Cell signaling involves the release of molecules that transmit signals between cells to maintain homeostasis. Hydrogen gas has been shown to act as a cell signaling molecule by modulating the activity of enzymes involved in cell signaling pathways. Specifically, molecular hydrogen inhibits the phosphorylation of enzymes like ASK1 and JNK that are activated in response to oxidative stress and inflammation. It also attenuates the phosphorylation of enzymes involved in the allergic response. These effects suggest hydrogen gas influences cell signaling pathways indirectly as a modulator, though its specific molecular targets are still unknown.

1. Cell Signalling and Molecular
Hydrogen
From AlkaWay International

2. Cell Signalling
• The ability of cells to perceive and correctly
respond to their microenvironment is the
basis of development, tissue repair, and
immunity as well as normal tissue
homeostasis.
• Errors in cellular information processing
contribute to the development of diseases
such as cancer, autoimmunity, and diabetes.

4. Cell signalling
• Cell signalling is the mechanism by which the
body responds to external and internal changes
in order to maintain homoeostasis.
• When a cell receives a stimuli it releases cellular
messengers in response to that stimuli.
• Cell signalling molecules can either travel to
neighbouring cells (eg. Neurotransmitters), to
cells in another part of the body (eg. hormones)
or act on the emitting cell.
• These messengers come in many forms,
including: proteins, minerals, lipids and gases.

5. Cell Signalling
• A cell signalling molecule is released by the
stimulated cell and travels to the target cell.
The molecule then either attaches to a
receptor on the cell surface, or enters the cell.
• This results in a change in the molecules that a
cell produces.
• This change in cellular output creates the
change required by the originating cell in
order to maintain homoeostasis.

6. How do signals cause
changes in cells?
• Signals may cause the cell to change what it is
doing in a variety of ways. Depending upon the
signal, things inside a cell may change, for
example, by:
• a change in intracellular conditions like ion
concentrations
• metabolic changes, like the activation of
enzymes that were previously inactive
• gene expression changes, like activation of
transcription of previously unexpressed genes

7. Cell to cell signalling

8. Cell Signalling and epigenetics

9. Gases as cell signalling
molecules
• Several gases have been identified as having a
cell signalling role in the body.
• These gases include: Nitric Oxide, Carbon
Monoxide, Hydrogen Sulphide and Molecular
Hydrogen.
• It is thought that they function through
modulating the activity of target enzymes
within the cell.

10. Hydrogen as a cell signalling molecule
• 4-Hydroxynonenal, or 4-HNE
induces oxidative stress,
produced by lipid peroxidation
• MDA (Malondialdehyde): a
marker for oxidative stress,
produced by lipid peroxidation
• 8-OH-dG: product of DNA
oxidation
• Transcriptional control: Control
of DNA replication
• Nrf2: The Nrf2 antioxidant
response pathway is the primary
cellular defense against the
cytotoxic effects of oxidative
stress.
• Ghrelin: hunger; also
neuroprotective
• FGF21: protects from diet
induced obesity, increases energy
metabolism

11. H2 and Allergic response
• H2 attenuates the phosphorylation of FcεRI-
associated Lyn and its downstream signalling
molecules
– FcεRI is receptor involved in allergy response and
controls the production of important immune
mediators
– Signals Lyn, which is an enzyme that ultimately
induces the mechanisms of the allergic response
– Phosphorolation is the action by which the
enzyme increases the activity of FcεRI

12. Inhibition of stress responses
• H2 inhibits the phosphorylation of ASK1 and its
downstream signalling molecules, p38 MAP
kinase, JNK, and IκB without affecting ROS
production derived from NADPH oxidase
• ASK1: an enzyme that transfers phosphate groups
from donor molecules to specific substrates, a
process referred to as phosphorylation
• Phosphorylation: Increases a molecules activity,
reactivity, and its ability to bind other molecules in
response to an array of stimuli such as oxidative
stress

13. H2 & Cell Signalling
Modulation
– p38 MAP kinase & JNK are MAPKs.
– MAPKs are involved in directing cellular responses to a
diverse array of stimuli, such as proinflammatory
cytokines. They regulate proliferation, gene expression,
differentiation, cell survival, and apoptosis
• So therefore H2 inhibits the activation of the
molecules involved in the response to stimuli such as
oxidative stress and inflammation
• NADPH: used by neutrophil white blood cells to
engulf microorganisms. TheROS generated are
those required to kill bacteria

14. H2 & Liver cancer
• Pre-treatment with H2 reduced fatty acid uptake
and lipid accumulation after palmitate overload
in HepG2 cells, which was associated with
inhibition of JNK activation
– JNK: type of enzyme that respond to environmental
stress stimuli and inflammatory cytokines. They also
play a role in the immune response.
– HepG2 cells are liver cancer cells
– Lipid accumulation and palmitate overload have been
associated to the development of some liver cancers
– So therefore H2 may decrease the mechanism by
which lipids may increase the development of
cancerous cells in the liver.

15. H2 & Cell Signalling
• These studies suggest that H2 influences some
signal transductions as an indirect modulator;
however, it is unlikely that H2 could directly
bind to some receptors involved in the signal
transductions.
• The primary target molecule of H2 has not
been identified in these signal transduction
pathways.
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