Antiviral Lactoferrin Now pitted against COVID-19

Antiviral Lactoferrin Now Pitted Against COVID-19

 by Noelle Patno, PhD

Lactoferrin (LF) has been advocated by researchers1–3 as a potential method to prevent or treat COVID-19. These recent reviews promote a hypothesis that the natural, endogenous compound which has shown antiviral capabilities for other viruses including SARS-CoV may be effective against the SARS-CoV-2 virus as well. With over 70 years since the discovery of this glycoprotein, this iron-scavenging milk protein now deserves greater attention. The current literature demonstrates that LF has many anti-inflammatory, immunomodulatory, and even anticarcinogenic effects; what remains to be discovered is its specific activity against the pandemic virus of our times, SARS-CoV-2. A large body of in vitroevidence suggests that lactoferrin may have efficacy because of its ability to inhibit viruses and bind to viral surface receptors, which are related to SARS-CoV-2 mechanisms. Now is the time to discover more about this glycoprotein and its potential against SARS-CoV-2.

Mechanism of binding to heparan sulfate

A recent paper (published in Cell, November 2020) demonstrated that SARS-CoV-2 infection depends on attachment to cellular heparan sulfate (HS) and ACE2.4 While ACE2’s role was predicted in January5 and subsequently demonstrated in March,6 this revelation in November reveals the importance of HS as an essential factor in the virus’s attachment and entry to infect the cell. Heparan sulfate, a complex carbohydrate on almost every cell’s surface, is useful to the host to determine the cell’s response to stimuli such as metabolic or inflammatory stimuli and critically as part of immune functions.7 However, many viruses hijack HS to bind and depend on it for their infection. In vitro evidence supports this mechanism for other viruses including the Nipah and Hendra viruses;8 entrovirus 71, which is associated with hand foot mouth disease;9 enteroaggregative E. coli, which is a significant cause of diarrhea and foodborne outbreaks;10 rift valley fever virus;11 and human papillomavirus.12 This list overlaps with the list of pathogenic viruses that lactoferrin inhibits in vitro, which includes but is not limited to the following: herpes simplex virus, hepatitis B virus, hepatitis C virus (HCV), avian flu, enterovirus 71, Japanese encephalitis virus, respiratory syncytial virus, influenza A virus, parainfluenza virus, cytomegalovirus, poliovirus, rotavirus, and human immunodeficiency virus (HIV), with clinical evidence for enterovirus 71, HCV, norovirus, and rotavirus.2 With lactoferrin’s previous ability demonstrated to prevent the Japanese encephalitis virus,13 alphavirus,14 Toscana virus,15 dengue virus,16 and the SARS pseudovirus17 from entering cells through HS receptors and infecting the cells, then LF has the possibility of preventing SARS-CoV2 from entering cells as well.

Potential mechanisms by which LF might help against SARS-CoV-2 are therefore the following:1

Prevent attachment to heparan sulfate receptors on the cell and inhibit viral entry4,13
Prevent attachment to ACE2 and inhibit viral entry/infection of the cell18

Prevent attachment to DC-SIGN, dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin receptor and thereby prevent infection of the cell3
Prevent attachment and viral entry via other receptors17

Inhibit viral replication15,19
Decrease IL-6,20 which is part of the cytokine storm

Current clinical trials evaluating lactoferrin in COVID-19

The table below lists the current clinical trials on clinicaltrials.gov evaluating lactoferrin in COVID-19.

Three recent publications further suggest that lactoferrin may help against SARS-CoV-2:

1. In vitro, bovine lactoferrin was able to decrease significantly the numbers of SARS-CoV-2-infected bronchial epithelial cell mimetics, the single compound mentioned in the abstract of the preprinted paper, and one of 17 dose-responsive compounds from a 1,425 library in a drug-repurposing high throughput screen19

2. The completed randomized clinical study listed above, in 32 patients with confirmed COVID-19 by RT-PCR, showed an early clearance of the virus, recovery from symptoms, and statistically significant reduction in IL-6 , with additional in vitro and in silico support for lactoferrin’s ability to prevent cells from infection through preincubation as well as simulated binding of lactoferrin to the ACE2 receptor.18

3. A 10-day study evaluating the effect of a liposomal bovine lactoferrin syrup that included vitamin C alone or with zinc (for a total of 256 to 384 mg of lactoferrin per day) and additional nasal and mouth spray or aerosol application for additional symptoms. IgM/IgG antibody rapid test in whole blood was used for confirmed COVID-19 diagnosis in 75 people. Symptoms were scored on a scale of 0 to 3 in severity twice a day for 10 days and then a follow-up after one month. By the fifth day, all patients recovered from respiratory distress and headache symptoms. The percentage of patients without symptoms of coughing, muscular pain, nasal congestion, tiredness, and diarrhea all increased by 48 hours and 5 days after study start.21

There are many limitations to the above three studies. The first two preprinted articles have not been peer-reviewed. The third lacked clear dosing instructions, did not use the more accurate SARS-CoV-2 diagnostic tests; did not follow-up test for the virus after-treatment; used additional interventions for subsets of patients; lacked more rigorous, randomized, and controlled design and more objective and validated methodology; and was not the complete data set for the study, among other limitations. Clinical studies on the effects of lactoferrin supplementation in COVID-19 patients is a promising and interesting research advancement to watch.

Citations

1. Campione E et al. Lactoferrin as protective natural barrier of respiratory and intestinal mucosa against coronavirus infection and inflammation. Int J Mol Sci. 2020;21(14):4903.

2. Chang R et al. Lactoferrin as potential preventative and adjunct treatment for COVID-19. Int J Antimicrob Agents. 2020;56(3):106118.

3. Wang Y et al. Lactoferrin for the treatment of COVID-19 (Review). Exp Ther Med. 2020;20(6).

4. Clausen TM et al. SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2. Cell. 2020;183(4):1043-1057.e15.

5. Wan Y et al. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol. 2020;94(7).

6. Hoffmann M et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-280.e8.

7. Simon Davis DA et al. Heparan sulfate: a ubiquitous glycosaminoglycan with multiple roles in immunity. Front Immunol. 2013;4.

8. Mathieu C et al. Heparan sulfate-dependent enhancement of henipavirus infection. mBio. 2015;6(2).

9. Kobayashi K et al. Heparan sulfate attachment receptor is a major selection factor for attenuated enterovirus 71 mutants during cell culture adaptation. PLOS Pathogens. 2020;16(3):e1008428.

10. Rajan A et al. Enteroaggregative E. coli adherence to human heparan sulfate proteoglycans drives segment and host specific tesponses to infection. PLOS Pathogens. 2020;16(9):e1008851.

11. de Boer SM et al. Heparan sulfate facilitates Rift Valley fever virus entry into the cell. J Virol. 2012;86(24):13767-13771.

12. Selinka H-C et al. Inhibition of transfer to secondary receptors by heparan sulfate-binding drug or antibody induces noninfectious uptake of human papillomavirus. J Virol. 2007;81(20):10970-10980.

13. Chien Y-J et al. Bovine lactoferrin inhibits Japanese encephalitis virus by binding to heparan sulfate and receptor for low density lipoprotein. Virology. 2008;379(1):143-151.

14. Waarts B-L et al. Antiviral activity of human lactoferrin: inhibition of alphavirus interaction with heparan sulfate. Virology. 2005;333(2):284-292.

15. Pietrantoni A et al. Bovine lactoferrin inhibits Toscana virus infection by binding to heparan sulphate. Viruses. 2015;7(2):480-495.

16. Chen J-M et al. Bovine lactoferrin inhibits dengue virus infectivity by interacting with heparan sulfate, low-density lipoprotein receptor, and DC-SIGN. Int J Mol Sci. 2017;18(9).

17. Lang J et al. Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans. PLoS One. 2011;6(8). doi:10.1371/journal.pone.0023710

18. Campione E et al. Pleiotropic effect of Lactoferrin in the prevention and treatment of COVID-19 infection: randomized clinical trial, in vitro and in silico preliminary evidences. bioRxiv. Published online August 17, 2020:2020.08.11.244996.

19. Mirabelli C et al. Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19. bioRxiv. Published online September 28, 2020.

20. Lepanto MS et al. Efficacy of lactoferrin oral administration in the treatment of anemia and anemia of inflammation in pregnant and non-pregnant women: an interventional study. Front Immunol. 2018;9.

21. Serrano G et al. Liposomal lactoferrin as potential preventative and cure for COVID-19. Int J Res Health Sci. 2020;8(1):8.

Noelle Patno, PhD is the Nutrition Scientist for Digestive Health at Metagenics. Dr. Patno received her PhD in Molecular Metabolism and Nutrition and Masters in Translational Science from the University of Chicago, studying the role of microbial components in intestinal epithelial cell survival related to inflammatory bowel disease. Prior to her graduate studies, Dr. Patno received a chemical engineering degree from Stanford University and worked as an engineer. She has personal experience and interest in preventive nutrition and nutritional therapies for chronic disease, and her current role involves researching and developing probiotics, prebiotics, and other nutritional programs for the promotion of digestive and overall health.

 

Are Artificial Sweeteners Really Harmless?

Medscape Medical News - August 19, 2022

New research discounts the long-held notion that aspartame and other nonnutritive sweeteners (NNS) have no effect on the human body.

In a study, researchers found that these sugar substitutes are not metabolically inert and can alter the gut microbiome in a way that can influence blood glucose levels.

The study was published online August 19,20-22 in the journal Cell.

Gut Reaction? 

Several years ago, a team led by Eran Elinav, MD, PhD, an immunologist and microbiome researcher at the Weizmann Institute of Science, Rehovot, Israel, observed that NNS affect the microbiome of mice in ways that could affect glycemic responses.

They have now confirmed this observation in a randomized controlled trial with 120 healthy adults.

Before the study, all participants strictly avoided NNS. During the trial, some remained NNS-free, while others used saccharin, sucralose, aspartame, or stevia daily for 2 weeks in doses lower than the acceptable daily intake.

Each NNS "significantly and distinctly" altered stool and oral microbiome, and two of the sweeteners (saccharin and sucralose) significantly impaired glucose tolerance, the researchers report.

"Importantly, by performing extensive fecal transplantation of human microbiomes into germ-free mice, we demonstrate a causal and individualized link between NNS-altered microbiomes and glucose intolerance developing in non-NNS-consuming recipient mice," they say.

They note that the effects of these sweeteners will likely vary from person to person because of the unique composition of an individual's microbiome.

"We need to raise awareness of the fact that NNS are not inert to the human body as we originally believed. With that said, the clinical health implications of the changes they may elicit in humans remain unknown and merit future long-term studies," Elinav said in a news release.

For now, Elinav says it's his personal view that "drinking only water seems to be the best solution.”

Weighing the Evidence 

Several experts weighed in on the results in a statement from the UK nonprofit organization, Science Media Centre.

Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, United Kingdom, notes that the study does not show a link between all NNS and higher blood glucose levels in the long term (only after a glucose tolerance test).

"It did suggest, though, that some individuals who do not normally consume sweeteners may not tolerate glucose as well after consuming six sachets of either saccharin or sucralose mixed with glucose per day," Mellor says.

Kim Barrett, PhD, distinguished professor of physiology and membrane biology, University of California, Davis, School of Medicine, concurs, saying, "this well-designed study indicates the potential for NNS to have adverse effects in at least some individuals."

The study also does not provide any information about how people who normally consume sweeteners or people with either type 1 or type 2 diabetes respond to NNS.

"Therefore, for some people, it is likely to be a better option and more sustainable approach to use sweeteners as a 'stepping stone,' allowing them to reduce the amount of added sugar in foods and drinks, to reduce their sugar intake, and still enjoy what they eat and drink, on the way to reducing both added sugar and sweeteners in their diet," Mellor suggests.

Kevin McConway, PhD, with the Open University, Milton Keynes, United Kingdom, says it's "important to understand that the research is not saying that these sweeteners are worse for us, in heath terms, than sugar.

"But exactly what the health consequences of all this, if any, might be is a subject for future research," McConway adds.

Kathy Redfern, PhD, lecturer in human nutrition, University of Plymouth, UK, agrees.

"We still have a lot to learn about the human microbiome, and although this study suggests two of the sweeteners tested in this study (sucralose and saccharin) significantly affected glucose tolerance, these deviations were small," she says.

The International Sweeteners Association also weighs in, saying, "No conclusions about the effects of low/no calorie sweeteners on glucose control or overall health can be extrapolated from this study for the general population or for people who typically consume sweeteners, including people living with diabetes."

They add that "a recent review of the literature concluded that there is clear evidence that changes in the diet unrelated to low/no calorie sweeteners consumption are likely the major determinants of change in gut microbiota."

Nevertheless, Redfern says the results "warrant further investigation to assess how small changes in glucose tolerance in response to NNS consumption may influence longer term glucose tolerance and risk for metabolic complications, such as type 2 diabetes."

The study had no specific funding. Elinav is a scientific founder of DayTwo and BiomX, a paid consultant to Hello Inside and Aposense, and a member of the scientific advisory board of Cell. Mellor has provided consultancy to the International Sweetener Agency and has worked on projects funded by the Food Standards Agency that investigated the health effects of aspartame. Barrett, McConway, and Redfern report no relevant financial relationships. 

Cell. Published online August 19, 2022. <https://www.cell.com/cell/fulltext/S0092-8674(22)00919-9>

Living on purpose

 During my meditation and movement practice this morning, I contemplated the meaning and expanse of living on purpose, or I could say the thought hit me like a freight train.

As can only happen in these energetic spaces, I was flooded with the concept:

ON PURPOSE...Intentionally, my reason for being and doing.

Purpose...the reason for which something is done or created or for which something exists. (noun)...Verb: Have as one's intention or objective.

So many of us struggle to find our purpose and I can honestly say that I am not sure if I have or haven't,  however I do believe it has something to do with what we chose to focus on, our intent, and we get to chose on a daily basis. It is therefore a good practice for me to mediate and move every morning to chose and be clear on what my focus or intent for the day will be.

I have chosen to focus on more love, and to live on purpose (intentionally). Meaning I have chosen to live my life with the purpose of opening up to more love for myself and to spread and share more love with others and through my work, I intend to help open the hearts of humanity to the love of the soul. I am choosing to see the miracle in everyone and everything.

Is that my purpose??? 

All I can do is to wake up every day and live on purpose and chose to do so all day. And for now that purpose is love, and I believe that with this intent and focus, I will be more fulfilled and it will lead to a deeper how and an even deeper purpose and my purpose will continue to unfold in more miraculous ways.

 

Are Diabetics Being Cheated?

Ronald Grisanti D.C., D.A.B.C.O., D.A.C.B.N., M.S., CFMP

A recent patient was concerned that despite watching her diet and taking her diabetes medication her hemoglobin A1C (HbA1c) keeps going up.

Remember, HbA1c is a lab test that shows the average level of blood sugar (glucose) over the previous 3 months. It shows how well you are controlling your diabetes. 

An elevated HbA1c greater than 5.7% indicates that the diabetes is not well regulated and is in fact accelerating aging, increasing your chances of getting painful neuropathies, kidney failure needing dialysis, cataracts, amputations, and retinopathy blindness.

What could possibly be missed by her primary doctor?

One major cause of the unregulated glycosylated hemoglobin is an unrecognized B6 deficiency.

An excellent “functional” test to check for a pyridoxine (B-6) deficiency is the xanthurenate organic acid test. An elevated xanthurenate test is a sensitive marker for a B-6 deficiency.

 

This is an Organic Acid Test from Genova

But wait.. there is more to the story.

You can take B-6 and it may not work.

Why?

Because of a zinc deficiency.

When hidden zinc deficiency is present, the body cannot convert B6 to its active form, pyridoxal-5-phosphate or P5P. P5P, essential in normalizing the glycosylated hemoglobin and its deficiency, is an indicator that improperly metabolized sugars are accelerating aging, cataracts, kidney failure, heart disease, nerve damage and more.

This is the intracellular nutrient test from Doctor's Data

But there is more to the story.

Elevated stored phthalates (plastics) in the body interfere with zinc metabolism.

This is a Phthalate Test from Genova

This is the power of functional medicine. Seeking to find the cause of the cause of the cause.

HbA1c ---> B-6 deficiency ---> Zinc deficiency ---> Stored Phthalates

I have never yet met a diabetologist who even orders the above much less knows how to interpret it.

To ignore fixing the chemistry in an overtly metabolic disease is outright wrong.

Unfortunately, what I have seen from reading thousands of medical records is the fact that most doctors merely resort to the one size fits all approach and medicate the disease. Rarely if ever have I read where a doctor investigated why the HA1C was elevated.

This results in a tragic waste of life as well as incurring an enormous and unnecessary expense and suffering.

You may be interested to know that because of the phthalate load, many folks (even without diabetes) unnecessarily get multiple diseases. These can range from Nonalcoholic steatohepatitis or NASH (a common, often “silent” liver disease), heart disease or cancers to Parkinson's disease, arthritis, or Alzheimer's.

Clearly they all lead to accelerated aging because of the shared causes.

For a doctor to check your glycosylated hemoglobin A1C every 3 months yet never know your zinc and B6 levels (among many others) is plain wrong in this sophisticated era.

Your life depends on the decisions you make. This information has a huge bearing on whether your diabetes blinds you in future years.

 

References:

Depeint F, et al, Mitochondrial function and toxicity: Role of B vitamins, one-carbon transfer pathways, Chemico-Biological Interactions 163:113-32, 2006

Jain SK, et al, Pyridoxine and pyridoxamine inhibits superoxide radicals and prevents lipid peroxidation, protein glycosylation and (Na+ + K+)-ATPase activity reduction in high glucose-treated human erythrocytes, Free Rad Biol Med 30:232-37, 2001

Onarato JM, et al, Pyridoxamine, an inhibitor of glycation reactions, also inhibits lipid peroxidation reactions, J Biol Chem, 275:21177-84, 2000

Metz TO, et al, Pyridoxamine traps intermediates in lipid peroxidation reactions in vivo: evidence on the role of lipids and chemical modification of protein and development of diabetic complications, J Biol Chem 278:42012-19, 2003

Booth AA, et al, Thiamine pyrophosphate and pyridoxamine inhibit the formation of antigenic advanced glycation endproducts: comparison with aminoguanidine, Biochem Biophys Res Commun, 220:113-19, 1996

Stitt A, et al, The AGE inhibitor pyridoxine and inhibits development of retinopathy in experimental diabetes, Diabetes 51:2826-32, 2000

Laines-Cessac P, et al, Mechanisms of the inhibition of human erythrocyte pyridoxal kinase by drugs, Biochem Pharmacol 54:863-70, 1997

The information on this website is not intended to replace a one-on-one relationship with a qualified health care professional and is not intended as medical advice. It is intended as a sharing of knowledge and information from the research and experience of Dr. Grisanti and his community. Dr. Grisanti encourages you to make your own health care decisions based upon your research and in partnership with a qualified health care professional. Visit www.FunctionalMedicineUniversity.com to find practitioners thoroughly trained in functional medicine. Look for practitioners who have successfully completed the Functional Medicine University's Certification Program (CFMP).  

The Universe gives us signs...

https://youtu.be/c_X_sPNUDes

the Universe gives us all signs and this piece speaks to that and brought tears to my eyes as it touched a truth deep inside me. I hope you get something from this too..

What if this is the moment that your life changes?

Belonging to life and opening to it's fullness

I recommend reading the book by Tara Brach and also love this reference in the book about fullness and belonging 

Remember we are NO-THING and all is affected by the attention and focus we place upon it.

Allow life to live through you. Enjoy every breath and every emotion as it flows in and through you.

Enjoy the following POEM...read it often and allow the energy of it to flow through you, too enhance your experiences and open your mind.

Radical Acceptance by Tara Brach, PH.D

Our intrinsic belonging to this world…we are No-THING…not limited to any passive experience

and everything belonging to the whole.

In Roger Keyes’s poem “hokusai says”

THE TEACHINGS OF A WISE JAPANESE ARTIST REMIND us of our belonging to life and of our capacity to open to its fullness.

Hokusai says – Poem by Roger Keyes

Hokusai says look carefully. 

He says pay attention, notice.

He says keep looking, stay curious.

He says there is no end to seeing.

He says look forward to getting old.

He says keep changing, you just get more who you really are.

He says get stuck, accept it, repeat yourself as long as it’s interesting.

He says keep doing what you love.

He says keep praying.

He says every one of us is a child, every one of us is ancient, every one of us has a body.

He says every one of us is frightened. 

He says every one of us has to find a way to live with fear.

He says everything is alive –shells, buildings, people, fish, mountains, trees.

Wood is alive.

Water is alive.

Everything has its own life.

Everything lives inside us.

He says live with the world inside you.

He says it doesn’t matter if you draw, or write books. 

It doesn’t matter if you saw wood, or catch fish.

It doesn’t matter if you sit at home and stare at the ants on your veranda

or the shadows of the trees and grasses in your garden.

It matters that you care.

It matters that you feel.

It matters that you notice.

It matters that life lives through you.

Contentment is life living through you.

Joy is life living through you.

Satisfaction and strength is life living through you.

Peace is life living through you.

He says don’t be afraid.

Don’t be afraid.

Look, feel, let life take you by the hand.

Let life live through you

Are we limiting ourselves?

 I had an interesting discussion this morning which led me to think about the ways we limit our experiences and life by what we attach to.

We get attached to certain ideas and belief systems and when those are challenged we tend to resist. and block the chance to experience a shift in our energy and perception. Through our ego/pain body we experience life in a distorted manner.

I see this is many things, like meditation. We may have pre-conceived ideas of what meditation is and therefore feel like we never get it right or that we can't or don't know how to meditate. Anytime you are just riding the waves of thoughts and feelings and not attaching or going down the rabbit hole with any of it, you are experiencing a form of meditation. That is why a long walk in the woods or on the beach or a nice bicycle ride leaves you feeling energized and or relaxed.

With our thoughts and ideas about how things should be, we limit experiencing how things actually are and we may even block ourselves from 'seeing' clearly.

How are you limiting yourself and your experiences and your true expression? 

I invite you to take some time to explore this.