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9.5.1: Koste en Voorkoming van Weerstand - Biologie

9.5.1: Koste en Voorkoming van Weerstand - Biologie


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Leerdoelwitte

  • Ondersoek die oorsake en gevolge van multi-middel-weerstandige organismes op gesondheidsorg

Voorkoming en beheer van mikrobiese weerstandbiedende organismes is een van die mees komplekse bestuurskwessies waarmee gesondheidsorgpersoneel te kampe het. Die kliniese en finansiële las vir pasiënte en gesondheidsorgverskaffers is verbysterend. Pasiënte wat besmet is met bakteriële stamme wat weerstand bied teen meer as een tipe of klas van middels (multidrug-weerstandige organismes, MDRO) het dikwels 'n verhoogde risiko van langdurige siekte, verlengde hospitaalverblyf en mortaliteit.

Die koste van sorg vir hierdie pasiënte kan meer as dubbel wees in vergelyking met dié sonder 'n MDRO-infeksie. Die alternatiewe medikasie wat hulle voorgeskryf word om die infeksie te oorkom, is dikwels aansienlik duurder. Multigeneesmiddelweerstand dwing gesondheidsorgverskaffers om antibiotika te gebruik wat duurder of meer giftig is vir die pasiënt.

Wanneer geen antibiotika doeltreffend is nie, kan gesondheidsorgverskaffers beperk word tot die verskaffing van ondersteunende sorg eerder as om 'n infeksie direk te behandel. In 'n 2008-studie van toeskryfbare mediese koste vir antibiotika-weerstandige infeksies, is beraam dat infeksies by 188 pasiënte van 'n enkele gesondheidsorginstelling tussen $13,35 en $18,75 miljoen dollar kos.

Navorsing en ontwikkeling van nuwe middels wat effektief is teen weerstandbiedende bakteriese stamme kom ook teen 'n prys. Om antimikrobiese weerstand te voorkom, moet die pasiënt en die gesondheidsorgverskaffer die toepaslike medisyne vir die siekte bespreek. Pasiënte moet voorskrifaanwysings volg en moenie medisyne deel of neem wat vir iemand anders voorgeskryf is nie; hierdie deugde moet streng beoefen word. Gesonde leefstylgewoontes, insluitend behoorlike dieet, oefening en slaappatrone, sowel as goeie higiëne soos gereelde handewas, kan help om siekte te voorkom. Hierdie praktyke help dus ook om die oorbenutting of misbruik van antibiotika en die ontstaan ​​van problematiese weerstandbiedende stamme te voorkom.

Daar is ook verskeie aksies wat deur die mediese gemeenskap geneem kan word om die ontwikkeling en verspreiding van antibiotika weerstand te help voorkom:

  • Voorkom infeksies waar moontlik deur inenting en ander toepaslike beskermende maatreëls.
  • Skryf nou-spektrum antibiotika voor, in teenstelling met breëspektrum antibiotika waar moontlik. Sodoende sal minder groepe bakterieë aan selektiewe druk blootgestel word wat weerstand tot gevolg sal hê.
  • Hou sekere middels as "dwelms van laaste uitweg" om slegs in die mees desperate gevalle gebruik te word om die blootstelling van mikrobes aan hierdie middels te verminder.
  • Skryf slegs antimikrobiese middels voor wanneer dit werklik nodig is. Vermy die voorskryf van antibiotika vir virale infeksies of geringe infeksies wat self kan oplos en probeer ander behandelings in die plek van antimikrobiese middels as dit beskikbaar is.
  • Gebruik dwelms in kombinasies. Alhoewel 'n patogeen weerstand teen een middel kan ontwikkel, sal die ander middel(s) in die kombinasie dit steeds kan beheer. Dit is 'n algemene strategie vir die behandeling van MIV en tuberkulose.
  • In gevalle waar behandelingsnakoming 'n probleem is, word direk waargenome terapie (DOT) soms gebruik. Dit behels dat gesondheidswerkers die voorgeskrewe middels toedien en bevestig dat dit behoorlik geneem word. DOT is die meeste toegepas vir die behandeling van tuberkulose as gevolg van die lang behandelingsperiode en oor die algemeen laer nakoming van behandeling.
  • Kies antibiotika wat minder geneig is om tot weerstand te lei, soos dié wat getoon word dat dit moeilik is om weerstand teen te ontwikkel en dié wat nie in die omgewing voortduur nie.

Ander bedrywe dra ook by tot en kan 'n rol speel in die voorkoming van antibiotikaweerstand. Landbou en akwakultuur gebruik groot hoeveelhede antibiotika wat in die omgewing vrygestel word en kan lei tot die ontwikkeling van antibiotiese weerstand. Daar is geen versperring tussen menslike patogene en omgewingsbakterieë nie, wat nie-patogene omgewingsbakterieë 'n potensiële reservoir van antibiotika weerstand maak. Daar word byvoorbeeld gedink dat vankomisien weerstandbiedend is Enterokokkus die eerste keer verskyn as gevolg van die gebruik van vankomisien-agtige antibiotika wat in beeste gebruik word. Onlangse regeringsregulasies het gepoog om hierdie risiko te verminder deur antibiotika in die landbou tot terapeutiese gebruik te beperk.

Kern punte

  • Antimikrobiese weerstand teen beskikbare middels vereis die ontwikkeling van nuwe middels om weerstandbiedende stamme effektief te behandel en mortaliteit as gevolg van bakteriële infeksies te verminder.
  • Antimikrobiese weerstand kan voorkom word deur goeie higiëne toe te pas, en verantwoordelik te wees met die gebruik van antibiotika.
  • Die behandeling van antibiotika-weerstandige bakteriese stamme is duur vir beide die pasiënt en die gesondheidsorgverskaffer. Die behandeling vereis verlengde hospitaalverblyf en duur medikasie.

Sleutel terme

  • multigeneesmiddel weerstandigheid: 'n Toestand wat 'n siekteveroorsakende organisme in staat stel om verskillende middels of chemikalieë van 'n wye verskeidenheid van struktuur en funksie te weerstaan ​​wat daarop gemik is om die organisme uit te roei.

Verstaan ​​en oorkom antibiotika weerstand

Kopiereg: © 2017 Lauren A. Richardson. Hierdie is 'n ooptoegangartikel wat versprei word onder die bepalings van die Creative Commons Erkenningslisensie, wat onbeperkte gebruik, verspreiding en reproduksie in enige medium toelaat, mits die oorspronklike outeur en bron gekrediteer word.

Mededingende belange: LR is 'n huidige betaalde werknemer by Openbare Biblioteek van Wetenskap.

Herkoms: Geskryf deur redaksie wat nie ekstern eweknie-geëvalueer is nie

Antibiotiese middels het 'n rewolusie in medisyne gemaak en ons moderne lewenswyse moontlik gemaak. Benewens hul noodsaaklike rol in die kliniek, word antibiotika in 'n groot verskeidenheid nie-mediese toepassings gebruik, van die bevordering van groei in vee, tot die behoud van boumateriaal teen kontaminasie, tot die behandeling van roes in boorde. Oorbenutting bedreig egter hul doeltreffendheid as gevolg van die bevordering en verspreiding van antibiotika-weerstandige bakterieë.

Antibiotika teiken en inhibeer noodsaaklike sellulêre prosesse, vertraag groei en veroorsaak seldood. As bakterieë egter blootgestel word aan middels onder die dosis wat nodig is om alle bakterieë in 'n populasie dood te maak (die minimum bakteriedodende konsentrasie of MBC), kan hulle muteer en antibiotiese behandeling weerstaan ​​deur natuurlike seleksie vir weerstandsverlenende mutasies. Hierdie genetiese mutasies kan ontstaan ​​uit die aanneming van 'n plasmied wat 'n weerstandsgeen kodeer of deur mutasie na die bakteriële chromosoom self.

Die kommer oor die toenemende voorkoms van middelweerstandige bakterieë word vererger deur die feit dat die ontdekking van nuwe antibiotika 'n vlietende seldsame gebeurtenis is. Die meeste klasse antibiotika op die mark is in die middel tot laat 20ste eeu ontdek. Daar is dus 'n beperkte arsenaal van middels om weerstandbiedende bakterieë te beveg, en bakterieë kan weerstandbiedend wees teen verskeie middels op 'n slag.

Gegewe die belangrikheid van antibiotika vir moderne medisyne, en die groeiende vrees rondom die bedreiging van weerstand, bestudeer wetenskaplikes elke aspek van antibiotika-weerstandigheid. Hierdie Oop Hoogtepunt bevat sommige van die voorpunt-navorsing van die Oop Toegang-korpus oor drie groot fokusareas: die sellulêre meganismes van weerstand, die evolusie en verspreiding van weerstand, en tegnieke vir die bekamping van weerstand.


Antibiotiese weerstand is een van die wêreld se mees dringende openbare gesondheidsprobleme wat mense in enige stadium van die lewe raak. Volgens data van die CDC (Center for Disease Control and Prevention) is ’n groot bydraende faktor tot antibiotika-weerstandigheid die oor-voorskryf van antibiotika – tipies voorgeskryf vir verkeerd gediagnoseerde siektes wat veroorsaak word deur virusse, wat nie op antibiotika reageer nie. Aangesien mediese koste en antibiotika-weerstandverwante sterftes elke jaar styg, is die behoefte aan vinniger diagnoses en presiese behandelingsopsies om antibiotikaweerstandigheid te bekamp duidelik. Bron

Miljard dollar-koste

In 2011 was daar ongeveer 400 000 hospitalisasies vir UTI's met 'n geraamde koste van $2,8 miljard. Bron

Miljoen oortollige voorskrifte

30% van antibiotika wat in die Verenigde State voorgeskryf word, is onnodig. Dit is altesaam 47 miljoen oortollige voorskrifte. Bron

Duisend sterftes wat verband hou met antibiotika-weerstandigheid

Elke jaar in die Verenigde State word minstens 2 miljoen mense met antibiotika-weerstandige bakterieë besmet, en ten minste 23 000 mense sterf as gevolg daarvan. Bron


EPIDEMIOLOGIE

Ten spyte van die afname in die voorkoms van tandkariës by kinders in die Westerse lande, bly karies by voorskoolse kinders 'n probleem in beide ontwikkelde en ontwikkelende lande. ECC is as epidemiese proporsies in die ontwikkelende lande beskou.[4,17]

'n Omvattende oorsig van die voorkoms van die karies op die maksillêre anterior tande by kinders, insluitend talle studies uit Europa, Afrika, Asië, die Midde-Ooste en Noord-Amerika, het die hoogste kariesvoorkoms in Afrika en Suidoos-Asië gevind.[18] Die voorkoms van ECC wissel na raming van 1 tot 12% by babas uit ontwikkelde lande.[19]

Voorkoms van ECC is nie 'n algemene bevinding relatief tot sommige Europese lande (Engeland, Swede en Finland), met die beskikbare voorkomsdata wat wissel van onder 1% tot 32%.[20,21] Hierdie syfer styg egter met as soveel as 56% in sommige Oos-Europese lande.[22] In die VSA dui voorskoolse kinders se data van 'n meer onlangse studie aan dat die voorkoms van tandkariës van kinders 2𠄵 jaar oud toegeneem het van 24% in 1988� tot 28% in 1999�. In die algemeen, met inagneming van alle 2𠄵-jariges, dui die 1999-2004-opname aan dat 72% van vervalle of gevulde tandoppervlaktes onbehandeld bly.[14,23,24] Die voorkoms van ECC-kinders in die algemene bevolking van Kanada is minder as 5%, maar in hoërisiko-bevolking word 50�% aangetas.[25,26,27] Studies toon dat die voorkomspersentasie van ECC in 25- tot 36-maande-jariges[28] 46% is en die gerapporteerde voorkoms in Inheemse Kanadese 3-jariges[29] was so hoog as 65%.

Gepubliseerde studies toon hoër voorkomssyfers vir 3-jariges, wat wissel van 36 tot 85%[30�] in die Verre-Oos-Asië-streek, terwyl hierdie syfer 44% is vir 8- tot 48-maande-jariges[33] Indiese studies. ECC is in die ontwikkelende lande teen epidemiese proporsies beskou.[34] Studies wat in die Midde-Ooste gedoen is, het getoon dat die voorkoms van karies by 3-jariges tussen 22% en 61% [35�] is en in Afrika is dit tussen 38% en 45%.[38,39]


Postprandiale hepatiese metabolietvloede

Vas hiperglykemie in T2D is die gevolg van verhoogde tempo van hepatiese glukoneogenese en EGP en van hepatiese insulienweerstandigheid, gekenmerk deur verminderde vermoë van insulien om hierdie proses te onderdruk 38,39,40,41. Dit kan wees as gevolg van direkte IR-gemedieerde sel-outonome of indirekte effekte (substraat beskikbaarheid, allosteriese regulering of redoksstatus) 42 (Fig. 1b). Onlangse studies het getoon dat hierdie indirekte effekte waarskynlik voortspruit uit insulienwerking op WAT en hoofsaaklik verantwoordelik is vir akute onderdrukking van glukoneogenese en EGP tydens postprandiale hiperinsulienemie 14 . In ooreenstemming met 'n geringe rol vir direkte lewereffekte van insulien, vertoon knaagdiermodelle met veranderde lewerinsuliensein relatief normale glukosetoleransie en kompenserende hiperinsulienemie, met verminderde hepatiese glikogeensintese as die enigste aanduiding van versteurde insulien wat 14,43,44,45,46 aandui. ,47 .

Direkte assessering van glikogeensintese deur 13C magnetiese resonansspektroskopie het laer tempo's van postprandiale en insulien-gereguleerde hepatiese glikogeensintese by mense met T2D 38,39 getoon. Die hoër halfmaksimale effektiewe konsentrasie en laer maksimum effek van insulien op hepatiese glikogeensintese 39 dui op verswakte IR-aktivering met daaropvolgende posttranslasionele modifikasies van die glikogeen sintetiese masjinerie en transkripsieregulering van glukokinase (Fig. 1b). Terwyl daar verwag word dat ander insulien-effekte, soos transkripsionele DNL-aktivering via sterolreseptor-verbeterende proteïen-1c (SREBP1c), afgestomp sal wees, word lewerinsulienweerstandigheid oor die algemeen geassosieer met verhoogde hepatiese TAG en NAFLD. Gevolglik is daar voorgestel dat slegs die FOXO1-afhanklike, maar nie die SREBP1c-afhanklike tak van insuliensein nie, gebrekkig is, wat selektiewe hepatiese insulienweerstandigheid voorstel 48 . Hierdie hipotese maak staat op die aanname dat DNL die hoofbron van hepatiese TAG is en op eksperimente wat verskillende rolle van insulienreseptorsubstraat (IRS)-1 en IRS-2, substraatspesifieke AKT-fosforilering of intrinsieke pad-sensitiwiteite vir insulien toon. Omgekeerd, NEFA herverestering is waarskynlik verantwoordelik vir die meerderheid van hepatiese lipogenese en baie lae-digtheid lipoproteïen (VLDL) afskeiding 49,50,51. Verminderde insulien-gestimuleerde hepatiese IR-kinase-aktiwiteit dui op 'n algemene proksimale abnormaliteit in T2D 52. Verder is DNL-opregulering nie uitsluitlik afhanklik van IR-kinase-aktiwiteit nie, maar kan ook plaasvind deur aktivering van koolhidraatreseptor-verbeterende bindingsproteïen (ChREBP) 53, mTORC1-SREBP1c 54 en fruktose-gestimuleerde paaie 55 (Fig. 1b). 'n Onlangse studie het bevind dat vetsuurverestering na TAG meestal afhanklik is van NEFA-lewering aan die lewer en onafhanklik van hepatiese insuliensein 16 . Hierdie alternatiewe hipotese verduidelik ook die ontwikkeling van NAFLD deur verhoogde NEFA-vloed afgelei van verhoogde lipolise deur insulienweerstandige WAT.

Benewens kalorie-oorlading, oefen makrovoedingstowwe spesifieke effekte uit deur entero-endokriene afskeiding te moduleer en, op sy beurt, pankreas-eiland en breinfunksie voordat dit die splanchniese bed bereik om insulienafskeiding direk te stimuleer en die lewer binne te gaan. Slegs ongeveer 33% van dieetkoolhidrate gaan die lewer binne, en dieetvet word beskou as slegs 10-20% van die lewervetsuurpoel 49 . Nietemin kan makronutriënte substrate vir die hepatiese asetiel-CoA-poel lewer, wat glukoneogenese allosteries stimuleer of voedingstofsensitiewe weë (ChREBP, mTORC en SREBP) aktiveer om die transkripsionele DNL-program gesamentlik te stimuleer. Verhoogde hepatiese asiel-CoA bevoordeel produksie van sn-1,2-DAG, sfingolipiede en TAG. In vetsugtige mense met NAFLD, die sn-1,2-DAG-PKCε-pad korreleer nou met hepatiese insulienweerstand 56,57,58,59,60, terwyl ceramide-JUN N-terminale kinase (JNK) meer korreleer met hepatiese oksidatiewe stres en inflammasie 58,61,62 ( Fig. 1b). In hierdie konteks het die verlaging van sellulêre ceramide deur dihydroceramide-desaturase 1 te ablasieer mitochondriale suurstofvloei en verbeterde steatose en glukosemetabolisme in insulienweerstandige muise 63 verhoog. Omgekeerd, mitochondriale C16:0 ceramide, gegenereer deur ooruitdrukking van ceramide sintase 6 (CerS6), interaksie met mitochondriale splitsingsfaktor (MFF) om mitochondriale fragmentasie, insulienweerstand en steatose 64 te bevorder. Die stilte van MFF het CerS6-afhanklike metaboliese abnormaliteite verhoed ten spyte van verhoogde C16:0-ceramied. Dit dui daarop dat die uitwerking van ceramiede op insulien-gestimuleerde glukosemetabolisme indirek kan voortspruit uit verswakte mitochondriale funksie met laer vetsuuroksidasie, wat aanleiding gee tot ander metaboliete, byvoorbeeld, sn-1,2-DAG of asetiel-CoA, eerder as van direkte ceramiedinterferensie met insuliensein. Onlangse studies dui op 'n kritieke rol van molekulêre kompartementering van sn-1,2-DAG's, spesifiek in die plasmamembraan, om nPKC-translokasie en insulienweerstand te veroorsaak. Muise wat met CGI-58 antisense oligonukleotied behandel is, vertoon verhoogde hepatiese TAG en DAG in lipieddruppels, word beskerm teen lipied-geïnduseerde hepatiese insulienweerstand en toon vermindering in plasmamembraan DAG en PKCε translokasie 65 .

Alvarez-Hernandez et al. het die vroegste dieet-geïnduseerde metaboliese veranderinge gemonitor deur die effek van 'n enkele orale versadigde vetlading in gesonde mense te ondersoek 66 . Hierdie studie het aan die lig gebring dat versadigde vet gelyktydig insulienweerstand in lewer, skeletspier en WAT induseer, en geassosieer word met 70% hoër koerse van hepatiese glukoneogenese en 20% laer koerse van netto hepatiese glikogenolise. Soortgelyke studies in muise het opgereguleerde uitdrukking van tolagtige reseptor (TLR) en inflammatoriese weë gevind, wat kan bydra tot vordering van NAFLD, insluitend nie-alkoholiese steatohepatitis (NASH) 66. Van kennis, chroniese oorvoeding het ook vlakke van derm-afgeleide endotoksiene verhoog wat TLR4-geïnduseerde sitokienvrystelling deur Kupffer-selle bevorder 67,68. Ander dermfunksies beïnvloed ook glukemie en diabetesrisiko: integrien β7-uitklopmuise, wat nie natuurlike dunderm intraepiteel T-limfosiete het nie, is metabolies hiperaktief en bestand teen vetsug en diabetes 69 . Laastens kan dieetgewoontes die dermmikrobiota beïnvloed, wat dermmetabolietvrystelling en insuliensensitiwiteit 70 moduleer. Mense met T2D en NAFLD toon duidelike metagenomiese handtekeninge saam met verhoogde vertakte ketting aminosure 71,72 en verminderde kortketting NEFA 73, wat liggaamsgewig en metabolisme kan beïnvloed.

Samevattend lei oorvoeding en WAT-disfunksie tot verhoogde WAT-lipolise, wat insulien-onafhanklike hepatiese lipogenese bevorder, wat lei tot verhoogde ektopiese lipiedneerslag en verhoogde hepatiese glukoneogenese as gevolg van verhoogde verhoogde asetiel-CoA-stimulasie van piruvaatkarboksilase sowel as verhoogde gliserolomskakeling na glukose. Hierdie meganisme vermy die voorheen gerapporteerde behoefte om selektiewe hepatiese insulienweerstand aan te roep om die onenigheid van verhoogde hepatiese lipogenese wat gelyktydig met verhoogde glukoneogenese 48 voorkom (Fig. 1b) te verduidelik. Dit is in ooreenstemming met onlangse studies wat toon dat gewigsverlies wat veroorsaak word deur baie lae-kalorie-diëte, hepatiese steatose en insulienweerstand in lewer vinnig normaliseer, maar nie intramiosellulêre lipiedinhoud of spierinsulienweerstand in individue met T2D 3,11,74 nie.


Inhoud

Die vroegste landplante het ongeveer 450 miljoen jaar gelede (Ma) in die Ordoviciese tydperk uit waterplante ontwikkel. Baie plante het aangepas by jodium-tekorte terrestriële omgewing deur jodium uit hul metabolisme te verwyder, in werklikheid is jodium noodsaaklik net vir dierselle. [2] 'n Belangrike antiparasitiese werking word veroorsaak deur die blokkering van die vervoer van jodied van dierselle wat natriumjodied simporter (NIS) inhibeer. Baie plantplaagdoders is glikosiede (as die kardiale digitoksien) en sianogene glikosiede wat sianied vrystel, wat sitochroom c-oksidase en NIS blokkeer, slegs giftig is vir 'n groot deel van parasiete en herbivore en nie vir die plantselle waarin dit nuttig blyk te wees in saadrusfase. Jodied is nie 'n plaagdoder nie, maar word deur groenteperoksidase geoksideer tot jodium, wat 'n sterk oksidant is wat bakterieë, swamme en protosoë kan doodmaak. [3]

In die Krytydperk het meer plantverdedigingsmeganismes verskyn. Die diversifikasie van blomplante (angiosperme) in daardie tyd word geassosieer met die skielike uitbarsting van spesiasie by insekte. [4] Hierdie diversifikasie van insekte het 'n groot selektiewe krag in plantevolusie verteenwoordig, en het gelei tot seleksie van plante wat verdedigingsaanpassings gehad het. Vroeë insekherbivore was mandibuleer en het plantegroei gebyt of gekou, maar die evolusie van vaatplante het gelei tot die mede-evolusie van ander vorme van herbivore, soos sapsuig, blaarontginning, galvorming en nektarvoeding. [5]

Die relatiewe oorvloed van verskillende spesies plante in ekologiese gemeenskappe, insluitend woude en grasvelde, kan deels bepaal word deur die vlak van defensiewe verbindings in die verskillende spesies. [6] Aangesien die koste van vervanging van beskadigde blare hoër is in toestande waar hulpbronne skaars is, kan dit ook wees dat plante wat groei in gebiede waar water en voedingstowwe skaars is, meer hulpbronne in anti-herbivore verdediging kan belê.

Rekords van herbivore Wysig

Ons begrip van herbivoor in geologiese tyd kom uit drie bronne: gefossileerde plante, wat bewyse van verdediging kan bewaar (soos stekels), of herbivore-verwante skade die waarneming van plantafval in gefossileerde diere-ontlasting en die konstruksie van herbivore monddele. [7]

Lank gedink as 'n Mesozoïese verskynsel, word bewyse vir herbivorie gevind byna so gou as fossiele wat dit kan wys. Soos voorheen bespreek, het die eerste landplante ongeveer 450 miljoen jaar gelede ontstaan, maar herbivorie, en dus die behoefte aan plantverdediging, bestaan ​​ongetwyfeld al langer. Herbivoor het eers ontwikkel as gevolg van mariene organismes binne antieke mere en oseane. [8] Binne minder as 20 miljoen jaar na die eerste fossiele van sporangia en stamme teen die einde van die Silurium, ongeveer 420 miljoen jaar gelede, is daar bewyse dat hulle verteer is. [9] Diere gevoed op die spore van vroeë Devoon-plante, en die Rhynie-kert verskaf ook bewyse dat organismes op plante gevoed het deur 'n "deurdring en suig"-tegniek te gebruik. [7] Baie plante van hierdie tyd word bewaar met ruggraatagtige enasies, wat moontlik 'n defensiewe rol gespeel het voordat dit gekoöpteer is om in blare te ontwikkel.

Gedurende die daaropvolgende 75 miljoen jaar het plante 'n reeks meer komplekse organe ontwikkel - van wortels tot sade. Daar was 'n gaping van 50 tot 100 miljoen jaar tussen elke orgaan wat ontwikkel en daarop gevoed word. [9] Gatvoeding en skeletvorming word in die vroeë Perm aangeteken, met oppervlakvloeistofvoeding wat teen die einde van daardie tydperk ontwikkel het. [7]

Co-evolution Edit

Herbivore is afhanklik van plante vir voedsel, en het meganismes ontwikkel om hierdie voedsel te verkry ten spyte van die evolusie van 'n diverse arsenaal van plantverdediging. Herbivore aanpassings tot plantverdediging is vergelyk met aanstootlike eienskappe en bestaan ​​uit aanpassings wat verhoogde voeding en gebruik van 'n gasheerplant moontlik maak. [10] Verhoudings tussen herbivore en hul gasheerplante lei dikwels tot wedersydse evolusionêre verandering, wat ko-evolusie genoem word. Wanneer 'n herbivoor 'n plant eet, selekteer hy vir plante wat 'n defensiewe reaksie kan oplewer. In gevalle waar hierdie verhouding demonstreer spesifisiteit (die evolusie van elke eienskap is te danke aan die ander), en wederkerigheid (albei eienskappe moet ontwikkel), word vermoed dat die spesie saam-evolueer het. [11]

Die "ontvlugting en bestraling" meganisme vir ko-evolusie bied die idee dat aanpassings in herbivore en hul gasheerplante die dryfkrag agter spesiasie was, [4] [12] en 'n rol gespeel het in die bestraling van insekspesies gedurende die ouderdom van angiosperme. [13] Sommige herbivore het maniere ontwikkel om plantverdediging tot hul eie voordeel te kaap, deur hierdie chemikalieë te sekwestreer en dit te gebruik om hulself teen roofdiere te beskerm. [4] Plantverdediging teen herbivore is oor die algemeen nie volledig nie, so plante is ook geneig om 'n mate van verdraagsaamheid teenoor herbivore te ontwikkel.

Plantverdediging kan oor die algemeen as konstitutief of geïnduseer geklassifiseer word. Konstitutiewe verdediging is altyd teenwoordig in die plant, terwyl geïnduseerde verdediging geproduseer of gemobiliseer word na die plek waar 'n plant beseer word. Daar is wye variasie in die samestelling en konsentrasie van konstitutiewe verdediging en dit wissel van meganiese verdediging tot verteerbaarheid verminderers en gifstowwe. Baie eksterne meganiese verdediging en groot kwantitatiewe verdediging is konstitutief, aangesien dit groot hoeveelhede hulpbronne benodig om te produseer en moeilik is om te mobiliseer. [14] 'n Verskeidenheid molekulêre en biochemiese benaderings word gebruik om die meganisme van konstitutiewe en geïnduseerde plantverdedigingsreaksies teen herbivore te bepaal. [15] [16] [17] [18]

Geïnduseerde verdediging sluit sekondêre metaboliete in, sowel as morfologiese en fisiologiese veranderinge. [19] 'n Voordeel van induseerbare, in teenstelling met konstitutiewe verdediging, is dat hulle slegs geproduseer word wanneer dit nodig is, en dus potensieel minder duur is, veral wanneer herbivorie veranderlik is. [19] Modusse van geïnduseerde verdediging sluit sistemiese verworwe weerstand [20] en plant-geïnduseerde sistemiese weerstand in. [21]

Chemiese verdediging Edit

Die evolusie van chemiese verdediging in plante word gekoppel aan die ontstaan ​​van chemiese stowwe wat nie by die noodsaaklike fotosintetiese en metaboliese aktiwiteite betrokke is nie. Hierdie stowwe, sekondêre metaboliete, is organiese verbindings wat nie direk betrokke is by die normale groei, ontwikkeling of voortplanting van organismes nie, [22] en dikwels as neweprodukte geproduseer word tydens die sintese van primêre metaboliese produkte. [23] Alhoewel daar gedink word dat hierdie sekondêre metaboliete 'n groot rol speel in verdediging teen herbivore, [4] [22] [24] het 'n meta-analise van onlangse relevante studies voorgestel dat hulle óf 'n meer minimale (in vergelyking met ander nie-sekondêre metaboliete, soos primêre chemie en fisiologie) of meer komplekse betrokkenheid by verdediging. [25] Verder kan plante vlugtige organiese verbindings (VOC's) vrystel om ander plante in die gebied van stresvolle toestande te waarsku. Hierdie giftige verbindings kan gebruik word om die herbivoor af te skrik of selfs die herbivoor se roofdier te lok.

Kwalitatiewe en kwantitatiewe metaboliete Edit

Sekondêre metaboliete word dikwels as óf gekenmerk kwalitatief of kwantitatief. Kwalitatiewe metaboliete word gedefinieer as gifstowwe wat inmeng met 'n herbivoor se metabolisme, dikwels deur spesifieke biochemiese reaksies te blokkeer. Kwalitatiewe chemikalieë is teenwoordig in plante in relatief lae konsentrasies (dikwels minder as 2% droë gewig), en is nie dosisafhanklik nie. [ aanhaling nodig ] Hulle is gewoonlik klein, wateroplosbare molekules, en kan dus vinnig gesintetiseer, vervoer en geberg word met relatief min energiekoste vir die plant. Kwalitatiewe allelochemikalieë is gewoonlik effektief teen nie-aangepaste algemene herbivore.

Kwantitatiewe chemikalieë is dié wat in hoë konsentrasies in plante teenwoordig is (5 – 40% droë gewig) en is ewe effektief teen alle spesialiste en algemene herbivore. Die meeste kwantitatiewe metaboliete is verteerbaarheidsverminderers wat plantselwande onverteerbaar maak vir diere. Die effekte van kwantitatiewe metaboliete is dosisafhanklik en hoe hoër hierdie chemikalieë se verhouding in die herbivoor se dieet, hoe minder voeding kan die herbivoor verkry deur plantweefsel in te neem. Omdat hulle tipies groot molekules is, is hierdie verdediging energiek duur om te vervaardig en in stand te hou, en neem dit dikwels langer om te sintetiseer en te vervoer. [26]

Die geranium produseer byvoorbeeld die aminosuur, quisqualic suur in sy blomblare om homself teen Japannese kewers te verdedig. Binne 30 minute na inname verlam die chemikalie die herbivoor. Terwyl die chemikalie gewoonlik binne 'n paar uur verdwyn, word die kewer gedurende hierdie tyd dikwels deur sy eie roofdiere verteer. [27] [28]

Antiherbivore verbindings Edit

Plante het baie sekondêre metaboliete ontwikkel wat betrokke is by plantverdediging, wat gesamentlik bekend staan ​​as anti-herbivore verbindings en kan in drie subgroepe geklassifiseer word: stikstofverbindings (insluitend alkaloïede, sianogene glikosiede, glukosinolate en bensoksasinoïede), terpenoïede en fenole. [29]

Alkaloïede is afgelei van verskeie aminosure. Meer as 3000 bekende alkaloïede bestaan, voorbeelde sluit in nikotien, kafeïen, morfien, kokaïen, kolgisien, ergoliene, strignien en kinien. [30] Alkaloïede het farmakologiese effekte op mense en ander diere. Sommige alkaloïede kan ensieme inhibeer of aktiveer, of koolhidraat- en vetberging verander deur die vorming van fosfodiesterbindings wat by hul afbreek betrokke is, te inhibeer. [31] Sekere alkaloïede bind aan nukleïensure en kan sintese van proteïene inhibeer en DNA-herstelmeganismes beïnvloed. Alkaloïede kan ook selmembraan en sitoskeletale struktuur beïnvloed wat veroorsaak dat die selle verswak, ineenstort of lek, en kan senuwee-oordrag beïnvloed. [32] Alhoewel alkaloïede op 'n verskeidenheid van metaboliese sisteme in mense en ander diere inwerk, roep hulle byna eenvormig 'n aversive bitter smaak op. [33]

Sianogene glikosiede word in onaktiewe vorms in plantvakuole gestoor. Hulle word giftig wanneer herbivore die plant eet en selmembrane breek wat die glikosiede toelaat om in kontak te kom met ensieme in die sitoplasma wat waterstofsianied vrystel wat sellulêre respirasie blokkeer. [34] Glukosinolate word op baie dieselfde manier as sianogene glukosiede geaktiveer, en die produkte kan gastro-enteritis, speekselafskeiding, diarree en irritasie van die mond veroorsaak. [33] Bensoksasinoïede, soos DIMBOA, is sekondêre verdedigingsmetaboliete kenmerkend van sekere grasse (Poaceae). Soos sianogene glikosiede word hulle as onaktiewe glukosiede in die plantvakuool gestoor. [35] By weefselontwrigting kom hulle in kontak met β-glukosidases van die chloroplaste, wat die toksiese aglykone ensimaties vrystel. Terwyl sommige bensoksasinoïede konstitutief teenwoordig is, word ander slegs gesintetiseer na herbivore besmetting, en word dus beskou as induseerbare plantverdediging teen herbivore. [36]

Die terpenoïede, soms na verwys as isoprenoïede, is organiese chemikalieë soortgelyk aan terpene, afgelei van vyf-koolstof isopreen eenhede. Daar is meer as 10 000 bekende tipes terpenoïede. [37] Die meeste is multisikliese strukture wat van mekaar verskil in beide funksionele groepe, en in basiese koolstofskelette. [38] Monoterpenoïede, voortgaande 2 isopreen-eenhede, is vlugtige essensiële olies soos sitronella, limoneen, menthol, kanfer en pineen. Diterpenoïede, 4 isopreen-eenhede, word wyd versprei in latex en harse, en kan redelik giftig wees. Diterpenes is verantwoordelik vir die maak Rhododendron blare giftig. Plantsteroïede en sterole word ook geproduseer van terpenoïde-voorlopers, insluitend vitamien D, glikosiede (soos digitalis) en saponiene (wat rooibloedselle van herbivore liseer). [39]

Fenole, soms genoem fenole, bestaan ​​uit 'n aromatiese 6-koolstofring wat aan 'n hidroksiegroep gebind is. Sommige fenole het antiseptiese eienskappe, terwyl ander endokriene aktiwiteit ontwrig. Fenole wissel van eenvoudige tanniene tot die meer komplekse flavonoïede wat plante baie van hul rooi, blou, geel en wit pigmente gee. Komplekse fenole genoem polifenole is in staat om baie verskillende tipes effekte op mense te produseer, insluitend antioksidanteienskappe. Enkele voorbeelde van fenole wat vir verdediging in plante gebruik word, is: lignien, silimarin en cannabinoïede. [40] Gekondenseerde tanniene, polimere wat uit 2 tot 50 (of meer) flavonoïedmolekules bestaan, inhibeer herbivore vertering deur aan verbruikte plantproteïene te bind en dit vir diere moeiliker te maak om te verteer, en deur in te meng met proteïenabsorpsie en verteringsensieme. [41]

Daarbenewens gebruik sommige plante vetsuurderivate, aminosure en selfs peptiede [42] as verdediging. Die cholinergiese gifstof, sikutoksien van waterhemlock, is 'n poliïne afkomstig van die vetsuurmetabolisme. [43] Oksalieldiaminopropionsuur is 'n neurotoksiese aminosuur wat as 'n verdedigende metaboliet in die grasertjie (Lathyrus sativus). [44] Die sintese van fluorasetaat in verskeie plante is 'n voorbeeld van die gebruik van klein molekules om die metabolisme van herbivore, in hierdie geval die sitroensuursiklus, te ontwrig. [45]

Meganiese verdediging Wysig

Baie plante het eksterne strukturele verdediging wat herbivore ontmoedig. Strukturele verdediging kan beskryf word as morfologiese of fisiese eienskappe wat die plant 'n fiksheidsvoordeel gee deur herbivore te weerhou om te eet. [46] Afhangende van die herbivoor se fisiese eienskappe (m.a.w. grootte en verdedigingswapens), kan plant strukturele verdediging op stamme en blare die weiding afskrik, beseer of doodmaak. Some defensive compounds are produced internally but are released onto the plant's surface for example, resins, lignins, silica, and wax cover the epidermis of terrestrial plants and alter the texture of the plant tissue. The leaves of holly plants, for instance, are very smooth and slippery making feeding difficult. Some plants produce gummosis or sap that traps insects. [47]

Spines and thorns Edit

A plant's leaves and stem may be covered with sharp prickles, spines, thorns, or trichomes- hairs on the leaf often with barbs, sometimes containing irritants or poisons. Plant structural features like spines and thorns reduce feeding by large ungulate herbivores (e.g. kudu, impala, and goats) by restricting the herbivores' feeding rate, or by wearing down the molars. [48] Trichomes are frequently associated with lower rates of plant tissue digestion by insect herbivores. [46] Raphides are sharp needles of calcium oxalate or calcium carbonate in plant tissues, making ingestion painful, damaging a herbivore's mouth and gullet and causing more efficient delivery of the plant's toxins. The structure of a plant, its branching and leaf arrangement may also be evolved to reduce herbivore impact. The shrubs of New Zealand have evolved special wide branching adaptations believed to be a response to browsing birds such as the moas. [49] Similarly, African Acacias have long spines low in the canopy, but very short spines high in the canopy, which is comparatively safe from herbivores such as giraffes. [50] [51]

Trees such as palms protect their fruit by multiple layers of armor, needing efficient tools to break through to the seed contents. Some plants, notably the grasses, use indigestible silica (and many plants use other relatively indigestible materials such as lignin) to defend themselves against vertebrate and invertebrate herbivores. [52] Plants take up silicon from the soil and deposit it in their tissues in the form of solid silica phytoliths. These mechanically reduce the digestibility of plant tissue, causing rapid wear to vertebrate teeth and insect mandibles, [53] and are effective against herbivores above and below ground. [54] The mechanism may offer future sustainable pest control strategies. [55]

Thigmonastic movements Edit

Thigmonastic movements, those that occur in response to touch, are used as a defense in some plants. The leaves of the sensitive plant, Mimosa pudica, close up rapidly in response to direct touch, vibration, or even electrical and thermal stimuli. The proximate cause of this mechanical response is an abrupt change in the turgor pressure in the pulvini at the base of leaves resulting from osmotic phenomena. This is then spread via both electrical and chemical means through the plant only a single leaflet need be disturbed. This response lowers the surface area available to herbivores, which are presented with the underside of each leaflet, and results in a wilted appearance. It may also physically dislodge small herbivores, such as insects. [56]

Mimicry and camouflage Edit

Some plants mimic the presence of insect eggs on their leaves, dissuading insect species from laying their eggs there. Because female butterflies are less likely to lay their eggs on plants that already have butterfly eggs, some species of neotropical vines of the genus Passiflora (Passion flowers) contain physical structures resembling the yellow eggs of Heliconius butterflies on their leaves, which discourage oviposition by butterflies. [57]

Indirect defenses Edit

Another category of plant defenses are those features that indirectly protect the plant by enhancing the probability of attracting the natural enemies of herbivores. Such an arrangement is known as mutualism, in this case of the "enemy of my enemy" variety. One such feature are semiochemicals, given off by plants. Semiochemicals are a group of volatile organic compounds involved in interactions between organisms. One group of semiochemicals are allelochemicals consisting of allomones, which play a defensive role in interspecies communication, and kairomones, which are used by members of higher trophic levels to locate food sources. When a plant is attacked it releases allelochemics containing an abnormal ratio of these herbivore-induced plant volatiles (HIPVs). [58] [59] Predators sense these volatiles as food cues, attracting them to the damaged plant, and to feeding herbivores. The subsequent reduction in the number of herbivores confers a fitness benefit to the plant and demonstrates the indirect defensive capabilities of semiochemicals. [60] Induced volatiles also have drawbacks, however some studies have suggested that these volatiles attract herbivores. [58]

Plants sometimes provide housing and food items for natural enemies of herbivores, known as "biotic" defense mechanisms, as a means to maintain their presence. For example, trees from the genus Macaranga have adapted their thin stem walls to create ideal housing for an ant species (genus Crematogaster), which, in turn, protects the plant from herbivores. [61] In addition to providing housing, the plant also provides the ant with its exclusive food source from the food bodies produced by the plant. Similarly, several Acacia tree species have developed stipular spines (direct defenses) that are swollen at the base, forming a hollow structure that provides housing for protective ants. Hierdie Acacia trees also produce nectar in extrafloral nectaries on their leaves as food for the ants. [62]

Plant use of endophytic fungi in defense is common. Most plants have endophytes, microbial organisms that live within them. While some cause disease, others protect plants from herbivores and pathogenic microbes. Endophytes can help the plant by producing toxins harmful to other organisms that would attack the plant, such as alkaloid producing fungi which are common in grasses such as tall fescue (Festuca arundinacea). [56]

Leaf shedding and color Edit

There have been suggestions that leaf shedding may be a response that provides protection against diseases and certain kinds of pests such as leaf miners and gall forming insects. [63] Other responses such as the change of leaf colors prior to fall have also been suggested as adaptations that may help undermine the camouflage of herbivores. [64] Autumn leaf color has also been suggested to act as an honest warning signal of defensive commitment towards insect pests that migrate to the trees in autumn. [65] [66]

Defensive structures and chemicals are costly as they require resources that could otherwise be used by plants to maximize growth and reproduction. Many models have been proposed to explore how and why some plants make this investment in defenses against herbivores.

Optimal defense hypothesis Edit

The optimal defense hypothesis attempts to explain how the kinds of defenses a particular plant might use reflect the threats each individual plant faces. [67] This model considers three main factors, namely: risk of attack, value of the plant part, and the cost of defense. [68] [69]

The first factor determining optimal defense is risk: how likely is it that a plant or certain plant parts will be attacked? This is also related to the plant apparency hypothesis, which states that a plant will invest heavily in broadly effective defenses when the plant is easily found by herbivores. [70] Examples of apparent plants that produce generalized protections include long-living trees, shrubs, and perennial grasses. [70] Unapparent plants, such as short-lived plants of early successional stages, on the other hand, preferentially invest in small amounts of qualitative toxins that are effective against all but the most specialized herbivores. [70]

The second factor is the value of protection: would the plant be less able to survive and reproduce after removal of part of its structure by a herbivore? Not all plant parts are of equal evolutionary value, thus valuable parts contain more defenses. A plant's stage of development at the time of feeding also affects the resulting change in fitness. Experimentally, the fitness value of a plant structure is determined by removing that part of the plant and observing the effect. [71] In general, reproductive parts are not as easily replaced as vegetative parts, terminal leaves have greater value than basal leaves, and the loss of plant parts mid-season has a greater negative effect on fitness than removal at the beginning or end of the season. [72] [73] Seeds in particular tend to be very well protected. For example, the seeds of many edible fruits and nuts contain cyanogenic glycosides such as amygdalin. This results from the need to balance the effort needed to make the fruit attractive to animal dispersers while ensuring that the seeds are not destroyed by the animal. [74] [75]

The final consideration is cost: how much will a particular defensive strategy cost a plant in energy and materials? This is particularly important, as energy spent on defense cannot be used for other functions, such as reproduction and growth. The optimal defense hypothesis predicts that plants will allocate more energy towards defense when the benefits of protection outweigh the costs, specifically in situations where there is high herbivore pressure. [76]

Carbon:nutrient balance hypothesis Edit

The carbon:nutrient balance hypothesis, also known as the environmental constraint hypothesis of Carbon Nutrient Balance Model (CNBM), states that the various types of plant defenses are responses to variations in the levels of nutrients in the environment. [77] [78] This hypothesis predicts the Carbon/Nitrogen ratio in plants determines which secondary metabolites will be synthesized. For example, plants growing in nitrogen-poor soils will use carbon-based defenses (mostly digestibility reducers), while those growing in low-carbon environments (such as shady conditions) are more likely to produce nitrogen-based toxins. The hypothesis further predicts that plants can change their defenses in response to changes in nutrients. For example, if plants are grown in low-nitrogen conditions, then these plants will implement a defensive strategy composed of constitutive carbon-based defenses. If nutrient levels subsequently increase, by for example the addition of fertilizers, these carbon-based defenses will decrease.

Growth rate hypothesis Edit

The growth rate hypothesis, also known as the resource availability hypothesis, states that defense strategies are determined by the inherent growth rate of the plant, which is in turn determined by the resources available to the plant. A major assumption is that available resources are the limiting factor in determining the maximum growth rate of a plant species. This model predicts that the level of defense investment will increase as the potential of growth decreases. [79] Additionally, plants in resource-poor areas, with inherently slow-growth rates, tend to have long-lived leaves and twigs, and the loss of plant appendages may result in a loss of scarce and valuable nutrients. [80]

One test of this model involved a reciprocal transplants of seedlings of 20 species of trees between clay soils (nutrient rich) and white sand (nutrient poor) to determine whether trade-offs between growth rate and defenses restrict species to one habitat. When planted in white sand and protected from herbivores, seedlings originating from clay outgrew those originating from the nutrient-poor sand, but in the presence of herbivores the seedlings originating from white sand performed better, likely due to their higher levels of constitutive carbon-based defenses. These finding suggest that defensive strategies limit the habitats of some plants. [81]

Growth-differentiation balance hypothesis Edit

The growth-differentiation balance hypothesis states that plant defenses are a result of a tradeoff between "growth-related processes" and "differentiation-related processes" in different environments. [82] Differentiation-related processes are defined as "processes that enhance the structure or function of existing cells (i.e. maturation and specialization)." [67] A plant will produce chemical defenses only when energy is available from photosynthesis, and plants with the highest concentrations of secondary metabolites are the ones with an intermediate level of available resources. [82]

The GDBH also accounts for tradeoffs between growth and defense over a resource availability gradient. In situations where resources (e.g. water and nutrients) limit photosynthesis, carbon supply is predicted to limit both growth and defense. As resource availability increases, the requirements needed to support photosynthesis are met, allowing for accumulation of carbohydrate in tissues. As resources are not sufficient to meet the large demands of growth, these carbon compounds can instead be partitioned into the synthesis of carbon based secondary metabolites (phenolics, tannins, etc.). In environments where the resource demands for growth are met, carbon is allocated to rapidly dividing meristems (high sink strength) at the expense of secondary metabolism. Thus rapidly growing plants are predicted to contain lower levels of secondary metabolites and vice versa. In addition, the tradeoff predicted by the GDBH may change over time, as evidenced by a recent study on Salix spp. Much support for this hypothesis is present in the literature, and some scientists consider the GDBH the most mature of the plant defense hypotheses. [ aanhaling nodig ] [ opinie ]

Landbou Edit

The variation of plant susceptibility to pests was probably known even in the early stages of agriculture in humans. In historic times, the observation of such variations in susceptibility have provided solutions for major socio-economic problems. The hemipteran pest insect phylloxera was introduced from North America to France in 1860 and in 25 years it destroyed nearly a third (100,000 km 2 ) of French vineyards. Charles Valentine Riley noted that the American species Vitis labrusca was resistant to Phylloxera. Riley, with J. E. Planchon, helped save the French wine industry by suggesting the grafting of the susceptible but high quality grapes onto Vitis labrusca root stocks. [83] The formal study of plant resistance to herbivory was first covered extensively in 1951 by Reginald Henry Painter, who is widely regarded as the founder of this area of research, in his book Plant Resistance to Insects. [84] While this work pioneered further research in the US, the work of Chesnokov was the basis of further research in the USSR. [85]

Fresh growth of grass is sometimes high in prussic acid content and can cause poisoning of grazing livestock. The production of cyanogenic chemicals in grasses is primarily a defense against herbivores. [86] [87]

The human innovation of cooking may have been particularly helpful in overcoming many of the defensive chemicals of plants. Many enzyme inhibitors in cereal grains and pulses, such as trypsin inhibitors prevalent in pulse crops, are denatured by cooking, making them digestible. [88] [89]

It has been known since the late 17th century that plants contain noxious chemicals which are avoided by insects. These chemicals have been used by man as early insecticides in 1690 nicotine was extracted from tobacco and used as a contact insecticide. In 1773, insect infested plants were treated with nicotine fumigation by heating tobacco and blowing the smoke over the plants. [90] The flowers of Chrysanthemum species contain pyrethrin which is a potent insecticide. In later years, the applications of plant resistance became an important area of research in agriculture and plant breeding, particularly because they can serve as a safe and low-cost alternative to the use of pesticides. [91] The important role of secondary plant substances in plant defense was described in the late 1950s by Vincent Dethier and G.S. Fraenkel. [22] [92] The use of botanical pesticides is widespread and notable examples include Azadirachtin from the neem (Azadirachta indica), d-Limonene from Citrus species, Rotenone from Derris, Capsaicin from chili pepper and Pyrethrum. [93]

Natural materials found in the environment also induce plant resistance as well. [94] Chitosan derived from chitin induce a plant's natural defense response against pathogens, diseases and insects including cyst nematodes, both are approved as biopesticides by the EPA to reduce the dependence on toxic pesticides.

The selective breeding of crop plants often involves selection against the plant's intrinsic resistance strategies. This makes crop plant varieties particularly susceptible to pests unlike their wild relatives. In breeding for host-plant resistance, it is often the wild relatives that provide the source of resistance genes. These genes are incorporated using conventional approaches to plant breeding, but have also been augmented by recombinant techniques, which allow introduction of genes from completely unrelated organisms. The most famous transgenic approach is the introduction of genes from the bacterial species, Bacillus thuringiensis, into plants. The bacterium produces proteins that, when ingested, kill lepidopteran caterpillars. The gene encoding for these highly toxic proteins, when introduced into the host plant genome, confers resistance against caterpillars, when the same toxic proteins are produced within the plant. This approach is controversial, however, due to the possibility of ecological and toxicological side effects. [95]

Pharmaceutical Edit

Many currently available pharmaceuticals are derived from the secondary metabolites plants use to protect themselves from herbivores, including opium, aspirin, cocaine, and atropine. [96] These chemicals have evolved to affect the biochemistry of insects in very specific ways. However, many of these biochemical pathways are conserved in vertebrates, including humans, and the chemicals act on human biochemistry in ways similar to that of insects. It has therefore been suggested that the study of plant-insect interactions may help in bioprospecting. [97]

There is evidence that humans began using plant alkaloids in medical preparations as early as 3000 B.C. [31] Although the active components of most medicinal plants have been isolated only recently (beginning in the early 19th century) these substances have been used as drugs throughout the human history in potions, medicines, teas and as poisons. For example, to combat herbivory by the larvae of some Lepidoptera species, Cinchona trees produce a variety of alkaloids, the most familiar of which is quinine. Quinine is extremely bitter, making the bark of the tree quite unpalatable. It is also an anti-fever agent, known as Jesuit's bark, and is especially useful in treating malaria. [98]

Throughout history mandrakes (Mandragora officinarum) have been highly sought after for their reputed aphrodisiac properties. However, the roots of the mandrake plant also contain large quantities of the alkaloid scopolamine, which, at high doses, acts as a central nervous system depressant, and makes the plant highly toxic to herbivores. Scopolamine was later found to be medicinally used for pain management prior to and during labor in smaller doses it is used to prevent motion sickness. [99] One of the most well-known medicinally valuable terpenes is an anticancer drug, taxol, isolated from the bark of the Pacific yew, Taxus brevifolia, in the early 1960s. [100]

Biological pest control Edit

Repellent companion planting, defensive live fencing hedges, and "obstructive-repellent" interplanting, with host-plant resistance species as beneficial 'biological control agents' is a technique in biological pest control programs for: organic gardening, wildlife gardening, sustainable gardening, and sustainable landscaping in organic farming and sustainable agriculture and in restoration ecology methods for habitat restoration projects.


Cancer Drug Resistance: Unraveling Its Complexity

It’s a heartbreaking story, and one that happens too often. A patient with advanced cancer receives a drug that helps shrink their tumors, allowing them more time with family, but then weeks or months later the cancer comes back and the drug no longer works.

Drug resistance remains one of the biggest challenges in cancer therapy. It exists across all types of cancer and all modes of treatment, including molecularly targeted therapy, immunotherapy, and chemotherapy. Solving the puzzle of why cancers become resistant to therapy and how to overcome or prevent it is a goal that NCI is pursuing on many fronts, including basic science to understand biological mechanisms and clinical trials testing new treatment strategies.

Multiple factors, within cancer cells themselves and in the local environment in which the cancer cells exist (the tumor microenvironment), contribute to how well a drug works. These factors may differ from patient to patient and even among tumors in a single patient. Tumors are made of diverse cells that may have different genetic, epigenetic, and metabolic characteristics that have different sensitivities to treatment. Tumors also consist of immune cells, blood vessels, fibroblasts, and other cells and components that interact with the cancer cells. These interactions often promote tumor development, progression, and response to treatment.

Having Faith in Science to Treat Prostate Cancer

Although a drug may kill some cancer cells, almost invariably a subset of them will be resistant and survive the treatment. Cancers often have multiple mechanisms for surviving and growing, which may change over time and in response to treatment. That is why combining treatments that have different mechanisms of action can kill more cancer cells and reduce the chance that drug resistance will emerge.

Most of the research on drug resistance has focused on identifying genetic mechanisms, such as mutations that alter a protein such that it impairs the binding of a drug. Research is revealing the importance of additional mechanisms of drug resistance, such as epigenetic factors that regulate the activity of genes and the dynamics between diverse cells in the tumor microenvironment. Overcoming resistance, then, requires understanding these complex biological processes in the first place, to better anticipate and steer the dynamic, multidimensional evolutionary process unfolding inside a patient with cancer.

Aided by advanced preclinical tools and new drug design approaches, NCI-funded researchers are revealing a clearer picture of cancer drug resistance and developing new treatment approaches to overcome it.

Targeting Cancer Cell Plasticity

Starting in 2006, doctors began to describe rare cases of patients with non-small cell lung cancer (NSCLC) whose cancers transformed into small cell lung cancer after treatment with EGFR inhibitors. This change in cell identity is one type of what scientists refer to as cell plasticity, and NCI-funded research is piecing together the puzzle of how it may hinder cancer treatment.

Cell plasticity is a cell’s ability to undergo changes that alter its appearance and function (its phenotype). These changes can occur in cancer cells because of genetic and nongenetic alterations, cues from other cells in the tumor microenvironment, and/or drug treatment. A cell’s ability to change and adapt offers it additional routes to resist treatment.

More recently, similar observations emerged from men with prostate cancer who were treated with androgen deprivation therapy: aggressive and deadly forms of neuroendocrine prostate cancers emerged. In addition to NSCLC and prostate cancer, scientists have described cell plasticity in several additional cancer types, including melanoma and breast cancer.

While different cancers demonstrate their own patterns of cell plasticity, NCI-funded research has revealed some biological mechanisms that are common across cancer types. For example, research supported by NCI has implicated EZH2, an enzyme that regulates gene expression, in the ability of both NSCLC and prostate cancer to change phenotypes. Thus, research on one cancer may enrich studies of resistance patterns in other cancers, resulting in the identification of treatments that could work for several cancer types. This example illustrates that our understanding of the fundamental and molecular mechanisms of cancer is fueling advances in precision oncology, including drugs approved to treat cancers with specific genetic abnormalities rather than where in the body the cancer started.

Treating Cancers Like Evolving Ecosystems

A tumor can be thought of as an ecological system that evolves over time. Researchers are therefore applying the concepts of evolutionary ecology to study cancer and its response to treatment. Evolutionary ecology is a scientific field that examines how interactions among species and between species and their environment shape species through selection and adaptation, and the consequences of the resulting evolutionary change.

As an example, NCI-funded research led by investigators at Cleveland Clinic and Case Comprehensive Cancer Center recently developed an "evolutionary game assay" that directly quantifies and describes the interactions between tumor cells that are sensitive and resistant to a targeted therapy in an experimental model of NSCLC. They found that the interactions between cells were different under different conditions. The researchers suggest that changing the types of interactions between cells—in other words, the "games they play"—can co-opt the cells’ evolution to better help the patient by preventing drug-resistant cells from “winning.”

Other NCI-funded studies are testing whether different drug doses and schedules might decrease the likelihood that drug resistance will develop as a result of evolutionary dynamics. For example, if drugs can be given in a way that allows a proportion of the easier-to-treat sensitive cells to disproportionately survive, they may compete with and block the growth of the resistant cells in the tumor. With this adaptive cancer therapy approach, it is possible that the tumor may never be completely eradicated, but it may remain relatively stable, thereby limiting the development of uncontrollable drug resistance.

Degrading—Not Blocking—the Target to Avoid Resistance

Using new technology to degrade proteins of interest, such as those that drive cancer cell growth, is an emerging cancer treatment strategy. One example of this technology is called proteolysis targeting chimera (PROTAC), in which molecules are generated that tag a specific protein for degradation by a cell’s normal machinery for getting rid of unwanted or damaged proteins. An advantage of this approach is that it can avoid some mechanisms of drug resistance seen with some cancer therapies, such as mutations in the target of a drug or overexpression of the target.

For example, NCI-funded researchers at Yale University created a PROTAC molecule as a potential treatment for advanced prostate cancer. Androgen receptor (AR) signaling plays a pivotal role in prostate cancer initiation and growth, and drugs that inhibit ARs are the standard of care for patients with metastatic disease. Unfortunately, most tumors treated with AR inhibitors eventually develop drug resistance. Some mechanisms of resistance result in continued AR signaling despite the presence of these drugs.

The PROTAC molecule the Yale team invented consists of an AR-targeting portion and a portion that binds selectively to a protein, called E3 ligase. The E3 ligase is part of the cell’s normal machinery that degrades proteins. With additional support from NCI’s Small Business Innovation Research (SBIR) program, Arvinas, Inc. of New Haven, Connecticut, is further developing and testing this PROTAC in clinical trials for patients with metastatic prostate cancer whose cancer has progressed after AR therapy.

With the help of NCI funding, PROTAC and other similar technologies have shown promise in addressing resistance in other cancer types, including chronic lymphocytic leukemia that has become resistant to the drug ibrutinib (Imbruvica).

Using Advanced Preclinical Models to Address Resistance

Researchers have traditionally used cancer cell lines to study mutations and other mechanisms that make cancer cells sensitive or resistant to therapies. But cell lines do not always share key features of cancers found in patients. In addition, cancer cell lines lack the three-dimensional structure of a tumor found in a person and the relationships with surrounding cells in the tumor microenvironment.

Animal models, such as mice that carry tumors implanted from a sample of a patient’s cancer, can more closely resemble the tumors found in humans. The tumor microenvironment and cancer growth, progression, and treatment effects of animal models more closely mimic those found in people. However, animal models are expensive, can take months to produce, and are not made in large enough quantities for testing more than a few drugs at a time. They also lack an intact immune system, making them inadequate to study the interaction between the immune system and cancer. While current cancer models are useful for answering some research questions, additional tools are needed.

NCI-funded researchers are leveraging new technologies and models to gain a fuller understanding of drug resistance. They include three-dimensional human tumor cultures and engineered platforms that support living human tissues, both of which incorporate cells that surround and interact with tumor cells in the tumor microenvironment to mimic conditions in the human body.

Miniature tumors called patient-derived tumor organoids are three-dimensional cancer cell clusters grown in the lab from a sample of a patient’s tumor. Scientists are using them in the laboratory to study various aspects of cancer biology, including mechanisms of drug resistance. Researchers have developed organoids from a variety of cancer types, including breast, prostate, liver, brain, and pancreatic cancer.

One example of this research is in pancreatic cancer, which is one of the most lethal cancer types, in part because it is largely resistant to treatment and is generally detected at a late stage after the cancer has spread. NCI-funded researchers at Cold Spring Harbor Laboratory in New York and their collaborators have created a “living library” of pancreatic cancer organoids derived from patient samples from multiple clinical institutions. In a retrospective analysis of a small number of patients, the organoid’s sensitivity to chemotherapy reflected the patient’s response to therapy. In addition, tumor sampling in a single patient over time predicted the development of chemotherapy resistance that paralleled disease progression in the patient. Understanding why resistance emerges and having models to help predict it could improve the selection of treatments for patients in the future.

Scientists are developing additional cancer models that accurately represent the structure and function of tumors in human organs and tissues. For example, tissue chips are three-dimensional cross sections of living human tissue on a device about the size of a computer memory stick. For cancer researchers, tissue chips and other engineered tumor systems are enhancing the understanding of tumor physiology and aiding cancer treatment research.

For example, NCI is funding research projects that are developing and using engineered tumor systems to study drug response and resistance in cancers of the brain, ovaries, and breast. In addition, NCI’s SBIR program has supported several companies developing cancer chips, including one developed by researchers at the University of Virginia and HemoShear Therapeutics, LLC of Charlottesville, Virginia, to assess drug sensitivity and resistance in pancreatic cancer.


Landmark TB Trial Identifies Shorter-Course Treatment Regimen

Results from an international, randomized, controlled clinical trial indicate that a four-month daily treatment regimen containing high-dose, or “optimized,” rifapentine with moxifloxacin is as safe and effective as the existing standard six-month daily regimen at curing drug-susceptible tuberculosis (TB) disease. This regimen is the first successful short-course treatment regimen for drug-susceptible TB disease in almost 40 years. TB is one of the most important global health problems. According to recent estimates from the World Health Organization, 10 million new TB cases and 1.4 million deaths from TB occurred globally in 2019. While the United States has achieved substantial progress in reducing TB, with fewer than 10,000 cases each year, too many people still suffer from TB disease.

The Phase 3, open-label trial, called Study 31/A5349, was led by the U.S. Centers for Disease Control and Prevention’s (CDC) Tuberculosis Trials Consortium (TBTC) with collaboration from the AIDS Clinical Trials Group (ACTG) funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. It is the largest drug-susceptible TB disease treatment trial that CDC or NIAID has ever conducted, with more than 2,500 participants ages 12 and older enrolled at 34 clinical sites in 13 countries. The trial included 214 people with HIV. Results were presented today at the virtual Union World Conference on Lung Health and have been submitted for publication.

Shortening treatment for TB disease can benefit patients, families, healthcare providers and health systems. Shorter TB disease treatment regimens can help patients more easily complete treatment for TB disease than they would on the existing standard regimen. This is especially important in the era of COVID-19, which has caused widespread disruptions to care and treatment access for many people with TB disease. The availability of shorter regimens enables patients to be cured faster, and has the potential to reduce treatment costs, improve patient quality of life, increase completion of therapy, and reduce development of drug resistance.

“The CDC’s TB Trials Consortium is a global leader in driving innovation and advances in TB treatment and prevention, such as this new four-month regimen,” said Philip LoBue, MD, FACP, FCCP, director of CDC’s Division of Tuberculosis Elimination. “These results help bring us closer to our goal of TB elimination, and we are grateful to the researchers, clinical staff, and most of all, study participants, for their important contributions.”

“These robust findings have the potential to change clinical practice by offering people with drug-susceptible TB an additional, shorter-course treatment option that is safe, effective and potentially more convenient,” said Carl W. Dieffenbach, PhD, director of the NIAID Division of AIDS. “The Study 31/A5349 trial was completed right on schedule, demonstrating the effectiveness of the collaboration between CDC and NIAID.”

Study 31/A5349 examined the efficacy and safety of two four-month regimens with high-dose rifapentine with or without moxifloxacin for the treatment of drug-susceptible TB disease. These were compared with the existing six-month regimen (2RHZE/4RH), which includes eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol and 18 weeks of daily treatment with rifampin and isoniazid.

One of the four-month regimens – 2PHZM/2PHM – included eight weeks of daily treatment with high-dose, or “optimized,” rifapentine, isoniazid, pyrazinamide, and moxifloxacin and nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin. At the conclusion of the trial, the four-month regimen met non-inferiority criteria for efficacy in all of the several planned analyses and was safe and well-tolerated.

A second new treatment regimen used in this study – 2PHZE/2PH – included eight weeks of daily treatment with the same dose of rifapentine, isoniazid, pyrazinamide, and ethambutol and nine weeks of daily treatment with rifapentine and isoniazid. This new regimen did not meet non-inferiority criteria when compared to the existing standard regimen.

The safety profile for this trial demonstrates that the proportion of patients who experienced adverse events was similar among patients in all three groups of participants (control and the two novel regimen groups). This means that the novel regimens do not pose greater risk to patients than currently used regimens.

Study 31/A5349 will inform future TB treatment in the U.S. CDC and NIH will continue to work with TB control programs and clinicians to improve available treatment and prevention regimens for TB disease.

EVENT:
Study 31/A5349 was presented today at the 51st Union World Conference on Lung Health, held virtually from October 20-24, 2020.

WHO:
CDC’s Division of Tuberculosis Elimination Director, Philip LoBue, and NIAID’s Division of AIDS Director, Carl Dieffenbach, are available for comment on this study’s implications for the future of TB disease treatment.


On the Cover

The cover image is based on the Original Article entitled A potent neutralizing nanobody against SARS-CoV-2 with inhaled delivery potential by Junwei Gai et al., MedComm. 2021 2:101-113. https://doi.org/10.1002/mco2.60

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