder, formerly called manic depression, a patient swings between an emotional high (manic episode) and severe depression. Treatment for the depressed phase includes an antidepressant along with a safeguard such as a mood stabilizer or antipsychotic drug to prevent a switch to a manic episode. A physician who misdiagnoses bipolar disorder as major depression could inadvertently trigger a manic episode by prescribing an antidepressant without a safeguard mood stabilizing drug.

The study found that heart rate variability, as measured by an electrocardiogram, indicated whether subjects had major depression or bipolar disorder. (Heart rate variability is a variation in the time interval between heartbeats.) The study, by senior author Angelos Halaris, MD, PhD and colleagues, was published in the World Journal of Biological Psychiatry.

“Having a noninvasive, easy-to-use and affordable test to differentiate between major depression and bipolar disorder would be a major breakthrough in both psychiatric and primary care practices,” Dr. Halaris said. Dr. Halaris said further research is needed to confirm the study’s findings and determine their clinical significance.

Dr. Halaris is a professor in Loyola’s department of psychiatry and behavioral neurosciences and medical director of adult psychiatry.

Major depression is among the most common and severe health problems in the world. In the United States, at least 8 to 10 percent of the population suffers from major depression at any given time. While less common than major depression, bipolar disorder is a significant mental health problem, affecting an estimated 50 million people worldwide.

The Loyola study enrolled 64 adults with major depression and 37 adults with bipolar disorder. All subjects underwent electrocardiograms at the start of the study. Each participant rested comfortably on an exam table while a three-lead electrocardiogram was attached to the chest. After the patient rested for 15 minutes, the electrocardiographic data were collected for 15 minutes.

Using a special software package, researchers converted the electrocardiographic data into the components of heart rate variability. These data were further corrected with specialized software programs developed by study co-author Stephen W. Porges, PhD, of Indiana University’s Kinsey Institute.

In measuring heart rate variability, researchers computed what is known to cardiologists as respiratory sinus arrhythmia (RSA). At the baseline (beginning of the study), the subjects with major depression had significantly higher RSA than those with bipolar disorder.

In a secondary finding, researchers found that patients with bipolar disorder had higher blood levels of inflammation biomarkers than patients with major depression. Inflammation occurs when the immune system revs up in response to a stressful condition such as bipolar disorder.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

The study is titled “Low cardiac vagal tone index by heart rate variability differentiates bipolar from major depression.” In addition to Drs. Halaris and Porges, other co-authors are Brandon Hage, MD, a graduate of Loyola University Chicago Stritch School of Medicine now at the University of Pittsburgh (first author); Stritch student Briana Britton; Loyola psychiatric resident David Daniels, MD; and Keri Heilman, PhD of the University of North Carolina.

Source: Jim Ritter – Loyola University Health System
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Distinguishing bipolar II depression from unipolar major depressive disorder: Differences in heart rate variability” by Hsin-An Chang Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Chuan-Chia Chang, Terry B. J. Kuo & San-Yuan Huang in World Journal of Biological Psychiatry. Published online November 14 2017 doi:10.3109/15622975.2015.1017606

Loyola University Health System “Simple EKG Can Determine Whether Patient Has Depression or Bipolar Disorder.” NeuroscienceNews. NeuroscienceNews, 20 November 2017.
<http://neurosciencenews.com/ekg-depression-bipolar-7991/&gt;.

Abstract

Distinguishing bipolar II depression from unipolar major depressive disorder: Differences in heart rate variability

Objectives. Bipolar II (BPII) depression is commonly misdiagnosed as unipolar depression (UD); however, an objective and reliable tool to differentiate between these disorders is lacking. Whether cardiac autonomic function can be used as a biomarker to distinguish BPII from UD is unknown.

Methods. We recruited 116 and 591 physically healthy patients with BPII depression and UD, respectively, and 421 healthy volunteers aged 20–65 years. Interviewer and self-reported measures of depression/anxiety severity were obtained. Cardiac autonomic function was evaluated by heart rate variability (HRV) and frequency-domain indices of HRV.

Results. Patients with BPII depression exhibited significantly lower mean R–R intervals, variance (total HRV), low frequency (LF)-HRV, and high frequency (HF)-HRV but higher LF/HF ratio compared to those with UD. The significant differences remained after adjusting for age. Compared to the controls, the patients with BPII depression showed cardiac sympathetic excitation with reciprocal vagal impairment, whereas the UD patients showed only vagal impairment. Depression severity independently contributed to decreased HRV and vagal tone in both the patients with BPII depression and UD, but increased sympathetic tone only in those with BPII depression.

Conclusions. HRV may aid in the differential diagnosis of BPII depression and UD as an adjunct to diagnostic interviews.

“Distinguishing bipolar II depression from unipolar major depressive disorder: Differences in heart rate variability” by Hsin-An Chang Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Chuan-Chia Chang, Terry B. J. Kuo & San-Yuan Huang in World Journal of Biological Psychiatry. Published online November 14 2017 doi:10.3109/15622975.2015.1017606

Toning or making elongated vowel sounds to heal your body

Practice making elongated vowels sound to become centered in your body, balance brain wabes and release fear and other emotions.

This practice helps your body especially the temporal lobe of the brain

Ah evokes a sense of relaxation…

Ee or Ay helps in concentration, releasing pain and anger…

Oh or Om warms skin temp and relax muscle tension

 

10 Toning Tips

1 Sit or lie down, close your eyes and relax your body
2 Take a deep breath, hold a moment and release
3 As you exhale, allow a quiet humming to occur as you push the breath out
4 Do this several times feeling your hum resonating deep inside
5 Inhale again and slowly exhale pushing out an AH vowel tone with the breath
6 Repeat as many times as you want focusing on love and your Heart Chakra
7 Play with the sound, Change the vowel tone to OH feeling your Power Center
8 Concentrate on the point between your eyebrows
9 Focus on your higher power, your angels, God or Nature
10 Feel the vibration of oneness as you breathe in the life force

Toning is a simple system using the breath and voice that has the effect of energizing and calming the body at the same time as well as centering and focusing the mind.  It requires no musical training, instruments or technology so it is the perfect tool to support your healing and going deeper into meditation.   As we learn to relax and calm the whirlpools of the mind, we are better able to support our well being.  We can use this system anytime we feel stress or want to calm our restless thoughts.

The mind is a very active system and in the busyness of our modern lives, we often need help in letting go of worrisome or troubling thoughts that have a tendency to repeat themselves as incessant tape loops.  Even if the thoughts aren’t negative, by their very repetition, they can wear us down.  We call it ‘monkey mind’ as it reminds us of a bothersome creature constantly nagging us to think thoughts that are unnecessary or harmful to our psyche.  The word ‘mantra’ in Sanskrit means ‘mind protection’ so by toning a sacred mantra, we are protecting our minds from our own negative interference.