Publications

High  hopes  are placed  on the  vaccine  specifically  immunizing against  the  new  virus , but  this  vaccine  is  not  yet available and  may  be not  ready  and  accessible  to all  who  will  need it in  time.   Therefore  beside  the  usual hygiene  precautions,  I would  like  to  share   with  you  my  own  experience  to  prevent  right  now  this  infection.

     

Our mucus membranes of mouth, pharynx, throat, nose, are fragile, especially in a cold season. They are partly protected from invadors – viruses and bacteria – by the mucus produced and also by that of saliva. It is therefore necessary to salivate, especially during long lasting flights, in order to keep the mucus membranes wet. But in addition, I noticed myself that some products of natural origin were protecting me from respiratory infections.  

 

The first product   is a fermented preparation of papaya fruit extract, FPP, know  under the name of Immunage. FPP is a complex mixture of natural carbohydrates and other compounds resulting from long term yeast fermentation.

 

A number of   published  laboratory studies ( 1.) have shown that FPP has 3 main properties.  FPP is:  

    * anti-inflammatory

    * immunostimulatory, particularly at the level of mucus membranes

    * inducer of anti-oxydative enzymes. 

 

FPP is  commercially distributed as a powder in sachets of 3 gr. or 4.5 gr. For  maximal  efficacy the powder is placed under the tongue for several minutes, in order to allow dissolution by saliva, which will activate some of its  compounds and also permit per-lingual absorption. It can then be swallowed, eventually with a sip of water. 

 

 

Very simply, if one is potentially exposed to the virus, or if mild symptoms appear (possibly including swelling of mucus membranes, tickling of throat and nose), take immediately one sachet, a second one 6 hours later, and a third one before going to bed, all between meals. 

 

In  my  own  experience, symptoms  disappear very rapidly. However, it is advised to continue the same regimen at least for one week. 

There is no toxic effect and FPP can also be taken by diabetic persons.

 

The second product is a natural redox regulator compound, made of three amino-acids, glutathion. It has also detoxifying activity and is made naturally by our body. However, in case of infection or inflammation, oxidative stress consumes its active form and our  own internal production does not cope with the huge excess of harmful  oxidative molecules.  

The  best  preparation  I  know of  is  an orally absorbable form of active glutathione, complexed  with  vitamin  C. This form is now available (Ultrathione, Thyogen,  orders by internet). This product can be used jointly with FPP, reinforcing the action of the latter. 

It is also effective  in the case of persistent  fatigue, a  symptom  often occurring in seasonal flu infection. 

And  finally  it is  very appropriate to use  as  a complementary treatment of severe infections.  

Some viral strains (H5 N1, not H1 N1 so far),  possess  a  new  gene  coding for a  protein attacking a mitochondrial membrane.

As a result,  mitochondria  release  highly  toxic  oxygen  products  which  quickly  induce  the death  of macrophages, the  very first  defense  cells in  our  lungs . As  a consequence,  the  patient  may  then die of fulminant  pneumonia.      

Therefore  to  save  the  life of  patients, glutathione should  be  given  as  early   as  possible  after viral  infection   .

 

Yet  the  H1N1  virus  does  not  possess   this  nasty gene,  but  three  successive  mutations   can  make  it active. One has,  therefore,  to be   prepared  for  the  worst  .  Medical  doctors especially should  be  aware  of  the  danger  and how  to  prevent  it. 

 

The  last  product    I would  like  to mention is  alpha interferon from  leukocytes   .  Interferons  are  small  proteins produced  by the body  in  response  to  viral  infection.  They  induce  in  the  cells  not  yet  infected  a  potent  anti-viral state. They  are  part  of  the very  early  defense  against  any  kind  of  viral infection, but  the  flu virus  has  evolved to make a tricky   protein   which early  after  infection  neutralizes  the  effect  of  interferon.  In order  to counteract  the viral  protein  we  should  therefore  give  interferon  before  the  viral  infection  starts,  therefore  to individuals who  are highly  exposed  to the  virus,  for  instance  in  schools and  universities, and  public  transportation.  

 

The  interferon  already  commercialized  has  to be  injected  and  has  side  effects.   It  is  usually  used only in  severe diseases  such  as  multiple    sclerosis and  viral  hepatitis.    However,  a  small  American  biotech  company (Hemispher'x)  is making  interferons which  are  orally  active ( absorbable  under  the  tongue   like  FPP ) at  very low doses,  without inducing  side  effects. This  interferon  has  been  shown  to  protect  piglets from  death  caused  by  a virus  closely  related to  the  SARS  virus,  a  virus  different  from  influenza  virus,  but  also  causing  strong respiratory  disease. Therefore I would  advise  also to use this interferon for prevention of influenza virus infection . 

 

Of course  there  are  many more products available  with  similar properties,  but  these above  mentioned  products  I have  personally  used  for  many  years, with  excellent  results.                    

Even  when  the  vaccine  will  be  available,  these  products  can  reinforce  the specific immunity  induced  by  the vaccine .

 

In  the coming  months  I  hope  to share  with you more  helpful  information, still not very well know in the medical world . 

 

But do not forget: to prevent is always better than to cure… and good luck ! 

 

 

(1.)  Fermented Papaya Preparation as Redox Regulator in Blood Cells of B-Thalassemic Mice and     Patients 

Johnny Amer, Ada Goldfarb, Elizer A. Rachmilewitz and Eitan Fibach 

Phytotherapy research, 2008, Phytother res22; p 820-828 

 

Targeting Heat Shock Protein and Inflamatory Profile through Understanding Interleukin-6 Polymorphism 

F. Marotta, K. Koike, A. Lorenzetti, Y. Naito, F. Fayet, H. Shimizu, and P. Marandola 

 Nutraceutical Strategy in Aging, New York Academy of Sciences, 2007 

 

FPP ( Fermented Papaya Preparation) modulates Interferon-  induced Nitric Oxide production in the 

Mouse Macrophage Cell Line RAW 264.7 

Kobuchi and L. Packer  

ISSN : 1039-9712. Biochemistry and Molecular Biology Intl: 1997 Sep. 43:1, 141-52

 

Ethanol-Related Gastric Mucosal Damage: Evidence of a Free Radical-Mediated Mechanism  

and beneficial effect of oral supplementation with Fermented Papaya Preparation a Novel Natural 

Antioxidant 

F. Marotta, H. Tajiri, P. Safran, E. Fesce, G. Ideo  

ISSN: 0012-2823. Digestion 1999 ; 60 : 538-543 

 

Biological Effects of FPP (Fermented Papaya Preparation) 

Kobuchi H., Haramaki N., Marcocci L., Packer L. 

Antioxidant Food Supplement in Human Health. Academic Press. p 481-495.(1999)

 

Ferric Nitrilotriacetate Induced DNA and Protein Damage : Inhibitory Effect of a Fermented Papaya 

Preparation 

G.Rimbach, Qiong Guo, Takashi Akiyama, Seiichi Matsugo, Hadi Moini, F. Virgili, L. Packer 

ISSN : 0250-7005Anticancer Research 20 : 2907-2914 (2000)

 

Inhibition of influenza infection by glutathione. 

 

Cai J, Chen Y, Seth S, Furukawa S, Compans RW, Jones DP. 

 

Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA. jcai@learnlink.emory.edu 

 

Infection by RNA virus induces oxidative stress in host cells. Accumulating evidence suggests that cellular redox status plays an important role in regulating viral replication and infectivity. In this study, experiments were performed to determine whether the thiol antioxidant glutathione (GSH) blocked influenza viral infection in cultures of Madin-Darby canine kidney cells or human small airway epithelial cells. Protection against production of active virus particles was observed at a low (0.05-0.1) multiplicity of infection (MOI). GSH inhibited expression of viral matrix protein and inhibited virally induced caspase activation and Fas upregulation. In BALB/c mice, inclusion of GSH in the drinking water decreased viral titer in both lung and trachea homogenates 4 d after intranasal inoculation with a mouse-adapted influenza strain A/X-31. Together, the data suggest that the thiol antioxidant GSH has an anti-influenza activity in vitro and in vivo. Oxidative stress or other conditions that deplete GSH in the epithelium of the oral, nasal, and upper airway may, therefore, enhance susceptibility to influenza infection.

 

PMID: 12654482 [PubMed - indexed for MEDLINE] 

Free Radic Biol Med. 2003 Apr 1;34(7):928-36

 

Influenza A virus replication is dependent on an antioxidant pathway that involves GSH and Bcl-2. 

 

Nencioni L, Iuvara A, Aquilano K, Ciriolo MR, Cozzolino F, Rotilio G, Garaci E, Palamara AT. 

 

Department of Experimental Medicine and Biochemical Science, University of Rome La Sapienza, Italy. 

 

Growing evidence indicates that viral replication is regulated by the redox state of the host cell. We demonstrate that cells of different origins display differential permissivity for influenza A virus replication, depending on their intracellular redox power as reflected by Bcl-2 expression and glutathione (GSH) content. Bcl-2 expressing cells were found to have higher intracellular levels of GSH and to produce lower amounts of virus than Bcl-2 negative cells. Two different steps in the virus life-cycle were involved in Bcl-2/GSH mediated viral inhibition: 1) expression of late viral proteins (in particular hemagglutinin and matrix); and 2) nuclear-cytoplasmic translocation of viral ribonucleoproteins (vRNPs). Buthionine-sulfoximine-induced inhibition of GSH synthesis in Bcl-2 expressing cells caused an increase in the expression of late viral proteins but did not restore vRNP export to the cytoplasm. Collectively, our findings show that both Bcl-2 expression and GSH content contribute to the host cell's ability to down-regulate influenza virus replication, although their effects are exerted at different stages of the viral life-cycle. In certain cell populations, this form of down-regulation might conceivably favor the establishment of persistent viral infection. 

 

FASEB J. 2003 Apr;17(6):758-60. Epub 2003 Fe

 

3. Alterations in antioxidant defences in lung and liver of mice infected with influenza A virus. 

 

Hennet T, Peterhans E, Stocker R. 

 Institute of Veterinary Virology, University of Berne, Switzerland. 

 

We investigated the possible involvement of oxidative mechanisms in the pathogenesis of influenza A/PR8/34 virus infection in mice. As a biochemical marker of oxidative stress, we determined the endogenous concentrations of the antioxidants glutathione and vitamins C and E in their reduced and oxidized forms in the lungs, liver and blood plasma of control and infected animals. Following intranasal infection with 8 to 10 LD50, influenza virus was detected in the lungs, but not in the plasma, liver or other organs. Infection resulted in a decrease in the total concentration of glutathione and vitamins C and E, whereas no relevant change in the ratio of oxidized to total concentration of antioxidants was observed. Changes in the concentration of hepatic antioxidants were significant in the early stages of the infection. The results suggest that hepatic alterations may be caused indirectly by mechanisms related to the host response to virus infection. The observed general decrease in the antioxidant buffering capacity may reduce the ability of tissues to protect against potential oxidative stress. Such stress can occur during bacterial superinfections, which are common in influenza, thereby rendering the host more susceptible to the pathogenic effects of such agents. In addition, reactive oxygen species produced in the lung may inactivate protease inhibitors, resulting in increased protease activity. Using an in vitro system consisting of alpha 1-antiprotease, trypsin and HOCl as the oxidant, we have shown that the infectivity of influenza viruses can be increased up to 10,000-fold by proteolytic cleavage of haemagglutinin, leading to activation of the fusogenic properties of this protein. 

 

PMID: 1530963 [PubMed - indexed for MEDLINE]

J Gen Virol. 1992 Jan;73 ( Pt 1):39-46.

 

5. Expression of influenza virus hemagglutinin activates transcription factor NF-kappa B. 

 

Pahl HL, Baeuerle PA.  

Biochemical Institute, University of Freiburg, Germany. 

 

Influenza virus infection initiates transcription of a variety of genes for cytokines such as tumor necrosis factor alpha (TNF-alpha), TNF-beta, interleukin 1 alpha, (IL-1 alpha), IL-1 beta, IL-2, IL-4, IL-6, IL-10, granulocyte macrophage colony-stimulating factor, and gamma interferon. However, the mechanism by which virus infection elicits cytokine expression remains unknown. Six influenza virus-induced cytokine genes are targets for the inducible transcription factor NF-kappa B, a central regulator of the human immune response. Here, we show that expression of a single influenza virus protein, the virion surface hemagglutinin, strongly activates NF-kappa B DNA binding and transactivation. Activation is inhibited in the presence of the antioxidant dithiothreitol, suggesting that, similar to the findings for previously described inducers of NF-kappa B, hemagglutinin expression generates radical oxygen intermediates which activate the transcription factor. Hemagglutinin is the first secretory and structural viral protein reported to activate NF-kappa B and thus represents a new class of inducers for this transcription factor. We discuss these results in the context of clinical complications of influenza virus infection. 

 

PMID: 7853480 [PubMed - indexed for MEDLINE]

J Virol. 1995 Mar;69(3):1480-4.

 

Influenza virus-induced NF-kappaB-dependent gene expression is mediated by overexpression of viral proteins and involves oxidative radicals and activation of IkappaB kinase. 

 

Flory E, Kunz M, Scheller C, Jassoy C, Stauber R, Rapp UR, Ludwig S. 

 

Institut fur Medizinische Strahlenkunde und Zellforschung (MSZ), Universitat Wurzburg, Versbacherstr. 5, D-97078 Wurzburg, Germany. 

 

Influenza A viruses are capable of inducing the expression of a variety of cytokine and proapoptotic genes in infected cells. The promoter regions of most of these genes harbor binding sites for the transcription factor NF-kappaB which is an important mediator of immune and inflammatory responses. Our present study is based on an observation that influenza A virus infection of cells stimulates transcriptional activation of the HIV-1 long terminal repeat (LTR) which harbors two regulatory NF-kappaB elements, and is aimed at identifying the molecular mechanisms involved in this process. We found that the expression of influenza virus hemagglutinin (HA), matrix protein (M), and nucleoprotein (NP), as single factors is sufficient to transcriptionally activate the HIV-1 LTR. This process is mediated by oxidative radicals because treatment of cells with pyrrolidine dithiocarbamate, a scavenger of such radicals, abolished the transactivating ability. Expression of different influenza proteins induces activation of NF-kappaB-dependent gene expression but not transcriptional activation of an AP-1/Ets-dependent promoter, indicating a selectivity for NF-kappaB transactivation. Furthermore, influenza protein expression induces activation of IkappaB kinase (IKK). Accordingly coexpression of a catalytically inactive mutant of IKK abolishes influenza protein induced activation of NF-kappaB as well as HIV-1 LTR-dependent reporter gene expression, suggesting that IKK is an important intermediate within this signaling process. Taken together, our results show that various influenza virus proteins act as viral transactivators to modulate transcriptional activity of kappaB-element harboring promoters such as the HIV-LTR. 

 

PMID: 10722660 [PubMed - indexed for MEDLINE]  

J Biol Chem. 2000 Mar 24;275(12):8307-14.

 

Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? 

 

Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, Gordon S, Guan Y, Peiris JS. 

 

Department of Microbiology, University of Hong Kong, Queen Mary Hospital, SAR, Hong Kong, China. 

 

BACKGROUND: In 1997, the first documented instance of human respiratory disease and death associated with a purely avian H5N1 influenza virus resulted in an overall case-fatality rate of 33%. The biological basis for the severity of human H5N1 disease has remained unclear. We tested the hypothesis that virus-induced cytokine dysregulation has a role. METHODS: We used cDNA arrays and quantitative RT-PCR to compare the profile of cytokine gene expression induced by viruses A/HK/486/97 and A/HK/483/97 (both H5N1/97) with that of human H3N2 and H1N1 viruses in human primary monocyte-derived macrophages in vitro. Secretion of tumour necrosis factor alpha (TNF alpha) from macrophages infected with the viruses was compared by ELISA. By use of naturally occurring viral reassortants and recombinant viruses generated by reverse genetic techniques, we investigated the viral genes associated with the TNF-alpha response. FINDINGS: The H5N1/97 viruses induced much higher gene transcription of proinflammatory cytokines than did H3N2 or H1N1 viruses, particularly TNF alpha and interferon beta. The concentration of TNF-alpha protein in culture supernatants of macrophages infected with these viruses was similar to that induced by stimulation with Escherichia coli lipopolysaccharide. The non-structural (NS) gene-segment of H5N1/97 viruses contributed to the increase in TNF alpha induced by the virus. INTERPRETATION: The H5N1/97 viruses are potent inducers of proinflammatory cytokines in macrophages, the most notable being TNF alpha. This characteristic may contribute to the unusual severity of human H5N1 disease. 

 

PMID: 12480361 [PubMed - indexed for MEDLINE]

Lancet. 2002 Dec 7;360(9348):1831-7.

 

 

Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. 

 

Chan MC, Cheung CY, Chui WH, Tsao SW, Nicholls JM, Chan YO, Chan RW, Long HT, Poon LL, Guan Y, Peiris JS. 

 

Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region of China. mchan@hkucc.hku.hk 

 

BACKGROUND: Fatal human respiratory disease associated with influenza A subtype H5N1 has been documented in Hong Kong, and more recently in Vietnam, Thailand and Cambodia. We previously demonstrated that patients with H5N1 disease had unusually high serum levels of IP-10 (interferon-gamma-inducible protein-10). Furthermore, when compared with human influenza virus subtype H1N1, the H5N1 viruses in 1997 (A/Hong Kong/483/97) (H5N1/97) were more potent inducers of pro-inflammatory cytokines (e.g. tumor necrosis factor-a) and chemokines (e.g. IP-10) from primary human macrophages in vitro, which suggests that cytokines dysregulation may play a role in pathogenesis of H5N1 disease. Since respiratory epithelial cells are the primary target cell for replication of influenza viruses, it is pertinent to investigate the cytokine induction profile of H5N1 viruses in these cells. METHODS: We used quantitative RT-PCR and ELISA to compare the profile of cytokine and chemokine gene expression induced by H5N1 viruses A/HK/483/97 (H5N1/97), A/Vietnam/1194/04 and A/Vietnam/3046/04 (both H5N1/04) with that of human H1N1 virus in human primary alveolar and bronchial epithelial cells in vitro. RESULTS: We demonstrated that in comparison to human H1N1 viruses, H5N1/97 and H5N1/04 viruses were more potent inducers of IP-10, interferon beta, RANTES (regulated on activation, normal T cell expressed and secreted) and interleukin 6 (IL-6) in primary human alveolar and bronchial epithelial cells in vitro. Recent H5N1 viruses from Vietnam (H5N1/04) appeared to be even more potent at inducing IP-10 than H5N1/97 virus. CONCLUSION: The H5N1/97 and H5N1/04 subtype influenza A viruses are more potent inducers of proinflammatory cytokines and chemokines in primary human respiratory epithelial cells than subtype H1N1 virus. We suggest that this hyper-induction of cytokines may be relevant to the pathogenesis of human H5N1 disease. 

 

PMID: 16283933 [PubMed - in process

Respir Res. 2005 Nov 11;6:135.

 

Oxidation of a critical thiol residue of the adenine nucleotide translocator enforces Bcl-2-independent permeability transition pore opening and apoptosis. 

 

Costantini P, Belzacq AS, Vieira HL, Larochette N, de Pablo MA, Zamzami N, Susin SA, Brenner C, Kroemer G. 

 

Centre National de la Recherche Scientifique, ERS 1984, 19 rue Guy Moquet, F-94801 Villejuif, France. 

 

Mitochondrial membrane permeabilization is a critical event in the process leading to physiological or chemotherapy-induced apoptosis. This permeabilization event is at least in part under the control of the permeability transition pore complex (PTPC), which interacts with oncoproteins from the Bcl-2 family as well as with tumor suppressor proteins from the Bax family, which inhibit or facilitate membrane permeabilization, respectively. Here we show that thiol crosslinking agents including diazenedicarboxylic acid bis 5N, N-dimethylamide (diamide), dithiodipyridine (DTDP), or bis-maleimido-hexane (BMH) can act on the adenine nucleotide translocator (ANT), one of the proteins within the PTPC. ANT alone reconstituted into artificial lipid bilayers suffices to confer a membrane permeabilization response to thiol crosslinking agents. Diamide, DTDP, and BMH but not tert-butylhydroperoxide or arsenite cause the oxidation of a critical cysteine residue (Cys 56) of ANT. Thiol modification within ANT is observed in intact cells, isolated mitochondria, and purified ANT. Recombinant Bcl-2 fails to prevent thiol modification of ANT. Concomitantly, a series of different thiol crosslinking agents (diamide, DTDP, and BMH, phenylarsine oxide) but not tert-butylhydroperoxide or arsenite induce mitochondrial membrane permeabilization and cell death irrespective of the expression level of Bcl-2. These data indicate that thiol crosslinkers cause a covalent modification of ANT which, beyond any control by Bcl-2, leads to mitochondrial membrane permeabilization and cell death. 

 

PMID: 10645010 [PubMed - indexed for MEDLINE] 

Oncogene. 2000 Jan 13;19(2):307-14.