PI3K koronavirusten toimintakentässä . Nykylääkkeistä COVID-19 taudissa.

•  PMC full text:

  J Exp Clin Cancer Res. 2020; 39: 86.

  Published online 2020 May 12. doi: 10.1186/s13046-020-01590-2

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  Drugs interfering with signal transduction and/or bioenergetics pathways

  Rapamycin and derivatives

  Rapamycin (sirolimus) has a long history of repositioning. It was first used as an antifungal, followed by an immunosuppressive agent in organ-transplanted patients and, more recently, also as an anticancer agent [2, 10]. Its cellular target has been named mTOR (mammalian Target Of Rapamycin) after the name of the compound itself, showing specific activity toward the mTORC1 complex [11]. Rapamycin is also effective in the therapy of the autoimmune lymphoproliferative syndrome [12]. Rapamycin decreases mTOR phosphorylation (mTORC1) [13], causing a downstream perturbation of this signal transduction pathway. The consequent catabolic inhibition and ATP shortage evokes the activation of AMPK [14] and of its substrate ACACA, promoting autophagy, a physiological procedure through which cells recycle old organelles or damaged proteins in order to provide an alternative energy supply [15, 16].
  mTOR inhibition counteracts viral replication and improves outcomes in patients infected by Andes virus [17], HCV [18], Middle-East respiratory syndrome coronavirus (MERS-CoV) [19] and H1N1 pneumonia [20]. In addition, rapamycin (alone or in combination with actinomycin D) has been recently proposed to interfere with the SARS-CoV-2 interactome in a systems pharmacology-based network medicine platform [5]. As specified above, rapamycin also presents immunosuppressant activity, which could be relevant in mitigating the SARS-CoV-2-induced inflammatory response.
  There are some rapamycin derivatives available, e.g. temsirolimus, everolimus and ridaforolimus, which display slightly different pharmacokinetic characteristics and may be worth evaluation in the treatment for COVID-19. Among these, ridaforolimus has been tested in phase II clinical trial compared with progestin or investigator choice chemotherapy in advanced endometrial carcinoma showing encouraging results, but elevated toxicity, confirming the significance of the mTOR pathway in these neoplasms [21].
  

  Chloroquine and hydroxychloroquine

  Chloroquine (CQ) is a drug characterized by several decades of clinical use due to its well-renowned preventive and curative antimalarial activity. More recently, CQ has attracted the oncologists for its ability of interfering with the late stages of autophagy, by producing cytoplasmic accumulation of non-functional autophagic vesicles [22]. Both normal and cancer cells utilize autophagy for energetic purposes, but cancer cells, due to their higher energy requirements, rely more actively on autophagy, especially after being stressed by radio- or chemotherapy [23,24,25]. Therefore, the association of first-line therapeutic approaches in cancer patients with autophagy inhibitors has been largely investigated [26, 27] and suggested [26,27,28] and clinically investigated in clinical trials, mainly in CNS tumors [29,30,31].
  CQ also possesses broad anti-infective and anti-viral properties [32], especially against flaviviruses, retroviruses and coronaviruses [33]. Indeed, CQ can interfere with sialic acid biosynthesis, compromising the post-translational modifications of the transmembrane viral binding proteins [34, 35], thus impairing viral penetration inside the cell. Indeed, interaction between SARS-CoV-2 and the membrane receptor angiotensin-converting enzyme 2 (ACE2), maximally expressed in lung alveolar epithelial cells, enterocytes of the small intestine, Leydig cells and Sertoli cells, strongly depends upon glycosylation [36]. CQ also induces alkalization of endosomes, thus inhibiting endocytosis of the viral particles and their enzymatic degradation by proteases [37,38,39], an essential step for the release of functional viral nucleic acid [33]. Furthermore, CQ improves viral antigen presentation and thus enhances T-cell-mediated immunity [40].
  Another major advantage of CQ is its ability to modulate the inflammatory response and reduce the synthesis of pro-inflammatory cytokines. This molecule has been used since decades in the treatment of abnormal inflammatory responses (sarcoidosis) and autoimmune disorders (rheumatoid arthritis; lupus erythematosus). The ability of CQ to reduce cytokine immune response [41] could be functional in governing the cytokine storm associated with COVID-19 [42].
  A mechanism similar to the one described for the inhibition of the autophagosomes could be speculated to impair formation and release of virion-containing vesicles by infected cells.
  Very recently, CQ has been used in COVID-19 therapy at the dose of 500 mg/day with favorable results [39], butother studies demonstrate high toxicity and scarce effect of either CQ [43] or its analogue hydroxychloroquine (HCQ) [44, 45] in treating patients with severe COVID-19.
  Since autophagy is regulated by the interplay between mTOR [46] and AMPK [15], the use of CQ in combination with drugs able to interfere with these pathways should be carefully evaluated.
  CQ has a well-known safety profile, but it is associated with toxic retinopathy, renal and cardiac toxicity, which occur when the safe dose is exceeded. HCQ possesses slightly different pharmacokinetic properties and displays less overall toxicity. HCQ is commercially available worldwide, which it is not the case for CQ, whose distribution has been discontinued in some countries [47]. Both CQ and HCQ are being considered for use to preventing COVID-19 in SARS-CoV-2 post-exposure and long-term prophylaxis [48]
• SI113 is a small molecule able to inhibit the activity of SGK1, an AKT-related kinase involved in the PI3K/mTOR pathway and in EMT [49]. This kinase plays a pivotal role in cancer proliferation and drug resistance [49, 50] and is sensitive to the small molecule SI113 [51], which is thus able to inhibit cancer cell growth in vitro and in vivo [52, 53] via a multifaceted mechanism of action, including inhibition of the PI3K/mTOR pathway and stimulation of autophagy [54].
  Infection by MERS-CoV, a cognate of SARS-CoV-2, induces a massive inflammatory response, possibly related with fibrosis, mainly via the upregulation of the T helper (Th) 1 and Th17 cells [55]. Of note, IL-17-producing Th cells are induced by the activity of SGK1 [56]. Additionally, experimental models of inflammatory bowel disease showed the role of Th17 and SGK1 as mediators of the Th17 switch [57]. Therefore, SI113 could deserve evaluation in the prevention of the cytokine storm-induced lung fibrosis.
  It should be noted that SI113 has never been used in humans, but it is effective in reducing tumor growth in cancer-bearing mice, appearing also well tolerated and non-toxic [52, 53]. Thus, SI113 cannot be considered a repurposed drug, although preclinical models indicate it as potentially effective in COVID-19 therapy. We included this drug in the present manuscript for the sake of completeness.
  

  Immunomodulatory medications

  Tocilizumab

  This compound is a humanized monoclonal antibody (MoAb) targeting interleukin-6 receptor (IL-6R). Pharmacology, pharmacokinetics, clinical efficacy, safety, and role of tocilizumab in rheumatoid arthritis (RA) are well-established [58] and possibly due also to its effect on the AKT/mTOR pathway [59]. Tocilizumab has also been approved for the treatment of the cytokine storm associated with cancer immunotherapy [60] or, more often, with CAR-T therapy [61, 62]. This MoAb does not have direct antiviral effects, but effectively contrasts the massive cytokine release syndrome displayed in severe COVID-19 by antagonizing the binding of IL-6, one of the cytokines most involved in this process, to its receptor [58]. After the first report of the effectiveness of tocilizumab in restraining the cytokine storm deriving from SARS-CoV-2 infection [63], this drug is currently under evaluation in a multicenter phase II clinical investigation in Italy on its efficacy and safety in patients with COVID-19 pneumonia [64]. The FDA has approved a phase III randomized, double-blind, placebo-controlled study to assess the effectiveness of tocilizumab in hospitalized patients with severe COVID-19 pneumonia [65]; in addition an increasing number of clinical trials involving the use of this drug in the treatment of COVID-19 are ongoing (https://clinicaltrials.gov/).
  

  Sarilumab and Emapalumab

  Sarilumab is an anti-IL-6Rα MoAb approved for moderate-to-severe rheumatoid arthritis [66] with a well-defined role also in blocking IL-6 action in cancer [67],while emapalumab, directed toward interferon (IFN)-γ, is used in the therapy of hemophagocytic lymphohistiocytosis [68, 69] and is employed in combination with anakinra, an IL-1R antagonist, in RA patients [70]. As tocilizumab, also sarilumab and emapalumab can effectively counteract the massive cytokine release related with SARS-CoV-2 infection. Agenzia Italiana del Farmaco (AIFA) approved the use of either sarilumab or emapalumab in phase II–III clinical studies involving hospitalized patients with COVID-19 pulmonary complications, with the aim to counteract the cytokine storm [64].
  

  Monalizumab

  Monalizumab is a MoAb directed toward NKG2A (CD94), a receptor for the recognition of MHC class I HLA-E molecules. NKG2A is gaining relevance as a key player in cancer-mediated immune checkpoint blockade and its neutralization by monalizumab restores the host immune response toward cancer [71]. Monalizumab is under clinical investigation in advanced gynecologic malignancies [72]. Interestingly, NKG2A appears overexpressed in cytotoxic T lymphocytes and natural killer cells in SARS-CoV-2-infected patients [73, 74], where it may reestablish the host immune response and increase survival in patients with severe pneumonia.
  

  Bacillus Calmette-Guérin

  Bacillus Calmette-Guérin (BCG), an invaluable tool for vaccination against tuberculosis, has been widely used as a concomitant therapeutic approach for lung cancer [75], and is considered as an overall protection from lung cancer incidence [76]. More recently, BCG has been successfully used for the local treatment of intermediate/high-risk bladder cancer [77].
  BCG presents recognized immunomodulatory properties [78] and is associated with reduced risk of asthma [79]. Immunization via BCG provides relief from airway inflammation through the inhibition of a TGF-β1-mediated epithelial-to-mesenchymal transition (EMT), inhibiting the related remodeling of the respiratory tract accompanied with loss of lung epithelial integrity and fibrotic evolution [80]. In the COVID-19 setting, epithelial integrity of the respiratory tract is fundamental, since permanent lung fibrosis is a serious risk for severe and critically severe COVID-19 survivors [42]. Therefore, BCG might reduce the risk of severe disease progression and potentially reduce the mortality and disability rate.
  

  Antiviral compounds

  Clearly, some of the drugs under consideration for repurposing for COVID-19 therapy are antiviral compounds, usually nucleoside analogues, i.e., small molecules mimicking ribonucleosides or deoxyribonucleosides able to inhibit viral replication after being incorporated within the viral nucleic acid sequence. These drugs have been used since decades as antivirals, although their clinical efficacy is often associated with the onset of drug resistance. Some antiviral drugs show interesting anticancer properties, being effective in inhibiting important signal transduction pathways, in vitro and in vivo [81, 82].
  

  Lopinavir plus ritonavir

  The association of the protease inhibitors lopinavir and ritonavir is an approved treatment for HIV treatment. It is effective in restraining the growth of urological malignancies in vitro, where induces endoplasmic reticulum stress, mTOR inactivation and AMPK boosting [83]. The same drug combination has been also evaluated in the treatment of cervical cancer patients [84].
  The association between lopinavir and ritonavir is effective in reducing the risk of adverse clinical outcomes and viral load in SARS patients [85]. On these bases, this cocktail has been proposed for the treatment of COVID-19, but a very recent clinical trial showed no benefits in adult patients with severe disease [86].
  

  Ribavirin

  This drug is a guanosine analogue and RNA synthesis inhibitor successfully employed in the therapy chronic hepatitis C virus (HCV) infection [87]. As far as cancer is concerned, this compound induces GTP depletion in HeLa cervical cancer cells [88] and is effective in inhibiting glioblastoma growth in vitro and in vivo in preclinical models [81]. Along this line, the efficacy of ribavirin in the oncological setting is being investigated in ongoing clinical trials in acute myeloid leukemia, oropharyngeal squamous cell carcinoma, and breast cancer [89]. Ribavirin is also endowed with COVID-19 anti-RNA-dependent RNA polymerase (RdRp) activity [4]. Clinical trials are ongoing, based upon available data regarding dosage and toxicity derived from broad experience on the use of this drug as an anti- HCV compound.
  

  Remdesivir

  This compound is not cancer-related, but deserves to be mentioned as a paradigmatic case of effective repositioning. It is a prodrug of an adenine analogue, thus a viral RNA polymerase inhibitor, used during the Ebola outbreak [90]. Remdesivir has been found effective in vitro against SARS-CoV-2 infection when administered in concomitance with the antimalarial CQ (see above) [91] and in vivo in a primate model (rhesus macaque), either as prophylaxis or therapy of MERS-CoV infection [92]. Presently, clinical trials on remdesivir in COVID-19 are enrolling patients and are supported by the National Institutes of Health (NIH) [93], USA and AIFA, Italy [64]. Compassionate use of remdesivir in COVID-19 patients in a single-arm clinical trial gave positive preliminary outcomes [94], which appear in contrast with the results published by another group [95]. While the debate over the efficacy of this drug is still open, according to the preliminary results reported in the ACTT NIH clinical trial [93], the FDA has given remdesivir an emergency use authorization restricted to patients affected by severe COVID-19 [96].
  

  Conclusions

  COVID-19: a lesson to be learned. The SARS-CoV-2 pandemic has been generated by a new strain of the coronavirus that has never previously been identified in humans. This virus is phylogenetically close to SARS-CoV, the causative agent of SARS. SARS-CoV-2, which reached humans via a spillover process from other animal species, possesses a peculiar tropism for the airway epithelium in humans, showing also elevated contagiousness and an extremely variable clinical course of its infection.
  The COVID-19 outbreak found the world definitely unprepared to handle such a global emergency. Similar concerns must be raised toward a potential novel strain possibly responsible for future viral outbreaks, in order not to replicate the extremely negative outcome of the influenza A H1N1 1918–1919 “Spanish” pandemic [97]. To this end, it is mandatory to work prospectively to produce or identify better antiviral drugs and prophylactic/therapeutic MoAb therapies, as well as possibly targeting vital pathogenic factors, such as, in the case of SARS-CoV-2, Spike protein RBD [36, 98] or the main protease M^pro [99] (nsp5). In addition, a study on the immune response of patients that have recovered from SARS-CoV-2 infection could be of great interest, in line with what was carried out for the Ebola survivors [100].
  The forcedly limited number of drugs briefly described in this review appear to act essentially through selected mechanisms, i.e.,
  a)  inhibition of the PI3K/AKT–SGK1/mTOR signaling cascade;
   b) inhibition of the cytokine storm; and
  c) inhibition of viral nucleic acid synthesis.
  The activation of the PI3K/AKT–SGK1/mTOR pathway appears fundamental for supporting the replication of various virus species in the host [17,18,19,20] by boosting their energy metabolism and reactive oxygen species production, especially in the cells of the immune system [101, 102].
   Therefore, drugs able to interfere with mTORC1 signaling can produce ATP shortage in the cells in which the virus is replicating, characterized by an excess of energy requirements. Such a metabolic pattern is reminiscent of the peculiar setup of the energy metabolism in cancer cells, i.e. Warburg effect [103, 104], where a pivotal role is played by the PI3K/AKT–SGK1/mTOR signaling cascade [10, 105, 106].
  Given the above, it is not surprising that all the non-specific antiviral drugs here described, i.e. the anticancer drugs repositionable in COVID-19 therapy deal with energy metabolism and inflammation.
  A set of the drugs described here, e.g. those with explicit antiviral effect, can be preferred for the early stages of SARS-CoV-2 infection, 
    while those dedicated to restraining the cytokine response – and without explicit antiviral effect - should be employed, if necessary, at later time points.
  Anyway, we should always consider that, even if the medications discussed in this review are safely in use in the clinics, the final decision for their administration in COVID-19 for compassionate and urgent use, when in the absence of validated clinical trials, should be taken solely after collegial approval by the clinical team taking care of the patient and under strict clinical surveillance.
   Indeed, unpredictable toxic side effects can arise, possibly linked with the patient clinical status or to the simultaneous administration of other drugs.
  Finally, an interesting evaluation on how COVID-19 pandemic will affect the clinical care in the seven comprehensive cancer centers of Cancer Core Europe is discussed in a timely paper [107]. The authors illustrate appropriate guidelines that can transform this pandemic into an opportunity, e.g. for the assessment of the clinical effects of de-escalating anticancer regimens, forcedly imposed in order to prevent or reduce iatrogenic neutropenia and lymphopenia.
  We hope that these findings may pave the way for a more comprehensive clinical experimentation on repurposing of ‘old’ drugs to the treatment of COVID-19, a line of research sustained by scant funds but of prime importance to face this new worldwide challenge.

HIV-1 myös näytttää kaapanneen myös IP6

• VIRUSES
  
   2018 Nov 15;10(11):640. doi: 10.3390/v10110640.
  

  IP6 Regulation of HIV Capsid Assembly, Stability, and Uncoating

  
  

  
  

  Robert A Dick  ¹ , Donna L Mallery  ² , Volker M Vogt  ³ , Leo C James  ⁴

  PMCID: PMC6267275
  DOI: 10.3390/v10110640
  Free PMC article
  
   Structures of immature EIAV Gag lattices reveal a conserved role for IP6 in lentivirus assembly.
  

  Dick RA, Xu C, Morado DR, Kravchuk V, Ricana CL, Lyddon TD, Broad AM, Feathers JR, Johnson MC, Vogt VM, Perilla JR, Briggs JAG, Schur FKM. PLoS Pathog. 2020 Jan 27;16(1):e1008277. doi: 10.1371/journal.ppat.1008277. eCollection 2020 Jan. PMID: 31986188 Free PMC article.
   
• Inositol phosphates are assembly co-factors for HIV-1.
  

  Dick RA, Zadrozny KK, Xu C, Schur FKM, Lyddon TD, Ricana CL, Wagner JM, Perilla JR, Ganser-Pornillos BK, Johnson MC, Pornillos O, Vogt VM. Nature. 2018 Aug;560(7719):509-512. doi: 10.1038/s41586-018-0396-4. Epub 2018 Aug 1. PMID: 30069050 Free PMC article. Abstract
  

  A short, 14-amino-acid segment called SP1, located in the Gag structural protein¹, has a critical role during the formation of the HIV-1 virus particle. During virus assembly, the SP1 peptide and seven preceding residues fold into a six-helix bundle, which holds together the Gag hexamer and facilitates the formation of a curved immature hexagonal lattice underneath the viral membrane^2,3. Upon completion of assembly and budding, proteolytic cleavage of Gag leads to virus maturation, in which the immature lattice is broken down; the liberated CA domain of Gag then re-assembles into the mature conical capsid that encloses the viral genome and associated enzymes. Folding and proteolysis of the six-helix bundle are crucial rate-limiting steps of both Gag assembly and disassembly, and the six-helix bundle is an established target of HIV-1 inhibitors^4,5. Here, using a combination of structural and functional analyses, we show that inositol hexakisphosphate (InsP6, also known as IP₆) facilitates the formation of the six-helix bundle and assembly of the immature HIV-1 Gag lattice. IP₆ makes ionic contacts with two rings of lysine residues at the centre of the Gag hexamer. Proteolytic cleavage then unmasks an alternative binding site, where IP₆ interaction promotes the assembly of the mature capsid lattice. These studies identify IP₆ as a naturally occurring small molecule that promotes both assembly and maturation of HIV-1.
  
• IP6 is an HIV pocket factor that prevents capsid collapse and promotes DNA synthesis.
  

  Mallery DL, Márquez CL, McEwan WA, Dickson CF, Jacques DA, Anandapadamanaban M, Bichel K, Towers GJ, Saiardi A, Böcking T, James LC. Elife. 2018 May 31;7:e35335. doi: 10.7554/eLife.35335. PMID: 29848441 Free PMC article Abstract
  

  The HIV capsid is semipermeable and covered in electropositive pores that are essential for viral DNA synthesis and infection. Here, we show that these pores bind the abundant cellular polyanion IP₆, transforming viral stability from minutes to hours and allowing newly synthesised DNA to accumulate inside the capsid. An arginine ring within the pore coordinates IP₆, which strengthens capsid hexamers by almost 10°C. Single molecule measurements demonstrate that this renders native HIV capsids highly stable and protected from spontaneous collapse. Moreover, encapsidated reverse transcription assays reveal that, once stabilised by IP₆, the accumulation of new viral DNA inside the capsid increases >100 fold. Remarkably, isotopic labelling of inositol in virus-producing cells reveals that HIV selectively packages over 300 IP₆ molecules per infectious virion. We propose that HIV recruits IP₆ to regulate capsid stability and uncoating, analogous to picornavirus pocket factors. HIV-1/IP₆/capsid/co-factor/reverse transcription.
  
• Multiple Roles of HIV-1 Capsid during the Virus Replication Cycle.
  

  Novikova M, Zhang Y, Freed EO, Peng K. Version 2. Virol Sin. 2019 Apr;34(2):119-134. doi: 10.1007/s12250-019-00095-3. Epub 2019 Apr 26. PMID: 31028522 Free PMC article. Review.Abstract
  

  Human immunodeficiency virus-1 capsid (HIV-1 CA) is involved in different stages of the viral replication cycle. During virion assembly, CA drives the formation of the hexameric lattice in immature viral particles, while in mature virions CA monomers assemble in cone-shaped cores surrounding the viral RNA genome and associated proteins. In addition to its functions in late stages of the viral replication cycle, CA plays key roles in a number of processes during early phases of HIV-1 infection including trafficking, uncoating, recognition by host cellular proteins and nuclear import of the viral pre-integration complex. As a result of efficient cooperation of CA with other viral and cellular proteins, integration of the viral genetic material into the host genome, which is an essential step for productive viral infection, successfully occurs. In this review, we will summarize available data on CA functions in HIV-1 replication, describing in detail its roles in late and early phases of the viral replication cycle.
  
• Revisiting HIV-1 uncoating.
  

  Arhel N. Retrovirology. 2010 Nov 17;7:96. doi: 10.1186/1742-4690-7-96. PMID: 21083892 Free PMC article. Review.

See all similar

IP6 voi imeytyä ihovoiteesta kehoon.

Harvinainen tgapa saada klehtoon  antioksidanttista edullista ja erittäin  välttämätöntä molekyyliä.
Ihovoiteen kauta  voi inositolihexafosfaattimuotoa  imeytyä havaittavia määriä. tämä  voisi olla ratkaisu  esim iäkkäiden henkilöiden   IP6- pitoisuuksein korjaamiseen kehossa. esim aivojen elektrisessä toiminnan ja betasolun  perusoskillatorisessa piirteessä  on IP6/IP3 suhteella merkitystä, sillä  ne autavat generoimaan basaalista oskillaatiota, , joka muuten  jo tyypin II diabeteksesa on kadonnut betasolulta.  Tällainen hyvin olennainen ja selektiivinen järjestelmä   elektrisesti ärtyville soluille joissa  pitää olla perusoskillaatio olemassa, on  vaikea palauttaa jos se  menee pois jenkoiltaan.  Siihen tarvitsee  strategista ajattelua ja tietämystä. fosfoinsotidikaskadista ja  niitten  järjestelmistä eri kudoksissa. Dieetillä ja ltahdonalaisella iikunnalla  ja toiminnalla on  tärkeä osuus.  Muta  jos nyt on mahdollsita saada IP6 ylävirran mutooa kehoon  ihovoiteena,  sitä tietä tulisi hydöyntää esim  vanhuksille, jotka eivtä pysty syömään  jyviä ja pähkinöitä ja muuta sellaista mistä fytiiniä nyt saa hgyvin ja  jos  suoliston toiminanssakin on jotain  hankaluuyksia,  ihon kauta voisi jokin  hyötyhippu tätä antioksidanttia  päästä  kehoon. Sen IP6 muoto on se, millä keho poistaa munuyaisista  ylimäärästä fosfaattia.  Tämä   tutkimus ei kuitenkaan selvittänyt  inkorporoituuko  ihon IP6  yleiseen inositoliaineenvaihduntaan vai erittyykö se suoraan pois munuaisista.  RAvintote4itse tullut fytiini IP6 pilkkoutuu ensin  inorgaaneiksi fosfaateiksi ja lopulta  vain  myoinositolia imeytyy  glukoosin kanssa kilpaillen soluihin ja riakstuu soluentsyymeillä kadkadiksi jossa  syklisesti toimii  ainakin 35 eri inositoliyhdistettä + niiden  entsyymisetit. Kun siitä syklitä tulee IP6 muotoa, se pääsee ulos solusta ja  tarpeen mukaan tasapainottaa  fosfaattitilannetta kehossa  munuaisen avulla. Sanotaan se on kehon vahvin antioksidantti.  Tämä  asia on mielestäni mielnkiintoinen, sillä JOS se suostuu  menemään  tuohon sykliin, se  antaisi  tärkeää IP6 molekyyliä ihan aivoihin asti, jossa IP6/IP3 tasapaino on kriittinen asia kuten mös sydämen ärtyvissä soluissa, varsinkin  kammioväliseinässä ja  atriumissa.

Ehkä  löytyy lisää artikkeleita aiata jo, kun on näin pitkä aika kulunut.  Tänään vain katselin vanhaa kansiota ja löysin tämän ihovoideasian.  Itse asiassa   SARS2 virus on kiinnostunut noista  PI-syklin jsenistä, koska  ne kuuluvat  endoplasmisten  vesikkelien kuljetusjärjestelmäänkin ja exosytoosiin.   esim. Rab- proteiinit toimivat tuossa järrejstelmässä  kuin tienviittoina ja sillä kartalla  SARS-2 tekee  mieleisiään interaktioita  päästäkseen juuri sinne minne  haluaa,  pakkautuu  kaksoiskelmujen sisään ja tekee  virioitaan, välttää lysosomin ja ohjautuu ulos solusta valmiina virioneina hyvin pakattuna.

. 2005 Apr;28(4):764-7.

doi: 10.1248/bpb.28.764.

Study of the Absorption of Myo-Inositol Hexakisphosphate (InsP6) Through the Skin

Felix Grases  ¹ , Joan Perelló, Bernat Isern, Rafel M Prieto

Affiliations

• PMID: 15802828
• DOI: 10.1248/bpb.28.764

Free article

 Abstract

Recently, some properties of myo-inositol hexakisphosphate (InsP(6)) are related to its dermatological use as discolouring agent, on preventing calcinosis cutis or due to its important role on premature aging. Some studies also seem to demonstrate a capacity of InsP(6) to inhibit skin cancer. In this paper, a first study of the absorption of InsP(6) through the skin is developed. Due to the correlation between InsP(6) absorption and its urinary excretion, these last values were used to evaluate this process. It was found that using a moisturizing cream as vehicle, the InsP(6) sodium salt was absorbed at significantly higher amounts than the InsP(6) calcium-magnesium salt. Maximum InsP(6) urinary concentrations were observed approximately at 14 d of 2% InsP(6) topical cream application, and gave 66.35+/-5.49 mg/l urinary InsP(6) when the sodium salt was used and 16.02+/-2.61 mg/l urinary InsP(6) when the calcium-magnesium salt was applied. When the InsP(6) topical cream administration ceased, the InsP(6) urinary excretion fell dramatically approximately during a period of 10 d. From these results, it can be deduced that by topical administration InsP(6) can achieve important concentrations in tissues and biological fluids, this demonstrating that it is possible to propose the topic use as a new InsP(6) administration route.

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   Abstract
  

  Myo-inositol hexakisphosphate (InsP6, phytate) is a molecule to which diverse beneficial properties have been attributed. Some of these properties are related to its dermatological use as discolouring agent, on preventing calcinosis cutis or due to its important role on premature aging. Other studies also seem to demonstrate a capacity of InsP6 to inhibit skin cancer. In this paper, the effect of the vehicle of topical administration of phytate is studied, using four groups of male Wistar rats (n = 6) fed with an InsP6 defficient diet and treated with a hydrophyl gel or an O/W moisturizing cream with two different concentrations of InsP6. Due to the correlation between InsP6 absorption and its urinary excretion, these last values were used to evaluate this process. It was found that phytate was absorbed through the skin using both a gel or a cream, demonstrating that its absorption is independent on the matrix used for topical treatment. However, urinary InsP6 values were slightly higher when using the gel, but in all cases values were much higher than those found with oral InsP6 treatment, due to the formation of insoluble species in the gastrointestinal tract when InsP6 is administered orally.
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  Inositol Hexakisphosphate Increases L-type Ca2+ Channel Activity by Stimulation of Adenylyl Cyclase

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  Affiliations

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