Wetenschappers ontrafelen nog steeds de geheimen van een stofje dat 50 jaar geleden is ontdekt op Paaseiland. Rapamycine wordt geproduceerd door bacteriën en lijkt een krachtige levenselixer te zijn. Ook kan het helpen tegen ouderdomsziektes.
In 2009 werd een baanbrekende studie gepubliceerd waaruit blijkt dat rapamycine het leven van muizen met 9 tot 14 procent verlengt.
In een andere studie werden muizen drie maanden lang met rapamycine geïnjecteerd. Hun leven werd met gemiddeld 60 procent verlengd.
Uit de natuur
Het middel heeft ook verjongende effecten, en kan haargroei stimuleren en haarverlies voorkomen. Het heeft zelfs positieve effecten bij de behandeling van ouderdomsziektes zoals alzheimer, maar ook diabetes en hart- en spieraandoeningen.
Vorig jaar verscheen er een onderzoek in GeroScience naar 333 volwassenen die rapamycine off-label namen. De overgrote meerderheid nam het tegen veroudering en 19 procent om dementie te voorkomen.
Rapamycine is niet in een laboratorium gemaakt, maar komt uit de natuur, zei professor Robert Lufkin van de University of Southern California.
Antibacteriële eigenschappen
In december 1964 reisde een team van 40 mensen onder leiding van Canadese wetenschappers af naar het eiland om het te verkennen. Ze ontdekten dat lokale bewoners nooit tetanus kregen, dankzij een metaboliet van Streptomyces hygroscopicus dat antibacteriële eigenschappen heeft.
De substantie zorgt ervoor dat schimmels en dingen eromheen afsterven en voorkomt dat de organismen groeien, zei professor Arlan Richardson van de University of Oklahoma.
Paaseiland heet eigenlijk Rapa Nui en om die reden is het stofje dat op het eiland is ontdekt ‘rapamycine’ gedoopt.
Geen serieuze bijwerkingen
Omdat het celgroei tegengaat, werd het later gebruikt als kankermedicijn. Lufkin merkte op dat rapamycine effectief is tegen diverse kankersoorten.
Professor Andrea Maier van de Vrije Universiteit Amsterdam zei dat rapamycine ontstekingsremmend werkt en het hartstelsel positief beïnvloedt.
Een review die in februari is gepubliceerd in The Lancet Health Longevity concludeert dat het gebruik van rapamycine bij gezonde mensen geen serieuze bijwerkingen veroorzaakt. Op dit moment lopen er bijna 100 klinische onderzoeken naar het middel.
Over de auteur: Robin de Boer is economisch geograaf. Volg hem hier op Substack.
ARCHIVOS
DE ETIQUETA: STREPTOMYCES HYGROSCOPICUS
Posted by José Félix
Rodríguez Antón in cáncer, CIENCIA
Etiquetas
Easter Island, glioblastoma, Hans Laurits, lymphomas, mTOR, Rapa Nui, rapamycin, Silorimus, Streptomyces hygroscopicus, Suren Sehgal, Valter Longo
Rapa Nui (Easter Island) is situated
in the southeastern Pacific Ocean, 163 km2, population 6.600 residents. Easter
Island is famous for its 887 extant monumental statues, called moai, created by the early Rapa Nui people. Is a
volcanic high island, dominated by hawaiite and basalt, the climate is
classified as a tropical rainforest climate (Af) that
borders on a humid subtropical climate.
A streptomycete was isolated from an Easter Island soil
sample and found to inhibit Candida albicans, Microsporum gypseum and
Trichophyton granulosum. The antibiotic-producing microorganism was
characterized and identified as Streptomyces hygroscopicus.
The antifungal principle was extracted with organic solvent from the mycelium,
isolated in crystalline form and named rapamycin.
Stresptomyces hygroscopicus (Actenomyces hygroscopicus synonimus)
is a bacterial species in the genus Streptomyces. It was first described
by Hans Laurits Jensen in 1931. He was born in Graese, he
came under the influence of Professor Weis in the Department of Plant
Physiology at the Agricultural University in Lyngby, Denmark. His growing
interest in soil microbiology. Main terms to his work have been supplied by
actinomycetes, coryneform bacteria, and both free-living and symbiotic nitrogen
fixing bacteria.
Scientific classification
§ Kingdom: Bacteria
§ Phylum: Actinobacteria
§ Class: Actinobacteria
§ Order: Actinomycetales
§ Family: Streptomycetaceae
§ Genus: Streptomyces
§ Species: hygroscopicus
§ Subspecies: hygroscopicus
angustmyceticus, S. hygroscopicus decoyicus, S. hygroscopicus glebosus,
S.hygroscopicus hygroscopicus, S. hygroscopicus ossamyceticus
Sirolimus, also known as rapamycin, is a macrolide, is used
in medicine to prevent organ transplant rejection and to treat lymphangioleiomyomatosis.
§ Was isolated for
the first time in 1972 by Suren Sehgal and
colleagues from samples of Streptomyces hygroscopicus found on Easter Island.
Sirolimus was initially developed as an antifungal agent.
However, this use was abandoned when it was discovered to have potent inmunosuppresive and antiproliferative properties due
to its ability to inhibit mTOR
§ In the 1980s, found to
have anticancer activity although the exact mechanism
of action remained unknown until many years later.
§ Rapamycin was also
it was approved by the US Food and Drug Administration in September 1999 and is marketed under the trade
name.
mTOR inhibitors are a class
of drugs that inhibit the mechanistic target of rapamycin (mTOR). One of the
most promising antiaging mechanisms was discovered by accident. In 2001
biologist Valter Longo of the University
of Souther Calirfornia went away for a weekend and forgot to feed yeast cells
that he was using in an experiment. He was surprised to discover that starving
them completely for a time made them live longer than usual. The reason, he
learned, lay in a cascade of molecular actions usually referred to by the
enzyme at its center, which is called mTOR.
This pathway was originally discovered years earlier thanks to a drug
called rapamycin, which was found in soil bacteria. The drug, scientists
learned, affected a mayor pathway regulation growth and division in the cell,
like the circuit breaker in a tiny factory. Researchers named the path mTOR
because it is a “mechanistic target of rapamycin”.
When mTOR is activated, the “factory” (that is, the cell)
§ producing new
proteins,
§ growing
§ and ultimately
dividing.
When mTOR is bloked, suchs as by rapamycin cell growth and replication
slow down or stop. This is why rapamycin has been effective as an
immunosuppressor to protect transplanted organs and more recently as a cancer
therapy; these conditions involve runaway cell division.
Silorimus inhibits IL-2 and other cytokines
receptor-dependent signal transduction mechanisms, via action on mTOR, and
thereby blocks activation of T and B cells. The mode of action of sirolimus is
to bind the cytosolic protein FK-binding protein 12 (FKBP12)
in a manner similar to tracrolimus. The sirolimus-FKBP12 complex inhibits the
mTOR. Target Of Rapamycin, pathway by directly binding to mTOR Complex 1
(mTORC1). mTOR has also been called FRAP (FKBP-rapamycin-associated
protein), RAFT (rapamycin and FKBP
target), RAPT1, or SEP.
Sirolimus is metabolized by the CYP3A4 enzyme
and is a substrate of the P-glycoprotein (P-gp) efflux pump. It has elinimation
half-life of 57-63 hours. The byosynthesis of the rapamycin core is
accomplished by a type 1 polyketide synthase (PKS) in conjunction
with a nonribosomal peptide synthetase (NRPS). The domains
responsible for the biosynthesis of the linear polyketide of rapamycin are
organized into three myltienzymes, Rap A, Rap B, Rap C, which contain a total
of 14 modules. Then, the linear polyketide is modified by the NRPS, Rap P, which
attaches L-pipecolate to the terminal end of the polyketide, and then cyclizes
the molecule, yielding the unbound product, pherapamycin.
When dosed appropriately, sirolimus can enhance the immune response to tumor targeting or otherwise promote
tumor regression in clinical trials. Sirolimus seems to lower the cancer risk
in some transplant patients. It was shown to inhibit the progression of dermal Kaposi´s sarcoma in
patients with renal transplants. Other mTOR inhibitors, such
as temsirolimus or eversolimus, are
being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma.
A combination therapy of doxorubicin and sirolimus has
been shown to drive AKT-positive lymphomas into
remission in mice. Sirolimus blocks AKT signaling and the cells lose their
resistance to the chemotherapy. Bcl-2-positive lymphomas were completely
resistant to the therapy; eIF4E-expressing lymphomas are
not sensitive to sirolimus.
mTOR inhibitors are a class of drugs that inhibit the mechanistic
target of rapamycin (mTOR), which is a serine/threonine-specific
protein kinase that belongs to the family of phosphatidylinositol-3
kinase (PI3K) related kinases (PIKKs), Mtor regulates cellular
metabolism, growth, and proliferation by forming and signaling through two
protein complexes: mTOR1 and mTOR2.
The most established mTOR inhibitors are so-called rapalogs, which have shown tumor responses in
clinical trials against various tumor types.
Many human tumors occur because of dysregulation of mTOR signaling, and
can conferhigher susceptibility to inhibitors of mTOR. Deregulations of
multiple elements of the mTOR pathway, like P13K amplification/mutation, PTEN loss
of function, AKT overexpression, and S6K1, 4EBP1, and eIF4E
overexpression have been related to many types of cancers. Therefore, mTOR is
an interesting therapeutic target for
treating multiple cancers, both the mTOR inhibitors themselves or in
combination with inhibitors of other pathways.
Relation links:
§ Rapamycin
http://www.nature.com/nri/journal/v15/n10/box/nri3901_BX1.html
§ mTOR
https://www.youtube.com/watch?v=hbWUkArdptA
Bibliography:
§ Wikipedia
§ Jensen, HL
(1931) “Contributions
to our knowledge of actinomycetales” Biodiversity Heritage Library.
§ Vézina,C;
Kudelski,A; Sehgal, S N (1975) “Rapamycin (AY-22,989), a new
antigungal antibiotic. I. Taxonomuy of the producing streptomycete and
isolation of the active principle”. The Journal of Antibiotics 28(10): 721-726.
§ Valter Long,
Fabricio,P; Pozza, F; Plethcer,S; Gendrom, C.M; Longo, VD (2001) “Regulation of
Logevity and Stross Resistence by Sch9 in Yeast”.
§ Chan S (2004) “Targeting the
mmammalian target of rapamycin (mTOR): a new approach to treating cancer”. Br J
Cancer 91(8)1420-4.
§ Wendel HG, De
Stanchina E, Fridman JS, et al (2004) “Survival signaling by Akt and Eif4e in
oncogenesis and cancer therapy”. Nature 428 (6980):332-7.Science Daily.
§ Novak, Kristine
(2004) “Therapeutics:
Means to an end” Nature Reviews Cancer 4:332.
§ Mayo Clinic
Researches (2009) “Formulate Treatment Combination Lethal To
Pancreatic Cancer Cells” Science, 292 (5515): 288-290. Doi:10//26/science.
§ Meric-Gernstam, F;
Gonzalez-Angulo, A.M. (2009) “Targeting the Mtor Signaling
Network for Cancer Therapy”. Journal of Clinical Oncology. 27 (13):2278-87.
§ Populo, Helena;
Lopez, José Manuel; Soarez, Paula (2012) “The mTOR Signaling
Patway in Human Cancer”. International Journal of Molecular Sciences.13 (12):
1886-918.
§ Bill Gifford
(September 2016) “Will defeat aging”. Scientific
American 58-60.
https://josefelixrodriguezantonweb.com/tag/streptomyces-hygroscopicus/
Metabolite extract of
Streptomyces hygroscopicus Hygroscopicus inhibit the growth of Plasmodium
berghei through inhibition of ubiquitin - proteasome system
,
Affiliations
· PMID: 23959495
Free article
Abstract
Streptomyces
hygroscopicus Hygroscopicus, a member of family of Actinomycetes produces
eponemycin a proteasome inhibitor that can inhibit Ubiquitin-Proteasome System
(UPS) function in eukaryotic cell. Previous study showed that coronamycin, an
active substrate isolated from Streptomyces sp. can act as anti-plasmodial,
antibacterial, and antifungal, however the research did not show the mechanism
of coronamycin in inhibiting the growth of Plasmodium. This research was done
to reveal if eponemycin that is contained in metabolite extract of S.
hygroscopicus can inhibit UPS function of Plasmodium berghei. This study was an
experimental study using P. berghei infected Balb/C mice as malaria model.
Samples were divided into 1 control group (group infected with P. berghei
without treatment) and 3 treatment groups (mice infected with P. berghei and
treated intra-peritoneal with metabolite extract of S. hygroscopicus dose 130
μg/kgBW, 580 μg/kgBW, and 2600 μg/kgBW for 5 days). The degree of parasitemia
and morphology of the parasite were measured from the first day of malaria
induction until the last treatment. The accumulation level of polyubiquitin was
measured using Western blot and ELISA method. The degree of parasitemia on day
6 showed significant differences among treatment groups and control (p=0,000).
Percentage of inhibition showed significant differences between control and
group treated with metabolite extract of S. hygroscopicus 2600 μg/kgBW. An
increasing dose of extract of S. hygroscopicus followed by an increasing of
inhibition in parasite growth (r=0,850). Probit analysis showed that ED50 was
9.418 μg/kgBW. There was a change in morphology of the parasite after
treatment. Parasite morphology became crisis form. There was an accumulation of
polyubiquitinated protein in the group treated with metabolite extract of S.
hygroscopicus 2600 μg/kgBW. It can be concluded that analog eponemycin in
metabolite of S. hygroscopicus is a potential candidate for new malarial drug
by inhibiting UPS function of the parasite and cause stress and dead of the
parasite.
