Cell Signalling and Molecular HydrogenFrom AlkaWay International

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.

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.

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.

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

Cell to cell signalling

Cell Signalling and epigenetics

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.

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

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

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

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. The ROS generated are those required to kill bacteria

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.

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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