Adaptogens, Bioregulatory Systems Medicine and Network Pharmacology

Have you ever wondered how life on Earth has managed to survive in the midst of volcanos, ice ages and asteroids? The answer is adaptation. Humans are remarkably adaptable. We’ve been able to adjust to almost any condition on the planet, while continuing to thrive as a civilization.

Think about this:

  • No other species lives in such a variety of places, including the Arctic, in deserts, in jungles, at sea, or in barren wastelands.
  • No other species has the ability to eat and digest such a wide variety of foods.
  • No other species is able to reconstruct their living environment to the degree that humans do.

Charles Darwin said it well: “It is not the strongest or the most intelligent of the species that survives. It is the one that is most adaptable to change.

Hormesis: The Key to Adaptation

The biological phenomenon of this adaptogenic quality of life is called “hormesis.” The principal pillars of my approach to health are to enhance adaptation, energy transfer efficiency, protection, and reproduction (hormonal health). Perhaps the most important of these is adaptation, but really, they are all interconnected. Everything is networked. Thus, the best approach to health is to support the networks of the body as a whole, to enhance robustness and our ability to auto-regulate and auto-organize at the molecular, cellular, and organ system levels. 

This is why adaptogenic formulas are the first step in building and enhancing robust health, and the most important supplemental support you can provide to your body. Every other supplement you take should be secondary to adaptogenic formulations.

Our approach to health and healing is not a fixed line, but a circle that is alive and in constant motion. It is not functional, but rather responsive, so although everything in our body has a function, ultimately what makes us alive and human is how our bodies respond.  Response implies a life-force that activates and regulates all components of energy transfer. This life-force is capable of listening to the “orchestra” (ie; network) and providing direction while constantly adapting. To function is robotic and programmed, while response is connected to wisdom and is alive. 

Medicine today continues to view the body in a fragmented way, including body systems, parts, genes, and microbiomes. Very few people, particularly in the medical profession, see the whole, but we have complex diseases that are characterized as polygenic and multifactorial. We are therefore best served with medicines—specifically plant medicines—that are pleotrophic, gentle, nourishing, strengthening, and assist in normalizing, or auto-regulating.

Thinking Outside the Current Medical Model

Herbal formulations contain multiple components that dock to multiple target sites and synergistically exert beneficial effects throughout a wide range of pathways. Through many years of clinical practice, I’ve realized that it is neither possible or appropriate to try and fit herbal medicine into or alongside the current conventional model. That is why I developed the Mederi Care model as a new way of thinking and combining various approaches that is inclusive of both holistic and allopathic medicine. The soul of this approach, however, is rooted in botanical medicine, combined with nutritional supplementation, food as medicine, life-style modifications, and spiritual care. Once this foundation is in place, then it is appropriate to evaluate if more specific, “heroic” (ie; pharmaceutical) medicine is needed, and if so, where it fits within the whole systems, unitive approach.

The molecular pathways that govern human disease consist of molecular circuits that coalesce into complex, overlapping networks. These network pathways are presumably regulated in a coordinated fashion, but such regulation has been difficult to decipher using only reductionistic principles. The emerging paradigm of “network medicine” proposes to utilize insights garnered from network topology (ie; the static position of molecules in relation to their neighbors) as well as network dynamics (ie; the unique flux of information through the network) to understand better the pathogenic behavior of complex molecular interconnections that traditional methods fail to recognize.[1]

Bioregulatory Systems Medicine

Bioregulatory Systems Medicine (BrSM) is a comprehensive, innovative approach in medicine. It embraces the complexity of diseases by supporting the general idea of autoregulation and addressing underlying dysregulating biological networks.

The objective of Bioregulatory Systems within the Mederi Care approach is to improve patient outcomes by supporting a patient’s autoregulatory capacity. This is accomplished through the Mederi Care toolboxes, specifically botanical and nutritional medicine, which is applied in a gentle, synergistic way. Botanical and nutritional medicine practiced within Mederi Care is primarily directed at enhancement of ‘Self-regulating Internal Community Networks,’ supporting and even directing, while allowing the freedom to improvise.

The poet and philosopher Mark Nepo says: “To be the best we can be, we have to meet the outer world with our inner world. I’ve always believed in the amazing resilience of the human spirit.” Nepo believed that life has been made just hard enough that we need one another. Through experiences of great suffering and great love, we are reduced to what is essential.

The most effective way to reduce the possibility of poor health and disease is to keep the root system healthy and robust. Adaptogenic herbs in combination have a synergistic and pleotropic effect.

Synergism Enhances the Actions of Plant Medicines

Synergistic plant medicines contain bioregulatory properties. Their actions are determined by both chemistry and synergy, as their biological activity often results from the additive or synergistic effects of their components.

Synergy means behavior of whole systems unpredicted by the behavior of their parts.”

― Buckminster Fuller

These synergistic strategies can be much more comprehensive and broader in their scope of effects than single-component drugs[2]. This concept is not new to science. Synergy is an ubiquitous phenomenon in nature, and is widely used in numerous scientific disciplines, including thermodynamics, biophysics, biochemistry, molecular biology, and neurobiology.[3]

Herbal medicines are often combinations of botanical extracts that have additive or synergistic effects.  For example, combining the four herbal (S. baicalensis, D. morifolium, G. uralensis and R. rubescens) extracts significantly enhanced their activity compared with extracts alone in a prostate cancer model.[4]

It is important not to confuse synergistic effect with additive effect. Synergy occurs when two or more drugs/compounds are combined to produce a total effect that is greater than the sum of the individual agents while an additive effect is an add up of individual effects where each individual agent is not affecting the other (no interactions).[5]

The synergy of biological effects of plants in medicine is well documented, and encompasses synergistic multitarget effects, physicochemical effects based on improved solubility, antagonization of resistance mechanisms, and elimination or neutralization of toxic substances.[6] As such, multi-combination and/or multi-system low dose medications, preferably of natural origin, are well suited for the bioregulatory medical approach and offer the potential for a graded response to treatment.[7]

Generally speaking, herbal and nutritional medicine within this model exhibits four fundamental advantages of a multicomponent, combinatorial strategy over a single-component strategy:

1. Synergistic effects target a wider range of information flow in disease-related biological networks;

2. Modest modulation allows for more efficient control of biological networks;

3. Low concentrations ensure higher safety of the whole combination;

4. Drug resistance is much less probable.[8]

According to Traditional Chinese medicine (TCM), every living thing is sustained by the balance of two opposing forces of energy, Yin and Yang. Together they make up Qi (pronounced ‘chee’), which is the vital energy that flows in, through and around the body.

Network Pharmacology: A New Way of Understanding Herbal Formulations

Network pharmacology stems from several pioneering works. The holistic theory and practice of TCM, as well as other herbal medicine systems, play a key role in the origin and rapid development of network pharmacology. The original hypothesis referring to the biological associations between TCM syndromes, herbal formula, and molecular networks was proposed in 1999 and 2002.[9]

Network pharmacology has been used to study multiple protein/gene target diseases. It describes the relationship between biological systems, drugs, and diseases from the perspective of the network. This is consistent with the holistic pattern differentiation theory of TCM[10] as well as Mederi medicine.

Mitochondrial Network Medicine

The mitochondrial network is constantly in a dynamic and regulated balance of fusion and fission processes, which is known as mitochondrial dynamics. Mitochondria make physical contact with almost every other membrane in the cell, thus impacting all cellular functions.[11] 

“Qi,” as noted above, describes energy-dependent body functions. This can broadly be correlated with mitochondria-energy dynamics.

[12]

The term adaptogen was first proposed in 1940 by a scientist from the USSR. Lazarev described Schisandra chinensis and other herbs as plant-derived adaptogens that non-specifically enhance human physiology.[13]

Adaptogens are the material basis of the bodily response to the external environment and can act on the immune system and the stress response system, as shown below.

The non-specific response mode, especially the hormone response mode, occurs when homeostasis is not the driving force.[14]

Schisandra Fortifies Mitochondrial (Qi) Antioxidant Status

Schisandra

Schisandra berry or Wu-Wei-Zi, meaning the “the fruit of five tastes” in Chinese, is a commonly used herb in TCM. Ancient Chinese herbalists noted the berry’s beneficial effect on the “Qi” of the five visceral organs.  Schisandra is one of the main researched primary adaptogens that I use in adaptogenic formulations.  It is perhaps my favorite adaptogen, but I believe combination formulas have many advantages over single herbs.

Schisandra berry is well-known for it’s “Qi-invigorating” properties. The herb has been shown to fortify mitochondrial antioxidant status, thereby offering the body generalized protection against noxious challenges, both of internal and external origin. Given the indispensable role of the mitochondrion in generating cellular energy, the linking of Schisandra chinensis berry extract (SCBE) to the safeguarding of mitochondrial function provides a biochemical explanation for its “Qi-invigorating” action.[15]

SCBE is a potent adaptogen, and has been shown to improve disease and stress tolerance, while increasing energy, endurance, and physical performance.

SCBE is helpful in the treatment of neurological, cardiovascular, and gastrointestinal disorders. It has been shown to decrease fatigue, relieve insomnia, reduce obesity, and provide protection from mitochondrial dysfunction. SCBE stimulates immunity, acts as a tonic, and exerts antioxidant, anti-inflammatory, antiviral, anticancer, anti-aging, anti- diabetic, and liver- and skin-protecting activities.

Effects of Schisandra chinensis fruit extracts and their bioactive compounds in mitochondria.

[16]

SCBE has been shown to restore impaired mitochondrial function, acting as a mitoprotective agent. Studies show that schisandrin, the identified active ingredient in SCBE, restored cytochrome c oxidase activity, and protected the opening of mitochondrial permeability transition. Furthermore, schisandrin improved ATP production, citrate synthase activity, and the process of mitochondrial fusion and fission.[17]

Recent studies investigating the various active compounds within schisandra identified a total of 78 compounds consisting of 13 prototype lignans and 65 metabolites (including isomers).[18]

Combining schisandra extract with other adaptogens and tonic herbs provides hundreds to thousands of active compounds swimming together, bathing the cells and molecules throughout the body. Complex formulas no longer act like the single herb, but in an entirely new way. Think of an orchestra, and perhaps what a single member playing an instrument might sound like. Then consider the entire orchestra, and all of the instruments working in harmony. As a jazz musician and an herbalist with an interest in network pharmacology, this is a perfect analogy for the way that herbs work together when combined in appropriate formulations.

On Pubmed alone, there are now 30 articles illustrating the increasing interest in network pharmacology and traditional herbal medicine.[19] Understanding network pharmacology and Bioregulatory Systems Medicineis the foundation of Mederi Care. I am grateful that this comprehensive, harmonious system of healing is gaining the recognition it deserves.

References


[1] Chan SY, Loscalzo J. The emerging paradigm of network medicine in the study of human disease. Circ Res. 2012 Jul 20;111(3):359-74. doi: 10.1161/CIRCRESAHA.111.258541. PMID: 22821909; PMCID: PMC3425394

[2] Lila MA. 2007. From beans to berries and beyond: Teamwork between plant chemicals for protection of optimal human health. Ann. N. Y. Acad. Sci.1114:372–80

[3] Corning PA. 1998. “The synergism hypothesis”: On the concept of synergy and its role in the evolution of complex systems. J. Soc. Evol. Syst.21(2):133–72

[4] Adams LS, Seeram NP, Hardy ML, Carpenter C, Heber D. Analysis of the interactions of botanical extract combinations against the viability of prostate cancer cell lines. Evid Based Complement Alternat Med. 2006 Mar;3(1):117-24. doi: 10.1093/ecam/nel001.

[5] Zhou, Xian et al. “Synergistic Effects of Chinese Herbal Medicine: A Comprehensive Review of Methodology and Current Research.” Frontiers in pharmacology vol. 7 201. 12 Jul. 2016, doi:10.3389/fphar.2016.00201

[6] Wagner H. Synergy research: approaching a new generation of phytopharmaceuticals. Fitoterapia. 2011 Jan;82(1):34-7. 

[7] Bioregulatory Systems Medicine. White Paper. Published February 2019 – Copyright © Biologische Heilmittel Heel GmbH. Rights Reserved

[8] Kong DX, Li XJ, Zhang HY. Where is the hope for drug discovery? Let history tell the future. Drug Discov Today. 2009 Feb;14(3-4):115-9. 

[9] Li S. (2007). Framework and practice of network-based studies for Chinese herbal formulaZhong Xi Yi Jie He Xue Bao. 5, 489–493.  10.3736/jcim20070501

[10] Zhang R, Zhu X, Bai H, Ning K. Network Pharmacology Databases for Traditional Chinese Medicine: Review and Assessment. Front Pharmacol. 2019 Feb 21;10:123.

[11] Pijuan J, Cantarero L, Natera-de Benito D, Altimir A, Altisent-Huguet A, Díaz-Osorio Y, Carrera-García L, Expósito-Escudero J, Ortez C, Nascimento A, Hoenicka J, Palau F. Mitochondrial Dynamics and Mitochondria-Lysosome Contacts in Neurogenetic Diseases. Front Neurosci. 2022 Jan 31;16:784880.

[12] Tian J, Huang Y, Wu T, Huang HD, Ko KM, Zhu BT, Chen J. The Use of Chinese Yang/Qi-Invigorating Tonic Botanical Drugs/Herbal Formulations in Ameliorating Chronic Kidney Disease by Enhancing Mitochondrial Function. Front Pharmacol. 2021 Jun 24;12:622498. doi: 10.3389/fphar.2021.622498. PMID: 34248614; PMCID: PMC8264145.

[13] Liao LY, He YF, Li L, Meng H, Dong YM, Yi F, Xiao PG. A preliminary review of studies on adaptogens: comparison of their bioactivity in TCM with that of ginseng-like herbs used worldwide. Chin Med. 2018 Nov 16;13:57.

[14] Panossian A, Wikman G, Wagner H. Plant adaptogens. III. Earlier and more recent aspects and concepts on their mode of action. Phytomedicine. 1999 Oct;6(4):287-300.

[15] Ko KM, Chiu PY. Biochemical basis of the “Qi-invigorating” action of Schisandra berry (wu-wei-zi) in Chinese medicine. Am J Chin Med. 2006;34(2):171-6. 

[16] Kopustinskiene DM, Bernatoniene J. Antioxidant Effects of Schisandra chinensis Fruits and Their Active Constituents. Antioxidants (Basel). 2021 Apr 18;10(4):620. doi: 10.3390/antiox10040620.

[17] Piao, Z.; Song, L.; Yao, L.; Zhang, L.; Lu, Y. Schisandrin restores the amyloid -induced impairments on mitochondrial function, energy metabolism, biogenesis, and dynamics in rat primary hippocampal neurons. Pharmacology 2021, 1–11.

[18] Wu Z, Jia M, Zhao W, Huang X, Yang X, Chen D, Qiaolongbatu X, Li X, Wu J, Qian F, Lou Y, Fan G. Schisandrol A, the main active ingredient of Schisandrae Chinensis Fructus, inhibits pulmonary fibrosis through suppression of the TGF-β signaling pathway as revealed by UPLC-Q-TOF/MS, network pharmacology and experimental verification. J Ethnopharmacol. 2022 May 10;289:115031. doi: 10.1016/j.jep.2022.115031. Epub 2022 Jan 26. PMID: 35091014.

[19] Lai, Xinxing et al. “Editorial: Network Pharmacology and Traditional Medicine.” Frontiers in pharmacology vol. 11 1194. 4 Aug. 2020, doi:10.3389/fphar.2020.01194

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What We Now Know about the SARS-CoV-2 mRNA Vaccine Delivery System that Should Concern Us

I have always been a proponent of medical freedom and believe that individuals should weigh the risk-to-benefit ratio when deciding anything when it comes to modern medicine. Unfortunately, so much of what we’re led to believe about the safety of the novel coronavirus vaccine is false and mis-leading. Although there many reputable doctors and scientists willing to voice concerns and openly debate the risks, their voices are not being heard by the majority of the public and their professional careers and reputations are being threatened and often smeared, distorted, and censored by the media. It is more important than ever to have truth and transparency when it comes to new technologies in medicine.

Traditional vaccines present the entire virus in a live-attenuated form (measles, mumps, rubella, varicella, rotavirus, Sabin oral poliovirus, yellow fever, and some influenza vaccines) or an inactivated form (Salk poliovirus, hepatitis A, rabies, and some other influenza vaccines), leading to a polyclonal response to not just one, but a number of viral proteins. This multiplicity of humoral and T cell responses probably explains why no convincing vaccine escape strains have been documented for these viruses; with the exception to this being the influenza virus.[1] The mRNA vaccines for COVID-19 however, are engineered in an entirely different way, with a far more complex design and effect.

Continue reading “What We Now Know about the SARS-CoV-2 mRNA Vaccine Delivery System that Should Concern Us”

Faith, Death, and Resurrection

“Faith is much better than belief. Belief is when someone else does the thinking.”

– Buckminster Fuller

If you ask most people, they will tell you that faith and belief are the same thing. But in truth, they are not.

According to Webster, the definition of belief is: “An opinion or judgement in which a person is fully persuaded.” Belief often comes from someone else. For example, your parents follow a certain religion, which is defined by a certain set of beliefs. Therefore, you take on that same belief system.

Belief or Faith?

Belief is in the mind, whereas faith is in the heart. They can intersect though, and even unite as one.

Faith comes from within, is spiritual, and sees love. This includes our own self-realization that forms or confirms our beliefs. But it is bigger than that. Faith requires action. If our faith doesn’t move us to do something or say something—to actually take action—it’s not really faith. “So you see, faith by itself isnt enough. Unless it produces good deeds, it is dead and useless.” – James 2:17.

Faith is taking the first step even when you dont see the whole staircase.”

  Martin Luther King, Jr.

The Difference Between Belief and Faith

Many of the people I work with have cancer. Many have advanced cancer, and often, their doctor tells them how long they have to live. The doctor may pronounce, “You have three to six months, perhaps a year to live,” and the person takes that to be the ultimate truth. And they begin to believe it, based solely on the doctor’s words, which is usually based on statistics and assumes few, if any, will beat the odds. Obviously, trying to predict how long someone has to live has serious effects on their well-being by imposing a belief that seems certain and final, and takes away any sense of hope and faith in a higher power.

I have many patients who are living many more years than anyone ever expected. And more than just surviving, they are thriving. I frequently tell my patients, “Don’t believe what you are told. Instead, focus on doing the best you can to live, and to live well. I will do the same, and hopefully, your healing team will embrace that same approach. As long as we’re doing the best we can, there is nothing to worry about.”

“Trust in the Lord with all your heart, and do not lean on your own understanding.” ~ Proverbs 3:5

Wisdom from the Desert Fathers

The Desert Fathers were Christian hermits who lived in the Egyptian desert in the third century AD. Following the example of Jesus, the monks devoted themselves to lives of prayer and austerity. The first Desert Father was Paul of Thebes, and the most well-known was Anthony the Great, who became known as both the father and founder of desert monasticism.

The Desert Fathers

Father Paul once visited Anthony when he was teaching three monks about a very difficult matter of faith. Paul withdrew into a corner and waited silently until Father Antonius was ready.

Antonius asked the youngest of the three monks what he thought about the matter. The young man responded immediately; what he lacked in knowledge, he supplemented with fire and enthusiasm. When he was finished, Father Antonius remained silent for a while, then said, “You havent found the right answer yet.

Then the second one got the floor. He was a little older, had read some books, and had more life experience. He chose learned words and formulated them more carefully. When he was finished, Father Antonius said, “You too have not found the right answer yet.

Finally, the oldest of the three was allowed to give an answer. He spoke thoughtfully, and you could tell he had read many books and had a long prayer experience. When he was finished, Father Antonius remarked, “You havent found the right answer yet.

The moment he opened his mouth to say something about the very difficult issue of faith himself, he turned to the old abbot and asked, “Father Paul, could you possibly say something about this?” Finally, Paul said: “I dont know…”

Father Anthony turned to his three disciples and with a raised finger, he said, “Father Paul has found the right answer.

These old stories prove to be relevant for today. “I dont know, is the correct answer to complex theological issues. How beautiful is that? It’s good to remember the next time you end up in a discussion or question in a matter about faith.

Faith, Courage, and Patience

Faith will empower our patience. Courage will sustain our perseverance. With that faith and courage, we can live with the forces of change. We will not set ourselves against them defiantly, as we are first inclined. And as we abide the changes in good faith, trusting that our life will unfold as we dreamed, or as it was intended, our despair and doubt fade. For we realize that our personal power and peace need not be the victims of things we do not know. We discover that those times of confusion and doubt need not undermine our connection to God and his universal wisdom. For that wisdom is living itself out in our lives, expressing its Divine guidance in ways we did not know.[1]

The Question of the Resurrection

Although Judaism does not have a definitive answer to the question of what happens after we die, resurrection has played an important role in Jewish eschatology.

“From the Torah: for it is written: ‘And the Lord said to Moses, Behold you shall sleep with your fathers; and this people will rise up’ [Deuteronomy 31:16]. From the Prophets: as it is written: ‘Your dead men shall live, together with my dead bodies shall they arise. Awake and sing, you that dwell in the dust; for your dew is as the dew of herbs, and the earth shall cast out its dead.’ [Isaiah 26:19]; from the Writings: as it is written, ‘And the roof of your mouth, like the best wine of my beloved, like the best wine, that goes down sweetly, causing the lips of those who are asleep to speak’ [Song of Songs 7:9].” Rabbi Meir also answered this question saying: “As it is said: ‘Then will Moses and the children of Israel sing this song unto the Lord’ [Exodus 15:1]. It is not said ‘sang’ but ‘will sing’; hence the Resurrection is deducible from the Torah.”[2]

For many Christians, ‘belief’ in the resurrection is fundamental to their religion. Most rehearse this belief every Easter Sunday, but then stick it away in the closet for the rest of the year. 

Illustration of Christ’s empty tomb, shown from the inside, looking out the opening to His cross with the sunrise behind

Faith is to believe what you do not see; the reward of this faith is to see what you believe.”

– Saint Augustine

Easter, referred to as Pascha within the Eastern Christian religion, is considered to be the most important Orthodox holy day of the year. Pascha comes from both the Greek and Latin words for “Easter,” the day celebrating when Jesus Christ rose from the dead. The verbal form of this word, pascho in Greek, means “to suffer.” Originally, the Hebrew word pasach referred to the Passover feast (Exodus 12) that was celebrated during the same week Jesus was crucified.

Faith Requires Trust and Intimacy

Father Richard Rohr believes that we can only experience true intimacy when we are willing to be vulnerable ourselves. He goes on to say that intimacy could be described as our capacity for closeness and tenderness toward things. It makes all love possible, and yet it also reveals our utter incapacity to love back as the other deserves.

I think that many of us are afraid of intimacy, of baring our deepest identity to another human or even to God. Yet people who risk intimacy are invariably happier and much more authentically human. Soulful intimacy is a gateway into the sacred realm of human and divine love.[3]

According to Father Richard Rohr:  The big and hidden secret is this: an infinite God seeks and desires intimacy with the human soul. The mystics (those who personally know the inner space of God) are aware that they have been let in on a big and wondrous secret. Anyone not privy to this inner dialogue would call such people presumptuous, foolish, or even arrogant. This is without a doubt “God’s secret, in which all the jewels of wisdom and knowledge are hidden (Colossians 2:3).”[4]

The Radical Transformation of a Caterpillar

There is nothing in a caterpillar that tells you it’s going to be a butterfly.”

– Buckminster Fuller

There is no scientific basis for resurrection. There is no way a living form could die, dissolve away, and be reassembled into another creature. Hold onto that thought…and now, start to imagine the transformation of a caterpillar into a butterfly. Truly, it is a miracle. If science was to look for evidence of death followed by resurrection, they wouldn’t need to go very far. It happens every day. Caterpillars die and are resurrected as butterflies, using the same fluids as the original life form.

I believe in God, only I spell it as Nature.” ~ Frank Lloyd Wright

Within its protective casing, the caterpillar radically transforms, eventually emerging as a butterfly or moth. But what does that radical transformation entail? 

Scientists have long been astonished by the transformation of caterpillars into butterflies. Before hatching, when a caterpillar is still developing inside its egg, it grows an imaginal disc for each of the adult body parts it will need as a mature butterfly or moth—discs for its eyes, for its wings, its legs and so on. The caterpillar eats voraciously during its entire lifespan, presumably to accumulate sufficient nutrients for the coming transition. When the time is right, the caterpillar spins itself into a silk coverlet (a cocoon) and digests itself. During the larval phase, the release of enzymes kills the caterpillar and destroys all of its organs, turning into a mushy soup, with nothing left of its former self. If one opens a larva, there is no sign of the original caterpillar; it is gone, except for the “imaginal cells” that survive.[5]

Then, through a miraculous sequence of events, a new set of instructions takes hold, and the amino acids in the larval soup are rearranged, carefully and meticulously, into an entirely new organism. The imaginal cells emerge, armed with genetic instructions for the transformation. Initially, the caterpillar’s immune system rejects the imaginal cells, but they continue to multiply. Finally, the imaginal cells begin to clump together, forming the organs of an entirely new organism with completely different anatomical features, including long legs and wings.

The fact that the caterpillar’s immune system attacks the new cells of the butterfly demonstrates that biologically, the two insect forms are entirely distinct life forms. Essentially, the caterpillar dies and is resurrected.[6]

One of the songs from the popular new Disney movie “Encanto” is “Dos Oruguitas,” the first Oscar-nominated song written entirely in Spanish. Dos Oruguitas translates into “Two (Little) Caterpillars.” The song is performed beautifully by the Colombian singer Sebastian Yatra.

The song describes two caterpillars in love. They rejoice in their togetherness, holding each other, staying together constantly through good and bad weather. Just as soulmates do! But somehow, they know that very soon, they will need to let go. The time comes when they turn into larvae, re-emerging as butterflies. There is nothing the caterpillars can do to stop the inevitable. The song and images evoked are beautiful, and state something that carries us beyond the mundane ordinary and into the truly meaningful extraordinary—the thought that we are called to live in the image of GOD.  There, we will go from crawling to flying and be truly happy.

Life After Death

Religions have debated the concept of death and resurrection for tens of thousands of years. And during the millennia, scientists have generally been silent about the likelihood of rebirth. After all, from an empirical point of view, there is nothing to say. There is no experiment that one can perform to prove or disprove the existence of life after death.[7]

Generally speaking, woman are in many ways stronger than men, and the bible highlights this as it regards faith. Other than John, it was all women at the cross, and the first witnesses of the Resurrection are women. This is beautiful, and I believe it is profoundly insightful.

Pope Francis said, “and they had accompanied him to the very end.” Even though the women initially reacted with fear, it is their “loving remembrance of their experience with the Master that enables the women to master their fear, and to bring the message of the Resurrection to the Apostles and all the others.” The Apostles and disciples found it hard to believe in the Risen Christ, not the women! “The women,” he attested, “are compelled by love and know how to welcome this announcement with faith.”

The Butterfly Effect and Transforming Ourselves

The “butterfly effect”  is the phenomenon whereby a small change at one place in a complex system can have large effects elsewhere. For example, a butterfly flapping its wings in Rio de Janeiro might change the weather in Chicago.[8]  I believe that everyone matters, everything matters, and every moment matters.  We are only scratching the surface of what we are capable of.  For all of us, limitations are a lack of faith and trust.

“Look at the birds of the air; they do not sow or reap or store away in barns, and yet your heavenly Father feeds them. Are you not much more valuable than they?” Matthew 6:28

“And why do you worry about clothes? See how the flowers of the field grow. They do not labor or spin.” Matthew 6:28

Happiness is not living without pain or suffering; but is the mastery within, to embody peace, joy, compassion, kindness and love. God has created us for interdependence as God has created us in God’s image—the image of a divine fellowship and Divine love. We must find the divinity within and in a sense resurrect twice, once in the world, and then again after the world. We are to be Kenosis, which in Eastern Christian theology means to empty oneself and become entirely receptive of God’s Divine will.

We all are aware that death will come eventually. The important questions are: What are we seeking in this life? What is our faith? How much do we trust? Are we willing to be authentically our Divine selves and through intimacy share that with others without limitation? In this way, we begin our own resurrection. This is our transformation from caterpillar to butterfly, from crawling on the earth to flying freely.

References


[1] © Leigh Sanders 99

[2] Ariela Pelaia, Resurrection in Judaism, Updated on March 28, 2019, https://www.learnreligions.com/jewish-view-of-resurrection-2076764; “Jewish Views of the Afterlife” by Simcha Raphael. Jason Aronson, Inc: Northvale, 1996.”The Jewish Book of Why” by Alfred J. Kolatch. Jonathan David Publishers Inc.: Middle Village, 1981.

[3] Adapted from Richard Rohr, Immortal Diamond: The Search for Our True Self (San Francisco, CA: Jossey-Bass, 2013), 159–160, 171–172, 174. 

[4] Adapted from Richard Rohr, Immortal Diamond: The Search for Our True Self (San Francisco: Jossey-Bass, 2013), 164–165, 166, 167, 168–169.

[5] Ferris Jabr, How Does a Caterpillar Turn into a Butterfly?, SCIENTIFIC AMERICAN, a Division of Springer Nature America, Inc. Aug 10, 2012, Copyright © 2012, Scientific American, Inc.

[6] Milton Packer, MD, Medscape Today, 02/22/2022, https://www.medpagetoday.com/opinion/revolutionandrevelation/97215?xid=nl_mpt_blog2022-02-16&eun=g1065123d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=MiltonPacker_021622&utm_term=NL_Gen_Int_Milton_Packer_Active

[7] Milton Packer, MD, Medscape Today, 02/22/2022, https://www.medpagetoday.com/opinion/revolutionandrevelation/97215?xid=nl_mpt_blog2022-02-16&eun=g1065123d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=MiltonPacker_021622&utm_term=NL_Gen_Int_Milton_Packer_Active

[8] https://www.vocabulary.com/dictionary/butterfly%20effect

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God as Our Mother

Icon Sophia within the dome of St. Sophia’s Cathedral in Kyiv, Ukraine.

In the Judeo-Christian tradition, we often refer to “Our Father” when speaking of the cosmic, all-encompassing God. Because God is not really man or woman, referring to God as “he” or “she,” when taken out of context, can be controversial.

But if we were to view God as two sides of the same coin, rather than exclusively one or the other, it might be more helpful. I see God as both masculine and feminine, and the feminine, although more hidden perhaps, is the stronger of the two.

I believe what the world needs now is the Divine Wisdom (Feminine) to be made manifest within all of us.

Continue reading “God as Our Mother”

Prayer for Ukraine

My heart and prayers are with the Ukrainian people during this tragic time of war. I feel a deep bond with Ukraine stemming from my spiritual and theological roots. Although I was baptized and raised as a Roman Catholic, and taught by Polish Franciscans, I am professed as a Secular Third Order Franciscan in the Eastern Byzantine Ukrainian Catholic Rite.

Below are photos of Holy Protection, the beautiful Ukrainian Franciscan monastery where I lived. It no longer exists, but the sister monastery, Holy Dormition, is still active. I spent a lot of time at that monastery as well. In both monasteries, I was the only non-Ukrainian, and I always felt welcome.

The photo above is of Sts. Volodymyr and Olha Church, in Lviv, Ukraine. It was built since the return of the church in the 1990s when Ukraine was freed from Russia.

The Ukrainian Greek Catholic Church is the largest Eastern Catholic Church in the world. While many such western churches use elaborate sculptural architectural elements, including on the icon screen, the saintly imagery of eastern Byzantine-Rite churches is represented exclusively through two-dimensional, painted icons, not through statues.

The Birth of the Eastern Byzantine Spiritual Tradition

The Eastern Byzantine liturgical, theological and spiritual tradition was born in the first six centuries AD in Constantinople, when it was the capital of the Eastern half of the Roman Empire. The rich traditions evolved from pre-Christian legacies reshaped over a millennium of Christian belief, and were influenced by its relation to the West and the Roman Church for over 400 years.

The Byzantine liturgy is a common inheritance of Eastern Orthodox and Eastern Catholic churches, including the Ukrainian Greek Catholic Church. Its beauty is said to have been the decisive factor that dazzled emissaries of the pagan Kyivan Prince Vladimir, who saw it in Constantinople and “did not know whether they were in heaven or on earth.”[1]

The Divine Liturgy of Saint John Chrysostom, the most frequently celebrated form of the liturgy, provides a good introduction to Byzantine worship in the Ukrainian Greek Catholic Church.

The liturgy invokes God, “Whose power is beyond comparison, Whose glory is beyond comprehension, Whose mercy is beyond measure, and Whose love for humankind is beyond expression.” “You dwell in the holies,” it continues, “with three-fold cries of holy the seraphim acclaim You, the cherubim glorify You, and all the heavenly powers worship You.” Even in (and perhaps through) such transcendent language, believers also see God present in their midst.[2]

Chanting/singing is integral to the liturgy. Almost the whole of it is chanted, even the Gospel reading. Liturgical music is solely dependent on a cappella singing, not on musical instruments.

“Pray for Ukraine Icon”

Icon of Sophia with daughters from a Ukrainian Greek Catholic Church in Ukraine

Praying For Peace

In recent days within the Ukraine, archbishop Sviatoslav Shevchuk of Kyiv-Halych, head of the Eastern-rite Ukrainian Catholic Church, traveled from Kyiv to meet with Cardinal Krajewski and with Archbishop Mieczyslaw Mokrzycki, head of the Latin-rite Archdiocese of Lviv. The three joined representatives of other Christian churches and other religions at the Latin-rite cathedral to pray for peace.

Archbishop Shevchuk turned to God, praying: “Before your eyes today we present the sorrow and pain of Ukraine. Mountains of corpses, rivers of blood and seas of tears. We pray for all those who gave up their lives for the homeland, for our army, for the sons and daughters of Ukraine, who shield lives with their own bodies in the face of the enemy.”

“We pray for all those innocently killed, peaceful people of Ukraine: women, children, the elderly. We pray for the victims of Mariupol who are being buried in massive common graves without Christian burial and honor,” he continued. “Receive our prayers for their eternal repose.”

Ukrainian citizens in the town of Bakhmach, some 175 kilometers (109 miles) northeast of the capital of Kyiv, attempted to block Russian tanks advancing, according to video footage that circulated on social media on Saturday.

Residents of Bakhmach, Ukraine, attempt to stop Russian tanks from advancing toward the capital Kyiv, February, 26, 2022. (Screengrab/Twitter)

The “National Spiritual Anthem” of Ukraine (МОЛИТВА ЗА УКРАЇНУ). This hymn is familiar to most Ukrainians. The English lyrics are as follows:

Lord, oh the Great and Almighty,
Protect our beloved Ukraine,
Bless her with freedom and light
Of your holy rays.

With learning and knowledge enlighten
Us, your children small,
In love pure and everlasting
Let us, oh Lord, grow.

We pray, oh Lord Almighty,
Protect our beloved Ukraine,
Grant our people and country
All your kindness and grace.

Bless us with freedom, bless us with wisdom,
Guide into kind world,
Bless us, oh Lord, with good fortune
Forever and evermore.

Take time to listen to this beautiful, heartfelt prayer. It brings tears to my eyes:

The most beautiful churches in Kyiv – WHAT IS UKRAINE


[1] Robert F. Taft, S.J., The Byzantine Rite: A Short History (Collegeville, MN: Liturgical Press, 1992), 16-28.

[2] Ukrainian Greek Catholic liturgy envisions heaven on earth, Catholic Cultures, March, 2022,

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Curcumin in Combination with Chemotherapy: A Positive Interaction

Fifty percent of all drugs, including cancer drugs marketed today, use the cytochrome P450 enzyme pathway for metabolism[1],[2] and frequently cause interactions. In brief, the cytochrome P4503A (CYP3A) subfamily is largely found in hepatocytes, with some presence in the intestine. Together with the transport protein P-glycoprotein (PGP) present in the small intestine, these 2 systems regulate metabolism of drugs and nutrients. Many foods, food components, and botanical supplements interact with the CYP3A and PGP metabolism, but even more importantly, an individual’s genome plays a significant role in how well one metabolizes and detoxifies various drugs including Aromatase and mTOR inhibitors. The effects of herbs on CYP3A and PGP is dose sensitive, meaning that often the dose would need to be very high in order to really impact these pathways. Another important factor is that much of the published research is either in vitro; animal in vivo, done with isolates (not whole herbs), and/or based on high dosages of these compounds. So, every referenced paper needs to be reviewed and analyzed for accuracy and relativity to how botanicals might impact both the effectiveness or toxicity of these and other drugs. The other factor is that to base interaction solely on P4503A and PGP is wrong. The ultimate question is still not answered, which is does this herbal combination either cause this drug to be less effective or does it increase the toxicity? In general, due to these nuances, evaluating the potential for negative drug-drug, nutrient-drug, or botanical-drug interactions metabolized through this pathway can be difficult and often lead to incorrect assumptions.

A previous blog of mine entitled, “The Truth about Herb-Drug Interactions: An Honest Evaluation of the Benefits and Risks When Weighing Scientific Data and Clinical Experience” https://www.donnieyance.com/the-truth-about-herb-drug-interactions-an-honest-evaluation-of-the-benefits-and-risks-when-weighing-scientific-data-and-clinical-experience/ provides critical backround for understanding the “good news” regarding the benefits of herb-and-drug combinations, and specifically curcumin rich turmeric extract and chemotherapy.

Many chemotherapeutic drugs have been used for the treatment of cancer, including doxorubicin, irinotecan, 5-fluorouracil, cisplatin, and paclitaxel. However, the effectiveness of chemotherapy is limited in cancer therapy due to drug resistance, therapeutic selectivity, and undesirable side effects.

Chemosensitization is one valuable strategy to overcome chemoresistance phenomena. Chemosensitization is based on the use of one drug to enhance the activity of another by influencing one or more mechanisms of resistance. The combination of therapies with natural compounds such as curcumin is likely to increase the effectiveness of drug treatment as well as reduce the incidence of adverse outcomes.

Curcumin, a polyphenolic isolated from Curcuma longa, belongs to the rhizome of Zingiberaceae plants.

Both in vitro and in vivo studies show that curcumin exerts many pharmacological activities with less toxic effects. Chemosensitization has been observed in cancers of the breast, colon, pancreas, gastric, liver, blood, lung, prostate, bladder, cervix, ovary, head and neck, and brain and in multiple myeloma, leukemia, and lymphoma. Similar studies have also shown that curcumin can sensitize a variety of tumors to gamma radiation including glioma, neuroblastoma, cervical carcinoma, epidermal carcinoma, prostate cancer, and colon cancer. The way in which curcumin acts as a chemosensitizer and radiosensitizer has been studied extensively. For example, it downregulates various growth regulatory pathways and specific genetic targets including genes for NF-κB, STAT3, COX2, Akt, antiapoptotic proteins, growth factor receptors, and multidrug-resistance proteins. Although it acts as a chemosensitizer and radiosensitizer for tumors in some cases, curcumin has also been shown to protect healthy organs such as the liver, kidney, oral mucosa, and heart from chemotherapy and radiotherapy-induced toxicity.[3]

The Bioavailability of Curcumin: Separating Truth from Fiction

Curcumin and other curcuminoids from Curcuma longa (turmeric) are important bioactive compounds exhibiting various pharmacological activities. Turmeric is widely consumed as part of the spice mix curry and as a dietary supplement. It has a long history of therapeutic application in traditional Asian medicine. The active components of turmeric, collectively known as curcuminoids, are among the most promising natural compounds studied across the globe today.

Clinical studies support the active role of curcuminoids in the management of chronic health conditions. Several pioneering studies have been conducted by major universities, research institutes and hospitals on Curcumin C3 Complex®, which have aided the understanding of the metabolic effects of curcumin.

Curcumin is a natural product with multiple biological activities and numerous potential therapeutic applications. However, the poor systemic bioavailability of the product fails to explain the potent pharmacological effects and hinders its clinical application.

The biological effects of curcumin in cellular and animal models are surprising considering its chemical and metabolic instability. Multiple studies have shown that, even with high doses of curcumin, the levels of curcumin in serum and tissues as well as its in vivo metabolites are extremely low after a short period of time.

With a lack of consensus on curcumin bioavailability and with various formulations making a variety of claims on the bioavailability (X times or XX times more than nearest competitor), consumers are understandably confused.

The reality is that after ingestion, little if any curcumin is present unchanged in systemic circulation.Furthermore, curcumin undergoes rapid non-enzymatic degradation in cell culture medium and possibly in vivo as well. Chemical transformation by human gut microbiota does not mean a loss in activity, but is actually a necessity for the therapeutic action of curcumin. Current thinking is that the molecular mechanisms of degradation of curcumin is necessary for interpreting in vitro and in vivo studies.

Compared to the parent compound curcumin, the degradation products mixture possessed higher O2.–-scavenging activity and stronger inhibition against fAβ formation. The docking simulations revealed that the bioactive degradation products make an important contribution to the experimentally observed enzymatic inhibition activities of curcumin.

Curcumin has been shown to possess low stability in aqueous solutions at physiological pH and degrades readily.. In phosphate buffer at pH 7.4, about 90% of curcumin degraded within 30 min and the degradation products have been identified as trans-6-(4′-hydroxy-3′-methoxyphenyl)-2,4-dioxo-5-hexenal, ferulic aldehyde, ferulic acid, feruloyl methane, vanillin, vanillic acid, and other dimerization end-products. 

Selected degradation products mentioned above were the major human metabolites after curcumin consumption, and their levels were much higher than those of its metabolic compounds.

Upon ingestion, curcumin forms several active metabolites undergoing phase I metabolism such as dihydrocurcumin, tetrahydrocurcumin, hexahydrocurcumin and octahydrocurcumin.

In course of its metabolism, it also forms degradation compounds such as ferulic acid and bicyclopentadione. While these phase I metabolites have shown to have beneficial biological activity, compounds such as curcumin glucuronides and sulfates formed after phase II metabolism have shown to be ineffective in independent studies.

Given that curcumin is readily degraded under physiological condition, recent findings strongly suggested that the degradation products should make important contribution to the diverse biological activities of curcumin.[4],[5],[6],[7]

Oral curcumin also improved cachexia and general health in colorectal cancer patients.[8] In a phase II trial involving 21 patients with advanced pancreatic cancer, curcumin demonstrated bioactivity by downregulating nuclear factor-κB and cyclooxygenase-2. Despite limited absorption, antitumor response was seen in two patients.[9]

Curcumin Combined with Various Chemotherapeutic Agents

Combined with 5-FU

  • Research suggests that the combination of 5-FU and curcumin may overcome drug-resistance induced by 5-FU. Pre-treatment with curcumin (5 µM) enhanced the chemosensitization of 5-FU (0.1 µM) and reversed the multidrug resistance in resistant mismatch repair (MMR)-deficient human colon cancer cells compared to 5-FU alone.[10]
  • The combination of curcumin (10 μM) and 5-FU (0.1 mM)/oxaliplatin (5 μM) enhanced the synergistic antitumor activity in gastric cancer (BGC-823) cell lines compared to curcumin or 5-FU/oxaliplatin alone by downregulating the Bcl-2 mRNA and protein expression and activating the Bax and caspases-3, 8, and 9 expressions. This study further demonstrated that the combination of curcumin (10 mg/kg) and 5-FU (33 mg/kg)/oxaliplatin (10 mg/kg) shows potent growth inhibition of BGC-823 xenograft tumors compared to folinic acid, 5-FU, oxaliplatin (FOLFOX) or curcumin alone. [11] 
  • A combination of curcumin (50 mg/kg/day for 40 days) and 5-FU (20 mg/kg once every 2 days for 40 days) inhibits cell proliferation against 5-FU resistant cells via suppression of epithelial-to-mesenchymal transition (EMT) compared to 5FU alone.[12]
  • In the context of breast cancer, a combination of curcumin (10 µM) and 5-FU (10 µM) significantly inhibited cell viability and enhanced apoptosis compared to 5-FU alone in vitro.[13]
  • In addition to the effects mentioned above, research indicates that combining 5-FU (50 µmol/L) and curcumin (25 µmol/L) can enhance the cytotoxicity against human gastric cancer (AGS) cells compared to 5-FU or curcumin alone.
  • In a further study focused on inflammation outcomes, this study found that the protein expression of COX-2 and NF-κB in human gastric cancer (MKN45) cells were diminished after co-treatment with 5-FU (50 µmol/L) and curcumin (25 µmol/L). This finding implies that curcumin sensitizes gastric cancer cells to 5-FU by modulating inflammatory molecules. The anti-gastric cancer activity is shown not only in in vitro study, but data from an animal study further demonstrated that curcumin enhanced the anticancer activity of 5-FU (52 mg/kg 5-FU + curcumin 74 mg/kg, every 3 days for 6 times in total) compared to 5-FU or curcumin alone, and without increasing the toxicity in nude mice bearing MKN45 tumor xenografts.[14]

Combined with Doxorubicin

Doxorubicin, one of the active single-agent drugs, is widely used for the treatment of cancers, including leukemia, lung, brain, prostate, ovarian, and breast. However, the clinical use of doxorubicin often led to critical cardiotoxicity and developed multidrug resistance. Substantial evidence showed that curcumin (4 mg/kg every 2 days for a total of 7 injections) exhibits a better treatment efficacy of doxorubicin (0.4 mg/kg) in cancer due to the efflux inhibitory effect of curcumin.[15],[16],[17],[18]

A study conducted by Guorgui et al.[19] has shown that combination of curcumin (5 µM) and doxorubicin (0.4 mg/mL) demonstrated a stronger additive effect by reducing the proliferation of Hodgkin lymphoma (L-540) cells by 79%. The pharmacokinetic study also revealed that curcumin (5 mg/kg) could enhance the absorption of doxorubicin (5 mg/kg) and decrease drug efflux in vivo, suggesting that curcumin downregulates the intracellular levels of ATP-binding cassette (ABC) drug transporters.[20]

While DOX alone does not decrease tumor weight, the combination of DOX and curcumin has been shown to significantly reduce tumor weight to 56.5% (p<0.05) to that of the control group. In combination, curcumin enhanced apoptosis by DOX and decreased cell viability. The curcumin-DOX combination also suppressed activation of caspase-3, -8, and -9 compared to DOX alone. It appears that curcumin increases DOX-induced antitumor activity by suppressing the main caspase pathway and activating the main caspase independent pathway. The combination of curcumin and DOX suppressed the reduction of glutathione peroxidase activity and increased lipid peroxide levels in the heart. Therefore, it is expected that curcumin may reduce the adverse reactions associated with DOX. According to researchers, results suggest that curcumin can be used as a modulator to enhance the therapeutic index of cancer patients and improve their QOL.[21]

Combined with Platin Agents

Cisplatin-based combination therapy has emerged as a standard therapy for metastatic and advanced bladder cancer,[22] demonstrating 15–20% improved survival and 50–70% response rate. However, nearly 30% of patients do not respond to initial chemotherapy and show recurrence within 1 year.[23] Cisplatin is an inorganic platinum agent which can induce DNA-protein and interstrand and intrastrand DNA crosslinks.[24]

While this crosslink can induce apoptosis and inhibit cell proliferation,[25] the efficacy of cisplatin is limited by the development of cell resistance. Co-treatment with curcumin (10 µM) and cisplatin (10 µM) has shown a potent synergistic effect by activating caspase-3 and upregulating phospho-mitogen-activated protein kinase (p-MEK) and phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2) signaling in bladder cancer cell lines (253J-Bv and T24) compared to curcumin or cisplatin alone.[26] In addition to the effects observed on bladder cancer, the combination of curcumin and cisplatin was shown to upregulate the expression of miR-186 via modulation of Twist1 in ovarian cancer compared to cisplatin alone.[27]

Synergism of Curcumin and Epigallocatechin-3-gallate

Drug resistance remains an ongoing challenge in ovarian cancer chemotherapy. Research has investigated the synergism in activity from the sequenced combinations of cisplatin (Cis) with curcumin (Cur) and epigallocatechin-3-gallate (EGCG) in ovarian cancer cell lines. The drugs were added in binary combinations: Cis combined with Cur, and Cis combined with EGCG to the human ovarian A2780 and A2780(cisR) cancer cell lines, using five different sequences of administration: 0/0 h, 4/0 h, 0/4 h, 24/0 h and 0/24 h. Addition of Cis 4 h before Cur and EGCG (0/4 h combination) produced the most synergistic outcomes in both the A2780 and A2780(cisR) cell lines. The cellular accumulations of platinum and platinum-DNA binding resulting from the 0/4 h combinations were greater as compared to the values using Cis alone, thus providing an explanation for the synergistic action. When sequenced combinations of Cis with Cur and with EGCG are applied to human ovarian A2780 and A2780(cisR) cancer cell lines, lower concentrations and shorter time gap between the two additions seem to produce a higher cytotoxic effect.[28]

Curcumin, EGCG (Green tea extract) and Resveratrol Immune Enhancing Anti-tumor

Curcumin, Resveratrol, EGCG and Beta glucan rich mushroom extract have shown promising immune-modulating effects, such as inhibiting myeloid-derived suppressor cells and enhancing natural killer and cytolytic T cells, in tumor-bearing animal models.

Many other studies involving either genetic models or xenograft models of other types of cancer have demonstrated that curcumin can reverse the tumor-favoring microenvironment, leading to further investigations of curcumin combined with standard cancer therapies. One study combined the anti-PD-L1 antibodies with bisdemethoxycurcumin (BDMC), a natural dimethoxy derivative of curcumin, in C57BL/6 mice with metastasized bladder cancer (MB49 cells).

They observed that BDMC alone increased levels of tumor-infiltrating CD8+ T cells, IFN-γ secretion in the blood, and decreased the number of tumor-infiltrating MDSCs.

Importantly, the combination of anti-PD-L1 antibodies with curcumin further enhanced the secretion of IFN-γ, granzyme B, and perforin from CD8+ T cells.[29]

Furthermore, curcumin has been combined with vaccines against tumor development. For instance, one group applied two vaccination strategies to BALB/c mice bearing triple-negative breast tumors (4T1 cells). One strategy gave the mice curcumin and all the vaccinations after tumors had developed. The other treated the mice with curcumin before they were inoculated with tumor cells and then vaccinated the animals after tumors developed. Interestingly, the second strategy was more effective against metastasis than the first, as it decreased the production of pro-inflammatory cancer promoting cytokines (IL-6), and increased levels of anti-tumor cytokines (IL-12 and IFN-γ).[30]

A cocktail of Turmeric- curcumin, Green tea epicatechin gallate and resveratrol—increased levels of tumor-infiltrating NK cells and CD8+ cytolytic T cells in C57BL/6 mice bearing HPV+ mouse lung cancer (TC-1 cells).

The combination formula repolarized tumor promoting M2-like TAMs to tumor fighting M1-like TAMs in the tumors.[31]

Combined with Taxanes

Docetaxel (30 or 75 mg) has been clinically approved and widely used for the treatment of metastatic castration-resistant prostate cancer.[32] However, prolonged treatment with docetaxel can cause severe toxicity in patients. A study found that the combined treatment of docetaxel (10 nM) and curcumin (20 µM) for 48 h significantly inhibited proliferation and induced apoptosis in prostate cancer (PC-3) (DU145 and PC3) cells compared to curcumin and docetaxel alone. The data further demonstrated that curcumin enhances the efficacy of docetaxel in PC-3 cells via modulation of COX-2, p53, NF-κB, phospho-Akt, PI3K, and receptor tyrosine kinase (RTK).[33] This finding implies that combining curcumin with conventional chemotherapy may act as an effective treatment regimen for patients with prostate cancer to reduce cytotoxicity and overcome drug-resistance induced by docetaxel.

Curcumin is a taxane sensitizer for tumors and chemoprotector for normal organs, including in cases of lung cancer.[34]

[35]

Combined with Gemcitabine

Curcumin induces apoptosis and inhibits the growth of orthotopic human non-small cell lung cancer xenografts. A research study evaluated the effect of curcumin on the expression of nuclear factor κB-related proteins in vitro and in vivo and on growth and metastasis in an intralung tumor mouse model.

H1975 NSCLC cells were treated with curcumin (0-50μM) alone, or combined with gemcitabine or cisplatin. The effects of curcumin were evaluated in cell cultures and in vivo, using ectopic and orthotopic lung tumor mouse models. Western blot analysis showed that the expressions of IkB, nuclear p65, cyclooxygenase 2 (COX-2) and p-ERK1/2 were down-regulated by curcumin in vitro. Curcumin potentiated the gemcitabine- or cisplatin-mediated antitumor effects. Curcumin reduced COX-2 expression in subcutaneous tumors in vivo and caused a 36% decrease in weight of intralung tumors (P=.048) accompanied by a significant survival rate increase (hazard ratio=2.728, P=.036). Curcumin inhibition of COX-2, p65 expression and ERK1/2 activity in NSCLC cells was associated with decreased survival and increased induction of apoptosis. Curcumin significantly reduced tumor growth of orthotopic human NSCLC xenografts and increased survival of treated athymic mice. Researchers note that to evaluate the role of curcumin in chemoprevention and treatment of NSCLC, further clinical trials are required.[36]

Curcumin Induces PTEN and Improves the Cytotoxicty of Gemzar Against Pancreatic Cancer

Curcumin induces cancer cell growth arrest and apoptosis in vitro, but its poor bioavailability in vivo limits its antitumor efficacy. Researchers noted that in previous evaluations of the bioavailability of novel analogues of curcumin compared with curcumin, they found that the analogue CDF exhibited greater systemic and pancreatic tissue bioavailability.

In a study reported in Cancer Research, scientists evaluated the effects of CDF or curcumin alone or in combination with gemcitabine on cell viability and apoptosis in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer (PC) cell lines. Mechanistic investigations revealed a significant reduction in cell viability in CDF-treated cells compared with curcumin-treated cells, which were also associated with the induction of apoptosis, and these results were consistent with the downregulation of Akt, cyclooxygenase-2, prostaglandin E(2), vascular endothelial growth factor, and NF-kappaB DNA binding activity.

The researchers documented attenuated expression of miR-200 and increased expression of miR-21 (a signature of tumor aggressiveness) in gemcitabine-resistant cells relative to gemcitabine-sensitive cells. Interestingly, CDF treatment upregulated miR-200 expression and downregulated the expression of miR-21, and the downregulation of miR-21 resulted in the induction of PTEN. These results prompt further interest in CDF as a drug modality to improve treatment outcome of patients diagnosed with PC as a result of its greater bioavailability in pancreatic tissue.[37]

Mechanisms of action of combination curcumin and chemotherapy drugs in vitro and in vivo. Co-treatment with curcumin and chemotherapy drugs such as docetaxel, metformin, 5-fluorouracil, doxorubicin, cisplatin, and celecoxib enhance the synergistic effect via modulating several signaling pathways and thus inhibit cancers such as prostate, hepatocellular, gastric, Hodgkin lymphoma, bladder, and colorectal. Akt: protein kinase B; COX-2: cyclooxygenase-2; EGFR: epidermal growth factor receptor; MMP2/9: matrix metalloproteinase-2/9; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor kappa B; p-ERK1/2: phospho-extracellular signal-regulated kinase 1/2; PI3K: phosphoinositide 3-kinase; p-MEK: phospho-mitogen-activated protein kinase; STAT3: signal transducer and activator of transcription 3; VEGF: vascular endothelial growth factor; VEGFR2: vascular endothelial growth factor receptor 2.

[38]

Pathways whereby Curcumin inhibits multi-drug resistance

[39]

Combined with Paclitaxel

Paclitaxel (PTX) is a key member of the taxane family with potential anti-tumor activity against different cancers. Notably, PTX has demonstrated excellent proficiency in elimination of cancer in clinical trials. This chemotherapeutic agent is isolated from Taxus brevifolia and is a tricyclic diterpenoid. However, resistance of cancer cells into PTX chemotherapy has endangered its efficacy. In addition, administration of PTX is associated with a number of side effects such as neurotoxicity, hepatotoxicity, and cardiotoxicity, demanding novel strategies in obviating PTX issues.

Curcumin is a pharmacological compound with diverse therapeutic effects including anti-tumor, antioxidant, anti-inflammatory, and anti-diabetic properties. Curcumin appears to enhance the anti-tumor activity of PTX against different cancers. Additionally, curcumin administration reduces the adverse effects of PTX due to its excellent pharmacological activities.[40]

Combined with Metformin

Data from an in vitro study showed that combining metformin (10 mM) and curcumin (5 and 10 µM) can induce apoptosis and inhibit metastasis and invasion in HepG2 and PLC/PRF/5 cells. The anticancer effects could be attributed to the vascular endothelial growth factor (VEGF), MMP2/9, and vascular endothelial growth factor receptor 2 (VEGFR-2) inhibition, PTEN and p53 activation, and epidermal growth factor receptor (EGFR)/STAT3 and NF-κB/mTOR/Akt/PI3K suppression. Data from an in vivo study further showed that co-treatment with metformin and curcumin significantly suppressed hepatocellular carcinoma compared to curcumin (60 mg/kg) and metformin (150 mg/kg) alone in a xenograft mouse model.[41]

Combined with Celecoxib and COX-2 inhibitor

Celecoxib is another selective inhibitor of COX-2, an enzyme induced by different stimuli including inflammation.[42] Celecoxib (75 µM for 16 h) has shown an ability to induce apoptosis and suppress tumor angiogenesis in several types of cancer.[43] However, the long-term use of Celecoxib leads to an adverse outcome such as cardiovascular toxicity.[44] The combination of curcumin and Celecoxib was shown to reduce cancer cell growth in vitro compared to Celecoxib alone. A study reported by Lev-Ari et al. revealed that curcumin (10–15 µmol/L) and physiological dosage of Celecoxib (5 µmol/L) exhibited a synergistic inhibitory effect against human colorectal cancer (HT-29) cells. The study showed that the combination of curcumin and Celecoxib induces apoptosis in HT-29 cells via downregulation of COX-2 expression, suggesting that curcumin synergistically augments the growth inhibitory effects of Celecoxib in human colon cancer cell lines in vitro.[45]

Another anti-cancer property of curcumin seems to be overcoming multidrug resistance.[46] For example, it inhibits P-glycoprotein expression in mouse leukemia L1210/Adr cell lines. Cells treated with a combination of PI3K inhibitor and curcumin displayed lower P-glycoprotein expression in comparison to cells treated only with PI3K inhibitor. It was suggested that curcumin may act by inhibition of the PI3K/Akt/ NF-κB pathway.[47]

Curcumin was found to be a safe and non-toxic dietary supplement. Its efficacy of was studied during clinical trials.[48],[49]

In the mouse model, a high curcumin supplementation (100 mg/kg) was able to improve glucose and insulin intolerance through activating the AMPK pathway, showing the potential involvement of curcumin in metabolism.[50] Modulation of AMPK (AMP-activated protein kinase) improves glucose/insulin efficiency and adds the cancer suppressing effects of curcumin.  AMPK acts as a cellular energy sensor, and curcumin selectively can enhance normal cell AMPK signaling, while suppressing it within the cancer cell. [51],[52]

Curcumin in the Modulation of Aging

Overview of the impact of curcumin on ageing and age-related diseases (ARD) at the organismal and cellular level. On the organismal level, curcumin mimics caloric restriction (CR) and improves the effectiveness of physical activity (which mimics CR).[53]

In Conclusion

Natural compounds, including curcumin, resveratrol, EGCG, and β-glucan have shown synergistic promising immune-modulating, anti-tumor, and chemo-potentiating effects.

The results of these clinical studies are conclusive, and these studies have established a good foundation for further research focusing on implementing curcumin along with other botanical compounds in clinical oncology. It’s important to note, however, that I never use it as a soloist! I always use a formula that combines curcumin with EGCG, resveratrol, grape seed extract, quercetin, and other botanical extracts. This provides a harmonious approach that best supports healing.

References


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[6] Odaine N. Gordon1 , Paula B. Luis1 , Herman O. Sintim2 , and Claus Schneider, Unraveling curcumin degradation: Autoxidation proceeds through spiroepoxide and vinylether intermediates in route to the main bicyclopentadione, The latest version is at http://www.jbc.org/cgi/doi/10.1074/jbc.M114.618785, Copyright 2015 by The American Society for Biochemistry and Molecular Biology, Inc

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