Pinocembrin And Its Effect On Mitochondria

Pinocembrin, which is also known as 5,7-dihydroxyflavone (C15H12O4), has been obtained from plants such as Eucalyptus and Pinus heartwood. Pinocembrin is found in propolis, which is widely consumed by humans due to its medicinal properties. Actually, pinocembrin is a major component of propolis. It has been reported that pinocembrin induces cytoprotective effects in human cells.

Pinocembrin is an antioxidant and anti-inflammatory molecule, meaning that it acts against the deleterious effects elicited by reactive species/free radicals and attenuates inflammation. Some researchers also described an anti-tumor action of pinocembrin experimentally. Recently, our research group published a paper showing that pinocembrin is able to cause mitochondrial protection in the SH-SY5Y human neuroblastoma cell line.

These cells are utilized experimentally in order to investigate whether selected molecules would exert neuroprotection, for example. Additionally, the SH-SY5Y cells are used in Neurotoxicology in order to analyze the mechanisms underlying the deleterious effects of toxicants (pollutants, drugs, xenobiotics, others).

Mitochondria are organelles containing double membrane and are responsible for the production of adenosine triphosphate (ATP) in both animal and vegetal cells. The electron transfer chain is found in the inner mitochondrial membrane (IMM) and presents the protein complexes called complex I (NADH dehydrogenase), complex II (succinate dehydrogenase), complex III (coenzyme Q: cytochrome c-oxidoreductase), and complex IV (cytochrome c oxidase). Besides, coenzyme Q and cytochrome c are mobile components responsible for the electron transfer between the protein complexes of the electron transfer chain.

This system utilizes the energy released from the electron flux between these complexes to transport protons (H+) across the IMM. The concentration of the protons increases in the intermembrane space, generating a difference in charge and pH between the intermembrane space and the mitochondrial matrix. This is experimentally measured and is called mitochondrial membrane potential. The electrons and protons are obtained from substrates utilized by the cells such as fuels (glucose, fructose, fatty acids, amino acids, ketone bodies, others).

The energy obtained from these fuels is conserved and utilized to produce ATP in the mitochondria. Complex V (ATP synthase/ATPase) utilizes the proton gradient generated by the electron transfer chain to synthesize ATP from ADP and Pi. Oxygen gas (O2) is the final acceptor of electrons in the electron transfer chain. This O2 is obtained by the animals during breathing. The major role of O2 in animal cells is to accept electrons in the electron transfer chain. Therefore, we breathe to amplify the production of ATP in order to maintain the complexity of our cells! After being released from the mitochondria, ATP is used as a source of energy in different physiological events in the cells (muscle contraction, transport of ions across the plasma membrane, detoxification of ammonia, synthesis of proteins, synthesis of lipids, others).

Even though the electron transfer chain is crucial in the oxidative phosphorylation process, this is a major source of free radicals, which are able to cause damage to the cells due to their high reactivity. There is evidence showing a role for free radicals in neurodegeneration (Parkinson’s disease, Alzheimer’s disease, Huntington’s disease), schizophrenia, bipolar disorder, major depression, type I and type II diabetes mellitus, and cardiovascular disease, among others. The production of free radicals is also increased during infection and inflammation. Importantly, free radicals are not produced only in the mitochondria. However, they are a major source of free radicals and mitochondrial dysfunction, which is also observed in the disorders mentioned above, enhances free radicals generation.

Moreover, mitochondria are a target of several toxicants, such as cocaine, ecstasy, cyanide, heavy metals, ethanol, among others. Some drugs utilized pharmacologically may affect mitochondrial function, such as fluoxetine. Excessive intake of vitamins may also cause disruption in the mitochondrial function, leading to decreased cell viability, as observed experimentally. Mitochondrial also control cell death by the intrinsic apoptotic pathway, i.e. a coordinated event responsible for the controlled death of cells. Apoptosis is a physiological event that occurs during the human development and continues into the adulthood. Nonetheless, increased rates of cell death by apoptosis may result in tissue dysfunction, causing diseases in humans.

Therefore, the mitochondrial homeostasis is crucial to maintaining the normal function of the different cell types humans present in their body (with exception of the red blood cells, which do not present mitochondria). In this context, we have utilized pinocembrin in the SH-SY5Y cells aiming to reveal whether this natural compound would promote mitochondrial protection during the exposure of these cells to paraquat (an agrochemical that generates free radicals and induces cell death by different mechanisms experimentally). The cells were treated with pinocembrin at 1 – 25 µM for 4 h prior to the administration of paraquat for additional 24 h.

Pinocembrin Pretreatment’s Impact On Mitochondrial Function

We have found that pinocembrin pretreatment at 25 µM decreased the impact of paraquat on the mitochondrial function, as assessed through the analyses of the activities of the complexes of the electron transfer chain. Furthermore, pinocembrin reduced the production of free radicals by the mitochondria in the cells that were challenged with paraquat. Consequently, the levels of ATP were found in a normal range of the cells that were pretreated with pinocembrin and exposed to paraquat posteriorly. Pinocembrin decreased the levels of the molecular markers of redox disturbance (oxidative and nitrosative stress) in the membranes of the mitochondria isolated from the SH-SY5Y cells.

Interestingly, pinocembrin stimulated the production of antioxidant enzymes, which are responsible for the metabolism of free radicals and reactive species in the cells. The upregulation of these enzymes occurred through the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor. This is a protein responsible for the control of the expression of several genes, whose products (other proteins and enzymes) are involved in both antioxidant defense and detoxification in mammalian cells. When the Nrf2-dependent signaling was blocked, the mitochondria-related protective effects induced by pinocembrin were suppressed. Thus, pinocembrin is very likely to cause mitochondrial protection by a mechanism dependent on the activation of this transcription factor.

Future research would be necessary to evaluate whether pinocembrin is a cytoprotective agent also in vivo regarding mitochondrial function and dynamics. This is particularly important because the metabolism (biotransformation) of xenobiotics (and pinocembrin is a xenobiotic to the human body) modifies the molecules we ingest. It is necessary to excrete xenobiotics, decreasing their time of permanence in the body. Biotransformation may be viewed as a series of enzymatic reactions necessary to protect human cells against strange molecules.

Unfortunately, there are cases in which biotransformation generates toxic agents after modifying xenobiotics. Importantly, the investigation about the possible toxic effects that may result from the exposure to pinocembrin should be performed in order to ensure a secure concentration range that may be utilized by humans (and other animals) without affecting their health. Indeed, it is not recommended to use purified pinocembrin as a supplement, such as vitamin supplements are inadvertently utilized, for example. However, pinocembrin presents a pharmacological potential that needs to be investigated carefully.

These findings are described in the article entitled Pinocembrin Provides Mitochondrial Protection by the Activation of the Erk1/2-Nrf2 Signaling Pathway in SH-SY5Y Neuroblastoma Cells Exposed to Paraquat, published in the journal Molecular Neurobiology. This work was led by Marcos de Oliveira from the Federal University of Mato Grosso, Cuiaba, Brazil.

About The Author

MRD
Marcos Roberto de Oliveira

I have a degree in Biological Sciences (Molecular, Cellular and Functional Emphasis) from the Federal University of Rio Grande do Sul (2005) and a Masters and PhD from the Graduate Program in Biological Sciences: Biochemistry from the UFRGS Biochemistry Department. I concluded postdoctoral studies by the same institution. I have experience in the field of Biochemistry, with emphasis in Neurochemistry, Neurotoxicology, Cell Biology, Mitochondrial Function / Bioenergetics and Animal Behavior, working mainly in the following subjects: acute and chronic supplementation with bioactive molecules, animal behavior (mainly, locomotion and exploration anxiety and depression behaviors), mitochondrial function, oxidative stress, reticular stress, cellular signaling, neurochemistry and neurotoxicology. I collaborate with researchers from national institutions (in Rio Grande do Sul, Santa Catarina and Rio de Janeiro) and international researchers (Italy, United Kingdom, United States, Russia, India, Iran, Turkey, Australia, Pakistan). I am a member of the editorial board of international journals.

Speak Your Mind!

READ THIS NEXT

Sponges In The Great Barrier Reef Act As Ecological Indicators

Published by Anita Mary George College of Marine and Environmental Science, James Cook University and Queensland Museum These findings are described in the article entitled Can sponge morphologies act as environmental proxies to biophysical factors in the Great Barrier Reef, Australia? recently published in the journal Ecological Indicators (Ecological Indicators 93 (2018) 1152-1162). This work […]

Theoretical Yield: Formula And Calculator

In chemistry, theoretical yield is a term that describes the amount of product that would result from a chemical reaction, assuming that chemical reaction completes. A chemical reaction is only considered complete when the entire limiting reactant is used up and it is impossible to create more product from the remaining chemicals. Theoretical yield is […]

The Tomcat And The Genes: When Twins Drink …

Why is it that some people are spared from a hangover after an evening of alcohol, but others suffer? A group of US and Australian researchers suspect that part of the solution lies in the genes. They’re not the only ones.  Alcohol has been part of human culture for thousands of years, and the first […]

InSight Mission Will Reveal Mars’ Past Hidden Just Five Meters Below Its Surface

Rocky planets like Mars and Earth have formed during the early stages of our Solar System by acquiring their mass through collisions of planetesimals and protoplanets. Such energetic collisions, as well as the decay of radioactive heat producing elements and the process of core formation, produce a large amount of heat that has been stored […]

How To Write A Cursive Lowercase z

Have you ever wondered how to write a cursive lowercase “z”? Below you’ll learn some interesting facts about cursive, as well as how to write a cursive lowercase “z”. How To Write A Cursive Lowercase Z You can write a cursive lowercase “z” by picking a point that originates about a quarter of the way […]

The Importance Of Estimating Clay Mineral In Oilfields

Clay minerals consist of a fine-grained material which is classified according to their crystal structure into four major groups: kaolinite, chlorite, illite, and smectite. These minerals are important constituents in many types of rocks, like shales and sandstones. The last one is considered a very common type of reservoir rock for oil and gas. The […]

Finding Consistent Measurements For Drought And Flood Assessments

Several studies have found that both hydrological extremes (floods and droughts) are occurring more often and are becoming more intense in some regions of the world. But to come to these conclusions, most of the studies have dealt with floods and droughts separately and defined them in a way that does not reflect their “opposite-extreme” […]