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C.87-
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C.84-AIDS Vaccine Thai RV 144 Correlate Of Protection: Envelope gp120 V2 Loop, Which Induces Protect
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C.84-AIDS Vaccine Thai RV 144 Correlate Of Protection: Envelope gp120 V2 Loop, Which Induces Protective Neutralizing IgG Antibodies, Is A Marine Conus Mu-Conotoxin Binding To The Voltage-Gated Na+ Sodium Channel

 

Thai RV 144 vaccine efficacy is 31%; protective IgG target the gp120 V1-V2 loops. We analyse the V2 loop (Zolla-Pazner S, 2013) by Amino Acid (AA) sequences comparison by Basic Local Analysis Search Tool Protein (BLASTP) with visual search and three-dimensional (3D) structures of conotoxin (Xue T, 2003) and spider Atrax atracotoxin (Pallaghy PK, 1997). The 2 Thai vaccine strains V2 loops were screened on toxins binding to the voltage-gated Na  channel (NaCh). Result: 1) 3 mu-conotoxin active site AAs (K13, Q14, K16) (Conus Geographicus, Kinoshitai, Striatus, Betulinus chimera) (Ekberg J, 2008) are found in the Thai V2 loop (V172 crucial):

 

 

 

2) The vaccine MN strain V2 loop mimics the scorpion toxin NH2-terminus active site 1-KKEGY-5 (Kharrat R, 1989); its deletion abolishes the toxicity (El Ayeb M, 1986). Interestingly antibodies against scorpion toxin NH2-terminus 1-KKEGY-5 induce broad cross-reactive protection (Devaux C, 1996). The toxin precursor (Cn II-13, AaH, Bot IX chimera) (Possani LD, 2000) is included.

 

 

 

 

3) V2/V3 loops of HIV-2/SIV PBJ14 (fatal AIDS) were 3D superimposed on spider Atratoxin (Atx)/versustoxin, 2 NaCh ligands. Atrax Robustus is a very dangerous spider from Australia.

V2 loop YxxxWYxxDxxC is conserved in HIV-2.

V3 loop AA sequence is SGLVFH:

 

 

 

 

 

 

 

CONCLUSION

The scorpion venom concept of AIDS (Tran GMK, 1989, 1993, 1997) is confirmed by the homology between the Thai V2 loop and mu-conotoxin, a NaCh ligand. Omega-3, a NaCh modifier, is efficient in AIDS (Caprani A, 2012). AIDS vaccine should target V2/V3 loop, and avoid mitigating and deleterious IgA directd against the envelope first conserved region C1 (Haynes BF, 2012) (Tran GMK, Eur Conf Virol 2013, Lyon).

 
C.86-Breast Cancer And Virus: Molecular Homology Between Human Mammary Tumor Virus 3’Orf And Scorpio
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C.86-Breast Cancer And Virus: Molecular Homology Between Human Mammary Tumor Virus 3’Orf And Scorpion Toxin, A Ligand Of Voltage-Gated Sodium Na+ Channel. Omega 3, A Na+ Channel Modifier, Reduces The Risk Of Metastatic Breast Cancer.

Présentation Poster au 5° congress européen de virology (Lyon Septembre 2013) REF 017 Category: 03.Innate immunity against viruses


Breast cancer has multiple etiologies: Many virus were implicated [Epstein-Barr virus, Human oncogenic Papillomavirus, Adenovirus, Simian Virus 40 (SV40)]. Some discrepancies (Park DJ, 2011) can be relevant to this multiplicity of viruses. Other factors can be unrecognized: Genetics, radio-activity, aluminium, genetically modified organisms.

 

The human homologue of Mouse Mammary Tumor Virus (MMTV) (Bittner JJ, 1936), re-called

Human Mammary Tumor Virus (HMTV), was found in human Breast Cancer (BC), in variable % of cases:  74% in Tunisia, 42% in Australia, 38% in Italy, 36% in United States, 31% in Argentina, 0.8% in Vietnam (Levine PH, 2004). This geographical disparity may depend on various factors, such as the degree of mouse infection by MMTV (Stewart TH, 2000; Szabo S, 2005). The host susceptibility or resistance to MMTV is depending on the species genetic background, particularly the T Cell Receptor (TCR) Vbeta.

The MCF-7 and MDA-MB-231 breast cancer cell lines were demonstrated to be HTMV-positive (Wang Y, 1995); when injected in nude mice, they induce metastatic breast cancer (Shafie SM, 1980; Price JE, 1990). In 123 treated breast cancers, Bougnoux P (1995) found after 48 months 70% metastasis if the breast fat alpha-linolenic acid (omega-3 precursor) level was low (9% if it was high): Thus, omega-3 (18:3n-3) protects against metastasis.

 

 

As omega-3 modifies the voltage-gated Na+ channel (NaCh) (Xiao YF, 2001; Banu I, 2006), we looked for a NaCh ligand (scorpion toxin) in HMTV.

METHODS: Amino Acid (AA) sequence comparison.

RESULTS: we found a molecular homology between HMTV 3’orf and scorpion toxin chimera (Possani LD, 2000)/Euscorpius Flavicaudus (AAT76439) (58-71) implicated in development:

 

 

We demonstrated the HMTV oncogenicity by the discovery of 2 major oncogenes in the 3'ORF:

Mdm2, the p53 ligand (Tran GMK, 2004) and Notch-1 (Tran GMK, 1998). Furthermore,  MMTV is a hormonal virus, because it integrated upstream of and activated Aromatase (Int-5), the estrogen synthetase (Tekmal RR ,1997).

 

 

 

CONCLUSION

HTMV has 2 major oncogenes (mdm2, the p53 ligand, and Notch-1) and is a hormonal virus integrating upstream of and activating aromatase, the estrogen synthetase. HTMV 3’orf contains a scorpion toxin, explaining the metastasis protection conferred by omega-3, a NaCh blocker.The omega-3-rich soya diet in Asia, added to the low HTMV frequency in Asia (Japan, China, Vietnam), may explain the low asian breast cancer prevalence. We suggest to use omega-3 in association with  chemotherapy in metastatic breast cancer; and study other second generation NaCh ligands (Tran GMK, Allostery EMBO Conf 2013; Djamgoz MBA, 2006).

Green tea (Yang CS, 2010) associated with mushrooms were also very interesting alicaments (breast cancer risk reduction of 89%, with an odds ratio = 0,11 (Zhang M, 2009). Corossol (graviola) was re-assessed: It down-regulates EGFR expression (Dai Y, 2011).

BIBLIOGRAPHY

Banu I, Fraser SP, Djamgoz MBA. Docosahexaenoic acid (omega-3) blocks voltage-gated sodium channel activity and migration of MDA-MB-231 human breast cancer cells. Int J Biochem Cell Biol 2006, 38: 2173–82. Bittner JJ. Some possible side effects of nursing on the mammary tumor incidence in mice. Science. 1936, 84: 162. Bougnoux P, Lhuillery C. Acides gras polyinsaturés et cancérogenèse mammaire. In : Nutrition et cancer. CERIN Symposium, Paris, 1995: 119-32. Dai Y, Hogan S, Schmelz EM et al. Selective Growth Inhibition of Human Breast Cancer Cells by Graviola Fruit Extract In Vitro and In Vivo Involving Downregulation of EGFR Expression. Nutrition Cancer 2011, 63:795-801. Djamgoz MBA and Banu I. Dietary Compounds As Anti-cancer Agents: A Preliminary Evaluation of Ion Channels And Membrane Excitability As Possible Target Mechanisms. Turkish J Biochem 2006, 31: 57–68. El Ayeb M, Darbon H, Bahraoui EM et al. Differential effects of defined chemical modifications on antigenic and pharmacological activities of scorpion alpha and beta toxins. Eur J Biochem. 1986, 155: 289-94. Kharrat R, Darbon H, Rochat H et al. Structure/activity relationships of scorpion alpha-toxins. Multiple residues contribute to the interaction with receptors. Eur J Biochem. 1989, 181: 381-90. Levine PH, Pogo BG, Klouj A et al. Increasing evidence for a human breast carcinoma virus with geographic differences. Cancer. 2004, 101: 721-6.  Park DJ, Southey MC, Giles GG, Hopper JL. No evidence of MMTV-like env sequences in specimens from the Australian Breast Cancer Family Study. Breast Cancer Res Treat. 2011, 125: 229-35.  Possani LD, Merino E, Corona M et al. Peptides and genes coding for scorpion toxins that affect ion-channels. Biochimie. 2000, 82: 861-8. Review. Price JE, Polyzos A, Zhang RD et al. Tumorigenicity and Metastasis of Human Breast Carcinoma Cell Lines in Nude Mice. Cancer Res 1990, 50: 717-21. Shafie SM, Liotta LA. Formation of metastasis by human breast carcinoma cells (MCF-7) in nude mice. Cancer Lett. 1980, 11: 81-7. Stewart TH, Sage RD, Stewart AF et al. Breast cancer incidence highest in the range of one species of house mouse, Mus domesticus. Br J Cancer. 2000, 82: 446–51. Szabo S, Haislip AM, Garry RF. Of mice, cats, and men: Is human breast cancer a zoonosis? Microsc Res Tech. 2005, 68: 197-208. Tekmal RR, Keshava N. Role of MMTV integration locus cellular genes in breast cancer. Front Biosci. 1997, 2: d519-26. Tran MKG, Kirkiacharian S, Caprani A, Maurisson G. Molecular mimicry between HIV 1 Nef and human mdm2 ( mouse double minute 2), a ligand of p53, the major suppressor protein in oncology. XV Int AIDS Conf, Bangkok (Thailand), 2004: Abstr. WePeA5599.  Tran MKG, Kirkiacharian S. MMTV (Mouse Mammary Tumor Virus) 3'ORF mimicks the EGF family: EGF, Heregulin (c-Erb2 ligand), proto-oncogene Notch. Eurocancer 1998 (Boiron M, Marty M Ed). Paris, John Libbey Eurotext. p177 (P20). books.google.fr/books?isbn=2742002170. Tran GMK, Caprani A. Voltage-gated sodium Na+ channel allostery as the basis for the scorpion venom model of AIDS: Molecular homology between between spider toxin and HIV-2, and scorpion toxin and HIV-1 envelope gp41 sequence SWSNKS. Allostery EMBO Institut Pasteur Conf 2013, Sept 14-17, Paris. (On the site of : Positifs.org). Wang Y, Holland JF, Bleiweiss IJ et al. Detection of mammary tumor virus env gene-like sequences in human breast cancer. Cancer Res. 1995, 55: 5173-9. Xiao YF, Wright SN, Wang GK et al. Fatty acids suppress voltage-gated Na+ currents in HEK293t cells transfected with the alpha-subunit of the human cardiac Na+ channel. Proc Natl Acad Sci U S A. 1998, 9: 2680-5.  Yang CS & Wang X . Green Tea and Cancer Prevention. Nutrition Cancer 2010, 62: 931-7. Zhang M, Huang J, Xie X, Holman CD. Dietary intakes of mushrooms and green tea combine to reduce the risk of breast cancer in Chinese women. Int J Cancer. 2009, 124: 1404-8. Acknowledgements: Association Positifs.

 

 

 

 
C.85-Thai AIDS Vaccine RV 144: Molecular Homology Between HIV-1 Gp 120 Envelope First Conserved Regi
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C.85-Thai AIDS Vaccine RV 144: Molecular Homology Between HIV-1 Gp 120 Envelope First Conserved Region C1, Which Induces IgA Antibodies Increasing AIDS Risk, And The Complement Receptor CR1

Thailand RV 144 vaccine, despite gp120 V1/V2 loops neutralizing IgG, has a low 31% efficacy, mitigated by IgA antibodies against the first conserved region C1 (odds ratio 3.15) (Haynes BF, 2012). We analyse the biological significance of C1 by Basic Local Alignment Search Tool Protein (BLASTP) and visual Amino Acid (AA) sequences comparison: We screened C1 of the vaccine 2 Thailand strains and all HIV-1 strains (HIV Sequence Compendium 2012 Kuiken C, Los Alamos) on Homo Sapiens and found a molecular homology between C1 (AA 112-122) and Complement Receptor type 1 CR1 (CD35) isoform S (AA 2089-2099), in the CCP 32 [NP_000642]; the  corresponding numbering of allotype F is  AA 1639-1649, in the Sushi 25 [P17927]:
C1                                 112-WDQSL KP CVKL-122
C1 (strain CRF 37_cpx) (Powell RL, 2007) 112-WGPKL KP CVKL-122
CR1 isoform S  CCP 32              2089-WGPKL(H,P)CS RV-2099

 

 

 

Domain structure of human complement receptor CR1 and its most common cell expression profile. Human CR1 F allotype contains 30 Short Consensus Repeats (SCRs), each depicted by spheres. Indicated in red are the SCRs mediating binding to the C3b fragment (Hea JQ, 2008).

 

 

 

The tip of the complement receptor CR1 loop (Proline P2095) is read in retro inverso : 2096-(H,P)-2095, instead of 2095-PH-2096.

Such tip inversion exists: Epidermal Growth Factor (EGF) and Transforming Growth Factor-alpha (TGF-a) bind to the same EGF Receptor, despite different tip linear sequence, but in 3D have superimposed loop tip AAs (E and V):
Rat EGF          24 - E S V - 26
TGF-alpha      26 -(E,Q,V)- 24
Anti-C1 IgA harmfulness is explained by Wagner C (2006): Anti-complement receptor CR1 antibodies profoundly inhibit T cell proliferation by inhibiting Interleukin-2 (IL-2)/Interferon-gamma synthesis and IL-2 efficacy, explaining IL-2 clinical trials failure despite T4 cell rise (Pett SL, 2010). CR1 is decreased in lung tuberculosis (Senbagavalli P, 2008). It acts on macrophages and dendritic cells.

Conclusion

An AIDS vaccine must avoid anti-C1 IgA antibodies, because C1 is a molecular mimetic of CR1 and therefore the cross-reactive anti-C1 IgA are anti-CR1 auto-antibodies which profoundly inhibit T cell proliferation. These auto-antibodies could also promote lung tuberculosis. We advocate an AIDS vaccine devoid of this envelope gp120 first constant region C1 deleterious epitope to ameliorate the 31% efficacy observed with the Thai RV 144 vaccine.

An AIDS therapeutic vaccine (as was the case for Pasteur anti-rabies vaccine) would be more rapid to develop, step by step, than a classical prophylactic vaccine: The rapidity of a therapeutic vaccine is calculated in months, whereas for a prophylactic vaccine, each trial would take dozen of years. The same therapeutic vaccine, when finally successful, can be then converted in a prophylactic vaccine (following the anti-rabies vaccine example).

 

BIBLIOGRAPHY

 

Haynes BF, Gilbert PB, McElrath MJ et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med. 2012, 366: 1275-86. Hea JQ, Wiesmannb C, van Lookeren Campagnea M. A role of macrophage complement receptor CRIg in immune clearance and inflammation. Mol Immunol 2008, 45: 4041–47. HIV Sequence Compendium 2012 Kuiken C, Foley B, Leitner T, Apetrei C, Hahn B, Mizrachi I, Mullins J, Rambaut A, Wolinsky S, and Korber B, Eds. Published by Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, NM, LA-UR 12-24653.  Krych-Goldberg M, Moulds JM, Atkinson JP. Human complement receptor type 1 (CR1) binds to a major malarial adhesin. Trends Mol Med. 2002, 8: 531-7. Review. Pett SL, Kelleher AD, Emery S. Role of interleukin-2 in patients with HIV infection. Drugs. 2010 Jun 18;70(9):1115-30. Review. Powell RL, Zhao J, Konings FA et al. Circulating recombinant form (CRF) 37_cpx: an old strain in Cameroon composed of diverse, genetically distant lineages of subtypes A and G. AIDS Res Hum Retroviruses. 2007, 23: 923-33. Senbagavalli P, Geetha ST, Karunakaran K et al. Reduced erythrocyte CR1 levels in patients with pulmonary tuberculosis is an acquired phenomenon. Clin Immunol. 2008, 128: 109-15. Wagner C, Ochmann C, Schoels M et al. The complement receptor 1, CR1 (CD35), mediates inhibitory signals in human T-lymphocytes. Mol Immunol. 2006, 43: 643-51. Acknowledgements: Association Positifs.



 

 

 

 

 

 

 


 
C.83-BASES MOLECULAIRES DES « ALICAMENTS » DU CANCER DE LA PROSTATE : BLOCAGE DE NF-KB, STIMULATION
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C.83-BASES MOLECULAIRES DES « ALICAMENTS » DU CANCER DE LA PROSTATE : BLOCAGE DE NF-KB, STIMULATION DE P53 ET APOPTOSE MITOCHONDRIALE

Poster présenté à la journée  de l’ARTP du 20 novembre 2013

 

Introduction : Une alimentation anti-cancer de la prostate (KP), basée sur les mécanismes d’action moléculaires des « alicaments », renforce l’efficacité du traitement classique.

 

Methodes : Revue de la littérature, livres (David Servan-Schreiber (2010), David Khayat (2010), Denis Gingras/Richard Beliveau (2005).

 

Resultats : Le régime alimentaire du KP comprend : Thé vert, resvératrol, curcuma, jus de grenade, graines de lin, soja, sélénium, tomates cuites, algue brune, choux, alliacés, vitamine D3, café, baies de Goji, huile d’argan et sport.

Le thé vert (EGCG) inhibe NF-kB et stimule p53, est actif en clinique.

Le vin rouge (resvératrol) (1 verre/j) entraine une baisse de 40% du cancer. Il inhibe NF-kB, stimule p53, induit une apoptose et améliore la réparation des gènes.

Le curcuma (associé au poivre): L’incidence du KP est de 5/100 000 en Inde (consommation du curcuma), contre 104/100 000 aux USA (pas de consommation); la curcumine inhibe NF-kB et stimule p53.

Le jus de grenade divise par 3 la vitesse de propagation du cancer opéré en rechute.

Les graines de lin moulues ralentissent la croissance des tumeurs de 40%.

La génistéine du soja retarde la progression après traitement local, bloque la division  et stimule l’apoptose.

Le sélénium diminue de moitié les cancers (17 versus 35) sur 974 personnes.

La tomate cuite (lycopène) diminue le risque de 30%.

La fucoxanthine (algue brune) inhibe la croissance des cellules cancéreuses. Eviter les algues japonaises radio-actives.

Les crucifères [choux (sulforaphane)] sont plus efficaces que la tomate.

Les alliacés [ail (allicine, diallyl sulfide)] > 10g/j entrainent 50% moins de cancer qu’à  < 2g/j.

La vitamine D3 (2 000 UI/j) fait régresser le PSA.

Le café à fortes doses diminue de 60% le risque de KP mortel.

Les baies de Goji (Lycium Barbarum) induisent l’apoptose et inhibent la croissance d’une xénogreffe chez la souris.

L’huile d’argan (polyphénols) inhibe les cultures cellulaires de KP.

 

Conclusion: Les « alicaments » sont non toxiques, ont montré une réelle efficacité dans des études cliniques (vin rouge, jus de grenade, graines de lin, ail, soja, sélénium, tomate, café à fortes doses même décaféiné). Le mécanisme (pour le thé vert, le curcuma, le café et le vin rouge) est le blocage de NF-kB, la stimulation de p53 et l’induction de l’apoptose mitochondriale.

 

 

 

 
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