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FluEEZ

Viruses mutate at a much faster pace than their hosts. This is particularly true for RNA viruses such as influenza viruses and corona-viruses. It poses as a seemingly indomitable challenge for drug and vaccine makers. Currently approved ones, as many of you know, leave much room for improvement.

On the other hand, some, if not most, of the greatest medicines in human history came from nature --- aspirin, morphine, quinine, penicillin, metformin, artemisinin, the list goes on. Many of them are anti-infectives (which include anti-bacterials, antibiotics, anti-fungals, anti-protozoals, and anti-virals). Over the long history of traditional Chinese medicine (TCM), it has played a crucial role in helping the Chinese to overcome countless epidemics over the millennia, most notably during the 2002-2003 SARS epidemic. As a result, TCM was adopted from the very beginning of COVID-19 pandemic in China. National statistics showed that 91.5% of all patients used TCM.

 

In recent years, increasingly more scientific and clinical research data have substantiated the anti-viral power of a number of herbal products, often acting through distinct mechanisms of action, such as inducing interferons (key players of host anti-viral defense) and other enhancements of host immune function (see references below). Furthermore, biomedical researchers on COVID-19 in the past few months has yielded exciting new evidence that may explain the anti-viral power of herbal ingredients (see below).

Over the past 20 years, we have chosen concentrated extracts (standardized if available) of eight remarkable herbs to make one exceptional "cocktail", FluEEZ, in order to synergistically boost, and maintain the balance of, host immune function in face of viral infection. Here's the list of reasons why it is extraordinary:

  • FluEEZ has been successfully used and continuously perfected over the last two decades in Boston area integrative healthcare clinics. It is made of concentrated/standardized extracts from eight herbs, each of which is chosen for its unique property and function, based on traditional medicine expertise and latest biomedical research. It is encapsulated and bottled for convenient usage.

  • The selection and the carefully balanced proportion of these ingredients draw from the wisdom of traditional Chinese medicine, based on how they've been used in age-old formulae. Interestingly, according the latest version of "Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia" published by China's State Health Commission, herbs that we used have also been selected for recommended TCM formulae. Most importantly, we do NOT use herbs banned by the FDA, as some of those recommended formulae, such as Ma Huang and Xixin. Nor do we use possibly harmful herbs including Bing Lang, Kuan Dong Hua, and Ze Xie.

  • Amazingly, in the past few months researchers have added evidence by showing that main compounds in our ingredients may:

    • bind to SARS-CoV-2's highly conserved main protease, 3CLpro, indispensable for the replication of coronaviruses, and, amazingly, is perfectly ensconced in the core of the substrate-binding pocket, acting as a “shield” in front of the catalytic residues to prevent the peptide substrate approaching the active site (Scutellaria baicalin and baicalein)[3].

    • bind to angiotensin-converting enzyme II (ACE2), in addition to the ability to down-regulate pro-inflammatory cytokines, inhibit the accumulation of intracellular reactive oxygen species (ROS), inhibit thrombin, inhibit the hyperproduction of airway exudates, and induce endogenous interferon (Licorice glycyrrhizin)[4].

    • bind to the exact SARS-CoV-2 Spike protein interface for human ACE2 receptor binding (Orange peel hesperidin)[5].

  • FluEEZ, along with FluEEZ Nasal, successfully underwent rigorous in vitro and in vivo anti-influenza-virus studies from 1999 - 2000 (research results are available upon request).  Most importantly, it has been continuously used and highly valued for 20 years in Boston area integrative healthcare clinics.

REFERENCES:

[3] Su H. et al, Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro. bioRxiv doi: https://doi.org/10.1101/2020.04.13.038687

[4] Luo P, Liu D, Li J. Pharmacologic perspective: glycyrrhizin may be an efficacious therapeutic agent for COVID-19 [published online ahead of print, 2020 Apr 23]. Int J Antimicrob Agents. 2020;105995. doi:10.1016/j.ijantimicag.2020.105995

[5] Wu Canrong et al., Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computationalmethods, Acta Pharmaceutica Sinica B, https://doi.org/10.1016/j.apsb.2020.02.008

See below for research data around these herbs. 

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Echinacea Extract

Echinacea purpurea is one of the favorite herbs in North America. It has similar anti-viral and immune enhancing effects as Chinese herb Isatis root (Ban lan Gen). It is highly regarded in the German Homeopathic Pharmacopoeia and American Homeopathic Pharmacopoeia [31]. Echinacea has shown much immunomodulatory effect in many studies [31].

 

The main active ingredient of Echinacea are phenolic compounds, alkaloids and polysaccharides. A systematic review shows that echinacea has a clear immune stimulating effect [32], including increasing the level of interferon IFN-γ, increasing the number of white blood cells, and improving macrophages cell function [33]. In addition, echinacea ethanol extract also has a significant inhibitory effect on influenza viruses H5N1, H7N7, H1N1 [34].  Normally overemphasis on immune stimulation may exacerbate inflammatory exudation in the lungs. Studies show that while echinacea stimulates IL-10, it has no effect on IL-12 and TNF-α [35], supporting that the application of echinacea may not have such concern.

 

Echinacea polysaccharides stimulate the secretion of IFN-γ and IFN-β by macrophages [36]. The results of a study of 175 subjects suggested that echinacea extract can reduce the risk of influenza among tourists [37]. Moreover, short-term and long-term use of echinacea has lent little evidence of toxicity [38].

 

Bronchitis in children is mostly a viral infection. A review of 1280 children with bronchitis found that echinacea juice can shorten the course of this disease as compared to antibiotic treatment [39]. Echinacea extract has a significant effect in soothing throat and as analgesia. It can stimulate saliva secretion when put in mouth, and moisturizing throat is important to having respiratory immunity intact. Echinacea is often recommended to be taken with thyme in Europe and North America to treat upper respiratory tract infectious diseases [40].

REFERENCES:

[31] Bennet J. Oregano oil :the ultimate health guide to oregano essential oil-discover all oregano oil benefits, uses and recipes! (essential Oils,aromatherapy,alternative cures )[EB/OL ]. http ://www.goodreads. com/.

[32] Melchart D,Linde K,Worku F,et al. Immunomodulation with echinacea -a systematic review of controlled clinical trials[J]. Phytomedicine,1994,1(3):245-254.

[33] Seckin C,Kalayci GA,Turan N,et al. Immunomodulatory effects of echinacea and pelargonium on the innate and adoptive immunity in calves[J]. Food Agr Immunol,2018,29(1):722-761.

[34] Pleschka S,Stein M,Schoop R,et al. Anti-viral properties and mode of action of standardized

Echinacea purpurea extract against highly pathogenic avian influenza virus (H5N1,H7N7)and swine-origin H1N1 (S-OIV )[J ]. Virol J,2009,6 : 197-205.

[35] Yang G,Li KK,Liu C,et al. A comparison of the immunostimulatory effects of polysaccharides from tetraploid and diploid Echinacea purpura[J]. Biomed Res Int,2018 :8628531.

[36] McCann DA,Solco A,Liu Y,et al. Cytokine-and in-terferon-modulating properties of Echinacea spp. Root tinctures stored at -20 degrees C for 2 years[J]. J Interferon Cytokine Res,2007,27(5):425-436.

[37] Tiralongo E,Lea RA,Wee SS,et al. Randomised, double blind, placebo-controlled trial of echinacea supplementation in air travellers [J ]. Evid Based Complement Alternat Med,2012 :417267.

[38] Barrett B. Medicinal properties of Echinacea :a critical review [J ]. Phytomedicine,2003,10 (1): 66-86.

[39] Packer L,Wachtel-Galor S,Ong CN,Halliwell B. Herbal and traditional medicine :biomolecular and clinical aspects [M]. New York :Marcel Dekker, 2004 :654-655.

[40] Šmejkal K, Rjašková V.  Use of plant extracts as an efficient alternative therapy of respiratory tract infections[J]. Ceska Slov Farm,2016,65(4):139-160.

Licorice Extract (26% Glycyrrhizin)

The main compound glycyrrhizin (aka glycyrrhizic acid) extracted from licorice root has antiviral and antibacterial effects. Cinatl J et al. [6] compared the effects of glycyrrhizin, as compared to classic antiviral drugs ribavirin, 6-azauridine, pyrazofurin, mycophenolic acid, on SARS-CoV. The results show that glycyrrhizin is the most active in inhibiting replication of the SARS-associated coronavirus. Research from Hoever G et al. [7] also shows that glycyrrhizin and some of its derivatives have good anti-SARS-CoV effect. As we know, SARS-CoV-2 and SARS-CoV are similar and their encoded proteins are 95% - 100% homologous. In another study, glycyrrhizin is shown to promote T cell production of IFN-γ [8].

Recent studies have shown that SARS-CoV-2 and SARS-CoV use the same host receptor, ACE2 (angiotensin-converting enzyme 2), and glycyrrhizic acid can bind to ACE2 [9]. Another study shows that glycyrrhizic acid has an inhibitory effect on HIV propagation [10]. Moreover, licorice contains volatile oils, among which thymol and carvacrol have significant antiviral and bactericidal effects [11]. Not surprisingly, licorice is a key ingredient in three highly popular TCM formulae, Lian-Hua-Qing-Wen(连花清瘟), Gan-Cao-Gan-Jiang(甘草干姜)as well as Jin-Hua-Qing-Gan (金花清感)decoctions.

REFERENCES:

[6] Cinatl J,Rabenau H,Morgenstern B,et al. Glycyrrhizin,an active component of liquorice roots,and replication of SARS-associated coronavirus[J]. Lancet, 2003,361(9374):2045-2046.

[7] Hoever G,Baltina L,Michaelis M,et al. Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus[J]. J Med Chem,2005,48(4):1256-1259.

[8] Utsunomiya T,Kobayashi M,Pollard RB,et al. Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus[J]. Antimicrob Agents Chemother,1997,41(3):551-556.

[9] Chen HS,Du QH. Potential natural compounds for preventing 2019-nCoV infection [J/OL]. Preprints,2020,1-13.

[10] Sasaki H,Takei M,Kobayashi M,et al. Effect of glycyrrhizin, an active component of licorice roots, on HIV replication in cultures of peripheral blood mono-nuclear cells from HIV-seropositive patients [J ]. Pathobiology,2002,70(4):229-236.

[11] Farag MA,Wessjohann LA. Volatiles profiling in medicinal licorice roots using steam distillation and solid-phase microextraction (SPME )coupled to chemometrics[J ]. J Food Sci,2012,77 (11): 1179-1184.

Scutellaria Extract

Scutellaria baicalensis is a key component of several patented TCM medicines in China, including Shuang-Huang-Lian (双黄连) and Qing-Fei-Pai-Du (清肺排毒)decoctions that are highly recommended for the pandemic in China. It has the effect of “clearing heat and dampness, and treats lung heat cough, dampness”, etc. in the paradigm of TCM.

 

Scutellaria can regulate immune system and inhibit overactive autoimmune responses. Th17 T cells play a key role in autoimmune diseases. Th17 up-regulation aggravates bronchus, lung inflammation and asthma attacks, whereas IFN-γ, IL- 4 are inhibitors of Th17 cell differentiation [12]. Baicalin from scutellaria can inhibit the secretion of IL-17A and IL-6, promote the secretion of IL-10, reduce pulmonary inflammation, inhibit mucus secretion, and protect mice with Th17 / Treg related allergic asthma [13]. Baicalin from scutellaria can also improve the pathological changes of pulmonary bronchitis and emphysema in rats, regulate the expression of INF-α in lung tissues, and have preventative and therapeutic effect for chronic obstructive pulmonary disease (COPD) in rats [14].

 

Preliminary autopsy conducted by Professor Liu Liang's team found that COVID-19 can cause a large amount of very thick mucus exudation in patients' alveoli [15], which would explain the "ground glass opacity" in the lungs of COVID-19 patients as revealed by imaging. Since Baicalin can inhibit fibroblast proliferation and inflammation, it can be helpful with the inflammatory fibrosis of the lung [16].  In addition, baicalin combined with matrine can enhance the inhibitory effect on lipo-polysaccharide-induced pneumonia in mice [17]. Another report shows that baicalin can inhibit influenza virus, reduce the virus titer in rats after treatment, and decrease death rate from the infection [23].

 

The other main component of Scutellaria is baicalein. It can inhibit interleukin-mediated inflammation [18]. Allergic reactions caused by viral pneumonia aggravate inflammatory exudation, and baicalein can inhibit systemic allergic reactions by inhibiting the release of inflammatory mediators and degranulation of mast cells [19, 20]. Severe COVID-19 can cause acute respiratory distress syndrome (ARDS), which leads to refractory noncardiogenic pulmonary edema and pulmonary hypertension [21]. Baicalein can improve on monocrotaline-induced rat pulmonary hypertension by inhibiting vascular remodeling. The mechanism of pulmonary hypertension may be related to its inhibition of mitogen-activated protein kinase and NF-κB signaling pathway [22].

Most exciting discovery was done recently by Su H. et al[3]. They have stated it eloquently: "Baicalin and baicalein were identified as the first non-covalent, non-peptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography is distinctly different from those of known inhibitors. Baicalein is perfectly ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a “shield” in front of the catalytic dyad to prevent the peptide substrate approaching the active site. The simple chemical structure, unique mode of action, and potent antiviral activities in vitro, coupled with the favorable safety data from clinical trials, emphasize that baicalein provides a great opportunity for the development of critically needed anti-coronaviral drugs."  Bravo!

REFERENCES

[12] An X, Gong Y, Ye L, Jin M. Advance on studies of T helper 17 cells and its relative cytokines and bronchial asthma. Int J Respir, 2012,32(1):43-46.

[13] 王平. 黄芩苷对过敏性哮喘小鼠Th17/Treg 反应失衡的调节作用研究[D]. 吉林延边大学,2016.

[14] Chao H, Tang G, Wan Y. Baicalin has effects of prevention and cure on rats with chronic obstructive pulmonary disease by regulating IFN-γ. Int J Respir 2012,32 (1):18-21.

[15] Xu Z,Shi L,Wang YJ,et al. Pathological findings of COVID -19 associated with acute respiratory distress syndrome [J/OL ]. Lancet Respir Med, 2020,doi :10. 1016/S2213-2600(20 )30076-X.

[16] Bai L, Yang Y, Wan Q. Baicalin alleviated rheumatoid arthritis synovitis of SD rats through TLR2-NF-κB pathway.  Chinese Pharmacological Bulletin 2017,33(11):1569-1573.

[17] Wang F, Sun Y, Yin W, Fan K, Duan Z, Sun N, Li H.  Effects of matrine combined with baicalin on mouse pneumonia induced by LPS.  Chinese Pharmacological Bulletin 2018,34 (8):105-109.

[18] Dubravko J,Lower-Nedza AD,Brantner AH,et al. Baicalin and baicalein inhibit arc tyrosine kinase and production of IL-6 [J ]. J Chemistry, 2016 :2510621.

[19] Bae MJ,Shin HS,See HJ,et al. Baicalein induces CD4+ Foxp3+ T cells and enhances intestinal barrier function in a mouse model of food allergy[J]. Sci Rep,2016,6 :32225.

[20] 板本首正. 黄芩中黄芩素剂色苷酸二钠对肥大细胞脱颗 粒的抑制效果[J]. 国外医学院中医中药分册,1984,7(2):52.

[21] Ñamendys-Silva, S.A.; Santos-Martínez, L.E,Pulido T,et al. Pulmonary hypertension due to acute re-

spiratory distress syndrome [J ]. Braz J Med Biol Res. 2014,47(10):904-910.

[22] 魏泽卉. 黄芩素通过抑制血管重构改善野百合碱诱导的 大鼠肺动脉高压[D]. 太原院山西医科大学,2017.

Bupleurum Extract

The main active ingredient of bupleurum is Bupleurum saponin, which has a pronounced inhibitory effect on the influenza virus H1N1 [69]. Bupleurum extract was also shown to remedy allergic asthma [70]. It is known from the results of acute lung injury experiments that bupleurum extract reduces inflammation and the proportion of wet vs dry tissue in the lung, suggesting that inflammatory exudate and edema of the lung tissue are reduced [71]. An in vitro experiment in 2006 also showed that Bupleurum saponin can inhibit a human coronavirus 229E [72].

REFERENCES

[69] Fang W,Yang YJ,Guo BL,et al. Anti-influenza triterpenoid saponins (saikosaponins )from the roots of Bupleurum marginatum var. stenophyllum[J]. Bioorg Med Chem Lett,2017,27(8):1654-1659.

[70] Park KH,Park J,Koh D,et al. Effect of saikosaponin-A,a triterpenoid glycoside,isolated from Bupleurum falcatum on experimental allergic asthma[J]. Phytother Res,2002,16(4):359-363.

[71] Xie JY,Di HY,Li H,et al. Bupleurum chinense DC polysaccharides attenuates lipopolysaccharide-induced acute lung injury in mice [J ]. Phytomedicine,2012,19(2):130-137.

[72] Cheng PW,Ng LT,Chiang LC,et al. Antiviral effects of saikosaponins on human coronavirus 229E in vitro[J]. Clin Exp Pharmacol P,2006,33 (7):612-616.

Coptis Extract (containing 60% Berberine, the optimal amount based on our study)

Berberine is a key ingredient of Coptis, which is also known as goldthread and has a long history of use in ethnic medicines. In recent years it has been a focus area in herbal medicine research and has the potential to become one of the most important herbal supplement in the world.

 

A large body of research data is showing its effect in promoting overall wellness in many areas. For examle, a new review by Dr. Francesco Di Pierro (see reference below) on the benefits of berberine summarizes that berberine’s influence on the gut microbiome accounts for much of its health benefit, which includes promoting weight loss, lowering blood lipids and blood pressure, and improving blood sugar control. We have chosen berberine not only because of it's been a key herb for thousands of years, but also because it’s become an important part of our answer to improving health via modulating the microbiota.

REFERENCES

Impact of berberine on human gut bacteria. Di Pierro F. Nutrafoods (2018) 17:5-8.

Berberine Modulates Gut Microbiota and Reduces Insulin Resistance via the TLR4 Signaling Pathway.  Liu D, Zhang YLiu YHou LLi STian HZhao TExp Clin Endocrinol Diabetes. 2018 Sep;126(8):513-520. doi: 10.1055/s-0043-125066. Epub 2018 Jan 24.

Atractylodes (10:1 Concentrate)
 
Atractylodes is a genus of Asian flowering plants in the sunflower family. Increasingly more research data suggest the anti-inflammatory and anti-obesity activities of Atractylodis. Its rhizome was found to improve and adjust unhealthy gut flora (see reference below). In another study, astractylodes, fermented or not, exhibits marked anti-inflammatory, anti-adipogenic, and anti-obesity activities, as well as modulating the gut microbial distribution.

REFERENCES

The Metabolism of Polysaccharide from Atractylodes macrocephala Koidz and Its Effect on Intestinal Microflora.  R. Wang, G. ZhouM. WangY. Peng, and X. Li  Evid Based Complement Alternat Med. 2014; 2014: 926381.

Fermented Rhizoma Atractylodis Macrocephalae alleviates high fat diet-induced obesity in association with regulation of intestinal permeability and microbiota in rats.  Jing-Hua Wang, Shambhunath Bose, +2 authors Hojun Kim Scientific Reports 2015

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