Kyynpuremista jälleen uutisia Suomen lehdissä . Ruotsalaisohjeita

 http://www.iltalehti.fi/terveys/201607180094923_tr.shtml?_ga=1.67765716.438323517.1469133725

Katson erään vanhan kirjoitukseni tähän esiin vuodelta 2006 ja päivitän linkkejä.

Ohjeita kyynpuremasta  ruotsinkielellä. Suomalaisia kommentteja ohessa.

http://www.1177.se/Fakta-och-rad/Sjukdomar/Huggormsbett/

HUGGORMSBETT

Myrkyllisistä eläimistä saadaan informaatiota myrkytyskeskuksesta: 

https://www.giftinformation.se/djurregister/

"Vuosittain hoidetaan sairaalassa  250- 300 henkilöä kyynpureman takia ja heistä 20- 30%  on kohtalaisesta tai vakava-asteisesti oireilevia Kyynpureman jälkeiset reaktiot vaihtelevat kuitenkin vahvasti riippuen  kehoon joutuneen myrkyn määrästä.  25- 30 ¤:ssa  tapauksista  ei oireita tulekaan ja silloin ei mitään myrkkyä ole ruiskunut kehon sisään. On tavallista  havaita kaksi opientä puremajälkeä 6-9 millimetrin  päässä toisistaan".

Årligen vårdas cirka 250-300 personer på sjukhus till följd av huggormsbett och av dem får 20-30% måttliga till allvarliga symtom. Reaktionen efter huggormsbett varierar dock kraftigt beroende på mängd injicerat gift. I 25-30% av fallen uteblir symtom, vilket beror på att inget gift sprutats in. Vanligen ser man två små bettmärken med 6-9 mm mellanrum.

Oireet,  Symtom

"Jos kyy ruiskuttaa kehoon myrkkyään, aiheutuu  useimmiten heti  kipua ja myöhemmin  sinivihervää   turvotusta puremakohdan ympärille Jos kyse on vakavasta reaktiosta voi yleisoireita tulla jo varhain: huimausta, pahoinvointia ja oksentelua, ripulia, mahakipuja, hengitysvaikeuksia, verenpaineen putoamaa, sydänvaikutusta ja tajunnantason alenemaa. Turvotus ja ihon viherväksi värjäytyminen voi levitä ja käsittää koko purrun kehonosan ja myös osia vartalosta. Yleensä  turvotukset hellittävät parissa viikossa, mutta  pysyviä tai toistuvia vaivoja voi esiintyä".

• Om en huggorm injicerar gift medför det i de flesta fall smärta och senare en blåaktig svullnad kring bettstället. I allvarliga fall kan man redan tidigt bli allmänpåverkad med symtom som yrsel, illamående och kräkningar, diarré, buksmärtor, andningssvårigheter, blodtrycksfall, hjärtpåverkan och sänkt medvetandegrad. Svullnaden och missfärgningen kan spridas och omfatta hela den bitna kroppsdelen och också delar av bålen. I regel klingar svullnaden av inom ett par veckor men kvarstående eller återkommande besvär kan förekomma.

"Pidä mielessäsi  että sopivat kengät tai saappaat voivat suojata kyynpuremalta. Useimpia puree kyy jalkaantai nilkkaan   

 Älä    koskaan lähde  noukkimaan käärmeitä". 

 Tänk på

• att lämpliga skor eller stövlar kan skydda mot ormbett. De flesta blir bitna i foten eller ankeln.
• att aldrig plocka upp ormar.

 Eräs  uutinen kissoista ja koirista  7.6. 2005.   Sitaatti.

Time for business lehteä  jaettiin ohikulkijoille Göteborgin asemalla 7.6.2006. . Eräs artikkeli kiinosti. Se koski eläimia ja käärmeenpistoja. Artikkeli ketoo  lempieläintenm koirien ja kissojen, saamista kyynpuremista.

”1400 hundar och 4000 katter blir huggormsbitna i sommar. Även om mörkertalet är stort visar statistiken att minst 1400 hundar och 4000 katter blir huggomrsbitna i sommar. De flesta djur blir återställda om de får vård inom rimlig tid. Det är i nosen och i tassarna som ormen oftast biter- en konsekvens av djurens nyfikenhet och lek. Den bitna kroppsdelen svullnar upp. Tittar du noga kan du se bitmärken med 6-9 mms mellanrum. Giftet kan orsaka blodbrist och skada både levern och njurarna. Med veterinärvård inom rimlig tid kan djuret bli återställt. Ett tiotal hundar och katter dör däremot årligen.Men mörkertalet är stort. Våra uppgifter kommer från djur vars ägare köpt en försäkring för att kunna kosta på sitt djur veterinärvård. Men i dag är hälften av alla hundar och åtta av tio katter oförsäkrade. Dessa djur får oftast klara sig bäst de vill, säger Lotta Gunnarsson, veterinär på Agria Djurförsäkring.

Att vårda en hund som blivit ormbiten kostar snitt 2600 kronor. För katterna är genomsnittspriset något lägre, runt 2000 kronor.Men för djur som måste ha intensivvårdsbehandling stannar prislappen sällan under 10 000 kronor, fortsätter Lotta. Hon råder djurägare i ormtäta områden, som till exempel skärgården och skogslösa landskap, att be sin veterinär skriva ut kortison som de kan använda om olyckan skulle vara framme.

Framför allt under semestertider när det kan vara långt till veterinären, avslutar lotta Gunnarsson. Agrias veterinärs råd vid huggormsbett: inspektera och leta efter bettet. Ge kortison enligt veterinärens ordination. Om du kan få tag på is -lägg ett kylande omslag. Håll hunden i stillhet, speciellt om bettet tagit i tassar eller ben.Uppsök veterinär. Uppgifterna är beräknade med hjälp av Agrias skadestatistik. Hänsyn har tagits till djur som saknar försäkring eller som är försäkrade i annat  bolag." www.timeforbusiness.nu

KOMMENTTI

Tästä erosta ihmisten ja eläinten välisiin purematiheyksiin huomaa, että eläimet eivät osaa varoa käärmettä, kissalle se on tietysti leikkiin houkutteleva mato kalan veroinen ravinteena ja koiralle uteliaisuuden kohde ainakin, ellei lisäksi makupalalta näyttävä.

Sietää ehkä tiedottaa koirien ulkoiluttajille moisestakin vaarasta. Lapsille ja itselleen tietysti voi katsoa saappaat jalkaan, jos on tuntematonta seutua tarvottavana. Moni pieni lapsikaan ei osaa pelätä tai   välttää myrkyllisten ja vaarallisten eläinten vaaraa. 

Tavallisimpia ohjeita kyyn pistettyä:

• RAUHALLISENA PYSYTTELY on tärkeää, jotta verenkierto ei vilkastu turhan nopeaksi ja samalla levitä myrkkyä.
  LEPO paikallaan, jos mahdollista on myös hyvin tärkeä saman asian takia. Jos kädessä tai jalassa on purema, raajaa voi pitää koholle tuettuna
  Ei kannata tehdä yhtään mitään juuri pistokohtaan. JÄTÄ PISTOKOHTA RAUHAAN.
  Soita LÄÄKÄRILLE tai MYRKYTYSKESKUKSEEN.
  Kaikki kyynpuremat ihmiset tulee saattaa sairaalatarkkailuun tai terveyskeskukseen.
  Jos yleisoireet tulevat nopeasti on syytä kutsua AMBULANSSI.

Råd vid huggormsbett:

• Lugna den bitne, som kan vara rädd och orolig.
• Vila och håll den bitna kroppsdelen stilla, helst i högläge.
• Lämna bettstället helt i fred.
• Ring läkare eller Giftinformationscentralen för råd.
• Alla som blivit huggormsbitna bör observeras på sjukhus eller vårdcentral.
• Vid snabbt insättande allmänpåverkan ring nödsamtal  för ambulans.

KOMMENTTINI:

Älä ajattele, että " käärmekin pitää ottaa talteen terveyskeskusta varten talteen"! Ainakin jos se on tavallinen kyy, ei ole mitään  syytä ottaa sitä mukaan. Käärme on kiinnostunut lähinnä vain omasta elämästään ja on vain puolustautunut, jos olet sitä tallannut tai jos olet uhannut sen poikasia tai pesää tietämättäsi. Jos näet käärmeen lähellä, voi lähinnä odottaa sen lähtevän pakoon ensimmäisenä! Käärmeen intresseistä Pohjoismaissa ihmisen suhteen tietysti on hyvä kerätä tietoa.
 Mutta on paljon myös vieraita käärmeitä, joita on turistien mukana tullut ja maahan tuotettu ja sitten niitä on  ehkä päässyt karkaamaan vahingossa luontoon. Näillä on erilainen käyttäytyminen kuin kotimaisella kyyllä, jota voi pitää - sen kohtuullisissa mitoissa esiintyessä - hyötyeläimenä ja myyrien ym hävittäjänä. Jos käärme on kyystä poikkeava, on hyvä tehdä jokin havainto, sillä muitten myrkkykäärmeiden myrkyt ovat pahempia.. mutta havainnon tekemiseksi ei kannata altistua pahemmalle. On tavallista, että käärme voi herättää sellaistakin kauhua, että henkilö ei pysty noudattamaan mitään  yllä olevista ohjeista ja esim. keskittyy esim  käärmeen tappamiseen ja  perässä juoksemiseen, jolloin  saattaa  nopeastikin  lyyhistyä- tai joutuu paniikkiin ja pakokauhuun.

Myrkyssä olevat neurotoksiinit voivat aiheuttaa perifeerisiä halvauksia ja niillä on sydänvaikutusta. Käärmeenpurema saattaa aina olla tällaista pahintakin laatua, joten on syytä päästä ajoissa sairaalaan tai poliklinikalle;  hemolyysi voi alkaa vasta tuntien kuluttua, joten ensialun pienet puremat voidaan arvioida väärin, kun ei tidetä miten paljon myrkkyjä on pureman mukana tullut kehoon. Myrkkymäärät ovat erilaisia eri tilanteissa ja käärmeen asennoimisesta riippuviakin. Se voi säätää enemmän myrkkyä esiin. Myrkky säätyy eritavalla esim jos se vain yllätettynä puolustautuu tai jos se haluaa tappaa jonkin uhrin syödäkseen sen sitten. Myrkyn määrä on erilainen, jos se on juuri syönyt tai ollut viikkoja syömättä. Joten ihmisen osuus on vain päästä nopeasti hoitoon jäämättä pohtimaan käärmeen myrkyn mahdollista  kehitysfaasia.

 Suomalaisilla on tavallisesti mukana kesällä KÄÄRMEPAKKAUS. Niitä saa joka apteekista kautta koko maan ilman reseptiä.

”Lääkeopas

KÄÄRMEPAKKAUS    -ORGANON-
Reseptivalmiste
Lääkemuoto:
Tabletti, jossa on 1,5 milligrammaa vaikuttavaa ainetta.
Vaikuttava-aine:
Deksametasoni, joka kuuluu ns. kortisonivalmisteisiin.
Käyttötarkoitus:
Tabletteja käytetään ensiapuna käärmeen pureman sekä mehiläisen ja ampiaisen piston hoidossa.
Vaikutustapa:
Deksametasoni lievittää erilaisia yliherkkyys - eli allergiaoireita.
Annostus:
Käärmeen puremaan tai hyönteisen pistoon käytettäessä lääkettä tulee antaa mahdollisimman nopeasti tällaisen tapauksen jälkeen. Annettavien tablettien määrä riippuu iästä seuraavasti: 0 - 4 -vuotiaat: 1 tabletti, 5 - 10 -vuotiaat: 2 tablettia, 11 - 15 -vuotiaat: 3 tablettia, yli 15 -vuotiaat: 4 tablettia.

Lääkkeen ottaminen:
Käärmeenpureman ja mehiläisen piston ensiavussa otetaan tablettien kanssa mahdollisimman vähän nestettä. Pureman saanutta raajaa ei pitäisi liikuttaa, koska myrkky leviää tällöin nopeammin. Kyyn purema kuuluu lääkärin hoitoon.
Haittavaikutukset:
Tavanomaisessa käytössä haittavaikutukset ovat yleensä vähäisiä tai niitä ei tule lainkaan.
Raskaus ja imetys:
Pureman edellyttämän lääkeannoksen voi ottaa myös raskauden aikana ja imetyksen yhteydessä.
Säilytys:
Tabletit säilytetään kuivassa paikassa huoneenlämmössä, +15-+25 asteessa. Niitä ei pidä jättää talven ajaksi kylmilleen jäävälle kesämökille, koska pakkanen vähentää lääkkeen tehoa. Kelpoisuusaika pakkauksessa.
Pakkaukset:
Valmistetta saa 4 tabletin pakkauksissa.
ATC-koodi:
H02AB02
Markkinoija:
Oy Organon Ab
Tuotetiedot päivitetty: Lähde: Lääkeopas”

• SITAATTI  Ruotsalaisista  tänä kesänä päivitetyistä nettiohjeista: Hyvä muistaa kyitten mahdollisuus kun nyt on helleaalto!

"Huggormsbett

Skriv ut (ca 1 sida)

Huggormsbett gör oftast ont och visar sig för det mesta som två små hål eller prickar bredvid varandra på huden, med 6-9 millimeters mellanrum. Det är vanligt att det runt bettet uppstår en svullnad som kan sprida sig längs den kroppsdel som har blivit biten.

• 
  

  Huggorm.

  Mer information

Att bli biten av en huggorm kan leda till väldigt olika reaktioner. Knappt hälften av de som har blivit huggormsbitna får inte några symtom, vilket beror på att inget gift har sprutats in. En del får bara en obetydlig svullnad, medan andra kan bli mycket sjuka. Hur starkt du reagerar beror på mängden gift som har kommit in i kroppen och var du har blivit biten. Barn, gamla och gravida är särskilt känsliga.

Ring Giftinformationscentralen

Eftersom det är svårt att veta hur du reagerar på huggormsbett ska du alltid ringa Giftinformationscentralen via 112 eller på telefon 010-456 67 00 för att få råd när du har blivit huggormsbiten.

Åk till sjukhus

Alla som har blivit huggormsbitna ska till närmaste akutmottagning för observation.
Vid allmänpåverkan som illamående, kräkningar, magsmärtor, diarré, yrsel, kallsvettning, hjärtklappning, svullna läppar eller andningsbesvär ska du genast ringa 112 för hjälp med transport till sjukhus.
Är du opåverkad ska du inte åka ensam utan be om hjälp med att ta dig dit.

Innan du kommer till sjukhus

• Var stilla och vila eftersom giftet sprids fortare vid ansträngning.
• Håll den bitna kroppsdelen i stillhet, och gärna högt.
• Ta av åtsittande saker som skor, ringar och klocka eftersom området runt bettstället ofta svullnar upp.
• Lämna bettstället helt ifred. Försök inte suga ut giftet, kyla, värma eller dra åt ett skärp eller liknande runt den ormbitna kroppsdelen. Det kan förvärra förloppet.

Behandling med huggormsserum

Det finns huggormsserum som effektivt kan hejda sjukdomsförloppet om du har reagerat starkt på bettet.

Tipsa och dela

Skriv ut (ca 1 sida)

Senast uppdaterad:

2016-02-23

Redaktör:

Åsa Schelin, 1177 Vårdguiden"

HYVÄ myös tietää, että käärmeen myrkkyjä on paljon tutkittu ja niistä on tässäkin blogissa vähän tekstiä:  Käärmeenmyrkyn metalloproteinaaseista   (SVMPs)

Ottaen huomioon, että käärme syö harvoin ja kun se syö se nielee uhrin  nahkoineen karvoineen- ja sen takia sen myrkky on   yhdistelmä  vahvoja uhrin sulattavia metalloproteinaaseja.

Ihmiskehossakin on oma  säädelty metalloproteinaasien  työkalujärjestelmä, että keho sorvautuu  ajan myötä sopivasti   ja suonet toisaalta pysyvät aukinaisina ja  jätekudokset  siivottuina pois.
Mutta jos MMP järjestelmä menee pois jenkoiltaan, ei ole vielä  lääkkeellistä kykyä hallita tätä järjestelmää. Löytyy asia kerrallaan. Esim ebolaviruksen aiheuttama kehotuho onmyös  MMP-järjestelmän rajua  laavamaista  toimintaa, mikä johtaa ihmisen nopeaan menehtymiseen. MMP-järjestelmän aktivoituminen vaatii tietyn  asteittaisen kulun ja se on aikatekijä. Arvaamaton tekijä, koska MMP- järjestelmästä ei ole tarpeeksi tietoa.
 Toistaiseksi  ehkä vain suuri kortisonimäärä voisi  stabilisoida solukalvoja ensiapuna.

Angiotensiini II rajoittaa fibrinolyyttistä järjestelmää maksavauriossa

Select item 2667029114.

LÄHDE:  Attrition of Hepatic Damage Inflicted by Angiotensin II with α-Tocopherol and β-Carotene in Experimental Apolipoprotein E Knock-out Mice.

Gopal K, Gowtham M, Sachin S, Ravishankar Ram M, Shankar EM, Kamarul T.

Sci Rep. 2015 Dec 16;5:18300. doi: 10.1038/srep18300.

TIIVISTELMÄ

Angiotensiini II on yksi niistä säätelyllisistä peptideistä, joita mainitaan maksataudin patogeneesin yhteydessä. Tässä työssä tutkijoita kiinnostaa saada tietää, mikä piilee  E-vitamiinin ( alfa-tokoferolin) ja  beta-karoteenin terveysvaikutusten  taustalla  maksan patologiassa.  He tutkivat Angiotensiini II:n osuuden taustamekanismia maksavauriossa ja  sitä, voisiko  alfa-tokoferoli- ja beta-karoteenilisät  vähentää maksavauriota. 

 Maksavaurio  aiheutettiin Apoe(-/-)koehiirissä angiotensiini II- infuusioilla ja sen jälkeen annettiin  alfa-tokoferoli- ja  betakaroteenipitoista rehua 60 päivää.  Tutkimukset osoittivat, fibroosia, Kupfferin solujen hyperplasiaa, maksasolujen degeneroitumista ja maksasolujen apoptoosia, sinusoidien laajenemista ja verenvuotoja;  myös  nesteen kertymästä oli näyttöä; vapaitten happiradikaalien pitoisuus oli noussut ja AST ja ALT aktiivisuudet  olivat lisääntyneet. Lisäksi tPA ja uPA olivat alassäätyneet, koska niiden  inhibiittori  PAI-1 oli 42-kertaisesti ylössäätynyt. Alassäätyneenä olivat  MMP-2, MMP-9, MMP-12 ja M-CSF niissä eläimissä, jotka olivat Angiotensiini II:lla käsiteltyjä. 

Selvästi pystyivät  alfa-tokoferoli ja betakaroteenikäsittelyt kontrolloimaan vapaita happiradikaaleja (ROS), fibroosia, hepatosyytin degeneraatiota, Kupfferin solujen hyperplasiaa, hepatosyyttien apoptoosia, laskimosinusoidien laajenemista ja nesteen kertymistä sekä maksaentsyymien  pitoisuuksia.

Lisäksi  betakaroteenikäsittely vaikutti huomattavasti PAI-1, tPA ja uPA expressioiden kontrollia. 

Tutkijat tekivät johtopäätöksen, että  Angiotensiini II  vaikutti  selvästi  maksavaurioon mahdollisesti rajoittamalla fibrinolyyttistä järjestelmää. 

Tutkijat tekivät johtopäätöksen, että alfa-tokoferoli- ja betakaroteenihoidosta on terveydellistä  vaikutusta  maksan patologian korjaamisessa. 

Abstract

Angiotensin II is one of the key regulatory peptides implicated in the pathogenesis of liver disease. The mechanisms underlying the salubrious role of α-tocopherol and β-carotene on liver pathology have not been comprehensively assessed. Here, we investigated the mechanisms underlying the role of Angiotensin II on hepatic damage and if α-tocopherol and β-carotene supplementation attenuates hepatic damage. Hepatic damage was induced in Apoe(-/-)mice by infusion of Angiotensin II followed by oral administration with α-tocopherol and β-carotene-enriched diet for 60 days. Investigations showed fibrosis, kupffer cell hyperplasia, hepatocyte degeneration and hepatic cell apoptosis; sinusoidal dilatation along with haemorrhages; evidence of fluid accumulation; increased ROS level and increased AST and ALT activities. In addition, tPA and uPA were down-regulated due to 42-fold up-regulation of PAI-1. MMP-2, MMP-9, MMP-12, and M-CSF were down-regulated in Angiotensin II-treated animals. Notably, α-tocopherol and β-carotene treatment controlled ROS, fibrosis, hepatocyte degeneration, kupffer cell hyperplasia, hepatocyte apoptosis, sinusoidal dilatation and fluid accumulation in the liver sinusoids, and liver enzyme levels. In addition, PAI-1, tPA and uPA expressions were markedly controlled by β-carotene treatment. Thus, Angiotensin II markedly influenced hepatic damage possibly by restraining fibrinolytic system. We concluded that α-tocopherol and β-carotene treatment has salubrious role in repairing hepatic pathology.

Free PMC Article

Similar articles

Suomennosta 16.3. 2016 

Mikä pitää yll pinttynyttä maksakirroosia?

Select item 2661389118.

LÄHDE:  Persistence of cirrhosis is maintained by intrahepatic regulatory T cells that inhibit fibrosis resolution by regulating the balance of tissue inhibitors of metalloproteinases and matrix metalloproteinases.

Zhang X, Feng M, Liu X, Bai L, Kong M, Chen Y, Zheng S, Liu S, Wan YJ, Duan Z, Han YP.

Transl Res. 2016 Mar;169:67-79.e2. doi: 10.1016/j.trsl.2015.10.008. Epub 2015 Nov 6.

TIIVISTELMÄ (Suomennosta)
FIBROOSI on tulosta extrasellulaarisen matrixin (ECM)  epänormaalista kertymisestä ja fibroplasian tehottomasta purkaantumisesta.  Fibroottisissa kudoksissa  ja perifeerisessä veressä esiintyy  T-imusoluja (Treg) niillä potilailla, joilla on kirroosia tai hepatosellulaarista syöpää. (Solujen tuntomerkit
 CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs)).
Ei oikein  varmuudella tiedetä, mikä on näitten säätelyllisten T-imusolujen (Treg) osuus maksafibroosin progredioitumisessa. 
Tässä työssä tutkijat havaitsivat,  että  Treg- soluja oli runsaasti fibroplasia-kohtien ympärillä. Ja päinvastoin ajatellen:  Jos Treg soluja vähennettiin,  niin maksafibroosialueen  purkaantuminen edistyi.  
Treg-solujen vähentämisestä seurasi muutos MMP- ja TIMP- expressioissa:
MMP9 ja MMP1 vähenivät , 
MMP2 ja MMP14 lisääntyivät. 
Fibroosin purkaantumisessa (puhdistumisessa)  suhteet MMP9/TIMP1 ja MMP13/TIMP1 sekä  MMP14/TIMP2  kasvoivat merkitsevästi. 
Kupfferin solut ovat matrixmetalloproteinaasien (MMP)  päälähde. 
Tutkijat tekivät havainnon, että jos Kupfferin soluja ja Treg imusoluja viljeltiin yhdessä, niin Treg-solut pystyivät  estämään Kupfferin solujen MMP-expression jo pienissäkin suhteissa; Havaittiin myös että anti-TGF-beta pystyi merkitsevästi  reversoimaan   Treg- imusolujen  tekemää  MMP -inhibitiota. 
Lisäksi havaittiin, että Treg-imusolujen vähentämisen jälkeen hiiren maksassa aleni TGF-beta pitoisuudet  - ( mitä ei tapahdu  fibroosissa).
Jos vähennettiin sekä Kupfferin solut että Treg solut, ei saatu aikaan säikeen purkaantumista (puhdistumista)  hiirellä.  Tulokset  osoittavat, että  kirroosin pinttyneisyyttä ylläpitää lisääntyneet Treg solut fibroplasiakohdilla ja  siitä seuraava  MMP/TIMP-tasapainon muutos  ja Kupfferin solujen välittämän MMP-ilmenemän vaimentuminen  antaa myös osansa säätelylliseen prosessiin. . 

Abstract

Fibrosis is the result of the abnormal accumulation of the extracellular matrix and ineffective clearance of fibroplasia. CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are immunosuppressive lymphocytes that are highly expressed in the fibrotic tissues and peripheral blood of patients with cirrhosis or hepatocellular carcinoma. The role of Tregs in the progression of liver fibrosis is not well understood. Our experiments reveal that abundant of Tregs was scattered around sites of fibroplasia. Conversely, the depletion of Tregs promoted the resolution of liver fibrosis. As a consequence of Tregs depletion, the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) was altered; mmp9 and timp1 were reduced, whereas mmp2 and mmp14 were enhanced. The mmp9/timp1, mmp13/timp1, and mmp14/timp2 ratios were significantly increased in association with fibrosis resolution. Kupffer cells (KCs) are the main source of MMP. We observed that when KCs were cocultured with Tregs, the Tregs were able to inhibit MMP expression of KCs even at a low ratio; and anti-transforming growth factor-β (TGF-β) significantly reversed the inhibition of Tregs on MMP. Meanwhile, we also found that after Tregs depletion, TGF-β levels decreased in the mice liver, unlike in fibrosis. Furthermore, double depletion of both KCs and Tregs did not cause fiber resolution in mice. Thus, our results demonstrate that the persistence of liver cirrhosis is maintained by increased Tregs in the sites of fibroplasia and the subsequent regulation of the MMP/TIMP balance and that the suppression of KC-mediated MMP expression contributed to the regulatory process.
Copyright © 2016 Elsevier Inc. All rights reserved.

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Suomennosta 16.3. 2016 

Uutta strategiaa maksakirroosin parantamiseen , MMP8-fuusioproteiini

Select item 2652786020.

Adenoviral delivery of truncated MMP-8 fused with the hepatocyte growth factor mutant 1K1 ameliorates liver cirrhosis and promotes hepatocyte proliferation.

Liu J, Li J, Fu W, Tang J, Feng X, Chen J, Liang Y, Jin R, Xie A, Cai X.

Drug Des Devel Ther. 2015 Oct 16;9:5655-67. doi: 10.2147/DDDT.S92481. eCollection 2015.

ABSTRAKTI (suomennosta)  

 Maksakirroosi on krooninen maksatauti,  johtuu kroonisesta maksavauriosta,  joka aktivoi  maksantähtisoluja (HSC, stellate cells)  ja extrasellulaarisen matrixin (ECM)  erityksen. Kirroosin morbiditeetti ja mortaliteetti on maailmanlaajuisesti suurta lähinnä siksi, koska puuttuu tehokkaita hoito-optioita.   

 Tässä tutkimuksessa konstruoitiin fuusioproteiini, jonka osina on matrixmetalloproteinaasi MMP-8 ja ihmisen kasvutekijämutantti 1K1 ja proteiinia merkattiin cMMP8-1K1. Sitä johdattiin adenoviruksessa   iv injektioilla maksasoluihin  in vivo ja soluviljelmiin.   Tutkijat havaitsivat, että fuusioproteiini edisti maksasolujen proliferaatiota. Tämä johtui todennäköisesti kombinoidusta inhibitiosta   tyypin 1 kollageenin erityksessä   ja  extrasellularimatrixin hajottamisessa hepatosyytissä.. Tämä fuusioproteiini näytti myös parantavan maksakirroosia hiirimallissa. Nämä muutokset  näyttivät linkkiytyneen geeniexpression alavirran muutoksiin.   

Yhteenvetona nämä tulokset viittaisivat  maksakirroosin hoitostrategian mahdollisuuteen ja lisätyötä tällä alueella tarvitaan. 

 Abstract

Liver cirrhosis is a chronic liver disease caused by chronic liver injury, which activates hepatic stellate cells (HSCs) and the secretion of extracellular matrix (ECM). Cirrhosis accounts for an extensive level of morbidity and mortality worldwide, largely due to lack of effective treatment options. In this study, we have constructed a fusion protein containing matrix metal-loproteinase 8 (MMP-8) and the human growth factor mutant 1K1 (designated cMMP8-1K1) and delivered it into hepatocytes and in vivo and in cell culture via intravenous injection of fusion protein-harboring adenovirus. In doing so, we found that the cMMP8-1K1 fusion protein promotes the proliferation of hepatocytes, likely resulting from the combined inhibition of type I collagen secretion and the degradation of the ECM in the HSCs. This fusion protein was also observed to ameliorate liver cirrhosis in our mouse model. These changes appear to be linked to changes in downstream gene expression. Taken together, these results suggest a possible strategy for the treatment of liver cirrhosis and additional work is warranted. KEYWORDS: HGF; MMP-8; hepatocytes proliferation; liver cirrhosis PMID: 26527860

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Suomennos 16.3. 2016   Huom Oulussa tutkitaan MMP-8.

Maksafibroosi ja MMPs, Haku

Search results 16.3. 2016

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Select item 269701851.

Therapeutic effects of antigen affinity-purified polyclonal anti-receptor of advanced glycation end-product (RAGE) antibodies on cholestasis-induced liver injury in rats.

Xia P, Deng Q, Gao J, Yu X, Zhang Y, Li J, Guan W, Hu J, Tan Q, Zhou L, Han W, Yuan Y, Yu Y.

Eur J Pharmacol. 2016 Mar 9. pii: S0014-2999(16)30138-8. doi: 10.1016/j.ejphar.2016.03.017. [Epub ahead of print]

 Abstract

Cholestasis leads to acute hepatic injury, fibrosis/cirrhosis, inflammation, and duct proliferation.
We investigated whether blocking receptor of advanced glycation end-products (RAGE) with polyclonal anti-RAGE antibodies (anti-RAGE) could regulate acute liver injury and fibrosis in a rat bile duct ligation (BDL) model.
Male Wister rats received 0.5mg/kg rabbit anti-RAGE or an equal amount of rabbit IgG by subcutaneous injection twice a week after BDL. Samples of liver tissue and peripheral blood were collected at 14 days after BDL. Serum biochemistry and histology were used to analyze the degree of liver injury. Quantitative real-time PCR (qPCR) and immunohistochemical staining were used to further analyze liver injury.
 Anti-RAGE improved the gross appearance of the liver and the rat survival rate. Liver tissue histology and relevant serum biochemistry indicated that anti-RAGE attenuated liver necrosis, inflammation, liver fibrosis, and duct proliferation in the BDL model. qPCR and western blotting showed significant reductions in interleukin-1β expression levels in the liver by treatment with anti-RAGE.
 Anti-RAGE also significantly reduced the mRNA levels of α1(1) collagen (Col1α1) and cholesterol 7α-hydroxylase, and the ratio of TIMP-1/MMPs,   tissue inhibitor of matrix metalloproteinase-1 to matrix metalloproteinases (MMPs) in the liver.
 In addition, anti-RAGE regulated the transcriptional level of Col1α1 and MMP-9 in transforming growth factor-β-induced activated LX-2 cells in vitro. Anti-RAGE was found to inhibit hepatic stellate cell proliferation in vivo and in vitro. Therefore, anti-RAGE can protect the liver from injury induced by BDL in rats.Copyright © 2016. Published by Elsevier B.V. KEYWORDS:   Vitamin K1 (PubChem CID: 5284607); anti-RAGE; bile duct ligation; hepatic stellate cell; liver fibrosis; liver injury

PMID:26970185  Similar articles

Select item 269270422.

Solanum nigrum Protects against Hepatic Fibrosis via Suppression of Hyperglycemia in High-Fat/Ethanol Diet-Induced Rats.

Tai CJ, Choong CY, Shi YC, Lin YC, Wang CW, Lee BH, Tai CJ.

Molecules. 2016 Feb 25;21(3). pii: E269. doi: 10.3390/molecules21030269.

 Abstract BACKGROUND: Advanced glycation end products (AGEs) signal through the receptor for AGE (RAGE), which can lead to hepatic fibrosis in hyperglycemia and hyperlipidemia. We investigated the inhibitory effect of aqueous extracts from Solanum nigrum (AESN) on AGEs-induced RAGE signaling and activation of hepatic stellate cells (HSCs) and hyperglycemia induced by high-fat diet with ethanol. METHODS: An animal model was used to evaluate the anti-hepatic fibrosis activity of AESN in rats fed a high-fat diet (HFD; 30%) with ethanol (10%). Male Wistar rats (4 weeks of age) were randomly divided into four groups (n = 6): (1) control (basal diet); (2) HFD (30%) + ethanol (10%) (HFD/ethanol); (3) HFD/ethanol + AESN (100 mg/kg, oral administration); and (4) HFD/ethanol + pioglitazone (10 mg/kg, oral administration) and treated with HFD for 6 months in the presence or absence of 10% ethanol in dietary water. RESULTS: We found that AESN improved insulin resistance and hyperinsulinemia, and downregulated lipogenesis via regulation of the peroxisome proliferator-activated receptor α (PPARα), PPARγ co-activator (PGC-1α), carbohydrate response element-binding protein (ChREBP), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) mRNA levels in the liver of HFD/ethanol-treated rats. In turn, AESN may delay and inhibit the progression of hepatic fibrosis, including α-smooth muscle actin (α-SMA) inhibition and MMP-2 production. CONCLUSIONS: These results suggest that AESN may be further explored as a novel anti-fibrotic strategy for the prevention of liver disease.KEYWORDS: Solanum nigrum; advanced glycation end products (AGEs); hepatic fibrosis; hyperglycemia; hyperlipidemia

PMID:26927042 Free Article  Similar articles

Select item 269073373.

Protective Effect of Gallotannin-Enriched Extract Isolated from Galla Rhois against CCl₄-Induced Hepatotoxicity in ICR Mice.

Go J, Kim JE, Koh EK, Song SH, Sung JE, Lee HA, Lee YH, Lim Y, Hong JT, Hwang DY.

Nutrients. 2016 Feb 23;8(3). pii: E107. doi: 10.3390/nu8030107. Abstract

To investigate the toxicity, protective effects, and action mechanism of gallotannin-enriched extracts isolated from Galla Rhois (GEGR) against carbon tetrachloride (CCl₄)-induced hepatotoxicity in Institute for Cancer Research (ICR) mice, alterations in serum biochemical indicators, histopathological structure, antioxidative status, hepatic apoptosis-related proteins, and liver fibrosis regulating factors were measured in mice pretreated with GEGR for five days before CCl₄ injection. The GEGR/CCl₄ treated group showed decreased levels of three serum marker enzymes (ALP, AST, and ALT) representing liver toxicity, although LDH levels remained constant. Necrotic area indicating hepatic cell death significantly inhibited, while malondialdehyde (MDA) concentration and superoxide dismutase (SOD) expression were dramatically recovered in the GEGR preadministrated group. In mechanism analyses of GEGR, the formation of active caspase-3 and enhancement of Bax/Bcl-2 expression was effectively inhibited in the GEGR/CCl₄ treated group. The level of pro-inflammatory cytokines, TNF-α and IL-6, as well as the phosphorylation of p38 and JNK in the TNF-α downstream signaling pathway was rapidly recovered in the GEGR/CCl₄ treated group, while anti-inflammatory cytokine (IL-10) increased slightly in the same group. Furthermore, the GEGR/CCl₄ treated group showed a significant decrease in collagen accumulation results from alleviation of MMP-2 expression, TGF-β1 secretion and the phosphorylation of Smad2/3. Taken together, these results suggest that GEGR may induce remarkable protective effects against hepatic injury induced by CCl₄ treatment through upregulation of the anti-inflammatory and antioxidant system. KEYWORDS:Galla Rhois; hepatic fibrosis; hepatotoxicity; inflammation; oxidative stress    PMID: 26907337 Free Article Similar articles
 

Select item 268849624.

Zinc mediated hepatic stellate cell collagen synthesis reduction through TGF-β signaling pathway inhibition.

Kang M, Zhao L, Ren M, Deng M, Li C.

Int J Clin Exp Med. 2015 Nov 15;8(11):20463-71. eCollection 2015. Abstract 

This study is to investigate the effect and underlying mechanism of Zinc (Zn) on hepatic stellate cell collagen synthesis. The proliferation and collagen synthesis ability of LX-2 cells were detected after adding Zn. The collagen synthesis related proteins of MMP-13 and TIMP1 along with TGF-β signaling pathway related proteins were detected by Western blot. The role of TGF-β signaling pathway in collagen synthesis inhibition was identified by TGF-β RI siRNA silencing. 

Compared with control group, LX-2 cell proliferation ability was significantly inhibited at all Zn concentrations (50 μM, 100 μM and 200 μM). Zn at 50 μM did not affect the protein content of αSMA and type I collagen while 100 μM and 200 μM Zn could significantly inhibit αSMA expression. Compared with control group, gene expression and protein content of MMP-13 in 200 μM Zn group was significantly increased while no difference in gene expression and protein content of TIMP1 was found. TGF-β RI content in 200 μM Zn group was significantly decreased and the protein content of TGF-β RII was not affected. MMP-13 expression was significantly increased after TGF-β RI siRNA silencing. Further results showed that in LX-2 cells those TGF-β RI expression was inhibited, LX-2 cell proliferation ability and the expression of synthesis collagen related proteins of αSMA and type I collagen were greatly decreased. Zn could significantly inhibit the expression of αSMA and type I collagen by inhibiting TGF-β RI expression and promoting MMP-13 expression. KEYWORDS: Collagen synthesis; Zn; hepatic fibrosis; hepatic stellate cells PMID: 26884962 [PubMed] PMCID: PMC4723807 Free PMC Article PMID: 26884962 Free PMC Article Similar articles

 

Select item 268708005.

Inhibition of Cyclic Adenosine Monophosphate (cAMP)-response Element-binding Protein (CREB)-binding Protein (CBP)/β-Catenin Reduces Liver Fibrosis in Mice.

Osawa Y, Oboki K, Imamura J, Kojika E, Hayashi Y, Hishima T, Saibara T, Shibasaki F, Kohara M, Kimura K.

EBioMedicine. 2015 Oct 8;2(11):1751-8. doi: 10.1016/j.ebiom.2015.10.010. eCollection 2015 Nov.Abstract

Wnt/β-catenin is involved in every aspect of embryonic development and in the pathogenesis of many human diseases, and is also implicated in organ fibrosis. However, the role of β-catenin-mediated signaling on liver fibrosis remains unclear.
 To explore this issue, the effects of PRI-724, a selective inhibitor of the cAMP-response element-binding protein-binding protein (CBP)/β-catenin interaction, on liver fibrosis were examined using carbon tetrachloride (CCl4)- or bile duct ligation (BDL)-induced mouse liver fibrosis models. Following repetitive CCl4 administrations, the nuclear translocation of β-catenin was observed only in the non-parenchymal cells in the liver. PRI-724 treatment reduced the fibrosis induced by CCl4 or BDL. C-82, an active form of PRI-724, inhibited the activation of isolated primary mouse quiescent hepatic stellate cells (HSCs) and promoted cell death in culture-activated HSCs. During the fibrosis resolution period, an increase in F4/80(+) CD11b(+) and Ly6C(low) CD11b(+) macrophages was induced by CCl4 and was sustained for two weeks thereafter, even after having stopped CCl4 treatment. PRI-724 accelerated the resolution of CCl4-induced liver fibrosis, and this was accompanied by increased matrix metalloproteinase (MMP)-9, MMP-2, and MMP-8 expression in intrahepatic leukocytes. In conclusion, targeting the CBP/β-catenin interaction may become a new therapeutic strategy in treating liver fibrosis. KEYWORDS:

BDL, bile duct ligation; Beta-catenin; CBP, CREB-binding protein; CCL, c–c motif ligand; CCl4, carbon tetrachloride; CREB, cAMP-response element-binding protein; CXCL, c–x–c motif ligand; Fibrosis; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HCV, hepatitis C virus; HSC, hepatic stellate cell; Hepatic stellate cell; H–E, hematoxylin and eosin; Liver; MMP, matrix metalloproteinase; Macrophage; PBDL, partial BDL; SPARC, secreted protein acidic and rich in cysteine; TGF-β, transforming growth factor; TIMP-1, tissue inhibitor of metalloproteinase; αSMA, α-smooth muscle actin,

PMID:26870800[PubMed - in process]PMCID: PMC 4740320 Free PMC Article PMID:26870800 Free PMC Article  Similar articles

Select item 268634196.

Low Cardiac Output Leads Hepatic Fibrosis in Right Heart Failure Model Rats.

Fujimoto Y, Urashima T, Shimura D, Ito R, Kawachi S, Kajimura I, Akaike T, Kusakari Y, Fujiwara M, Ogawa K, Goda N, Ida H, Minamisawa S.

PLoS One. 2016 Feb 10;11(2):e0148666. doi: 10.1371/journal.pone.0148666. eCollection 2016.

Abstract BACKGROUND: Hepatic fibrosis progresses with right heart failure, and becomes cardiac cirrhosis in a severe case. Although its causal factor still remains unclear. Here we evaluated the progression of hepatic fibrosis using a pulmonary artery banding (PAB)-induced right heart failure model and investigated whether cardiac output (CO) is responsible for the progression of hepatic fibrosis. METHODS AND RESULTS: Five-week-old Sprague-Dawley rats divided into the PAB and sham-operated control groups. After 4 weeks from operation, we measured CO by echocardiography, and hepatic fibrosis ratio by pathological examination using a color analyzer. In the PAB group, CO was significantly lower by 48% than that in the control group (78.2±27.6 and 150.1±31.2 ml/min, P<0 .01="" b="">Hepatic fibrosis ratio

and serum hyaluronic acid, an index of hepatic fibrosis, were significantly increased in the PAB group than those in the control group (7.8±1.7 and 1.0±0.2%, P<0 .01="" 32.7="" 76.2="" and="" class="highlight" degree="" ml="" ng="" notably="" of="" p="" span="" the="">hepatic fibrosis significantly correlated a decrease in CO. Immunohistological analysis revealed that hepatic stellate cells were markedly activated in hypoxic areas, and HIF-1α positive hepatic cells were increased in the PAB group. Furthermore, by real-time PCR analyses, transcripts of profibrotic and fibrotic factors (TGF-β1, CTGF, procollargen I, procollargen III, MMP 2, MMP 9, TIMP 1, TIMP 2) were significantly increased in the PAB group. In addition, western blot analyses revealed that the protein level of HIF-1α was significantly increased in the PAB group than that in the control group (2.31±0.84 and 1.0±0.18 arbitrary units, P<0 .05="" and="" class="highlight" co="" conclusions:="" demonstrated="" for="" hypoxia="" low="" our="" responsible="" span="" study="" that="" tissue="" were="">hepatic fibrosis in right failure heart model rats. PMID:26863419[PubMed - in process]PMCID: PMC4749189 Free PMC Article PMID:26863419 Free PMC ArticleSimilar articles

Select item 268531527.

Chlordecone potentiates hepatic fibrosis in chronic liver injury induced by carbon tetrachloride in mice.

Tabet E, Genet V, Tiaho F, Lucas-Clerc C, Gelu-Simeon M, Piquet-Pellorce C, Samson M.

Toxicol Lett. 2016 Feb 4. pii: S0378-4274(16)30021-2. doi: 10.1016/j.toxlet.2016.02.005. [Epub ahead of print] Abstract

Chronic liver damage due to viral or chemical agents leads to a repair process resulting in hepatic fibrosis. Fibrosis may lead to cirrhosis, which may progress to liver cancer or a loss of liver function, with an associated risk of liver failure and death. Chlordecone is a chlorinated pesticide used in the 1990s. It is not itself hepatotoxic, but its metabolism in the liver triggers hepatomegaly and potentiates hepatotoxic agents. Chlordecone is now banned, but it persists in soil and water, resulting in an ongoing public health problem in the Caribbean area. 
 We assessed the probable impact of chlordecone on the progression of liver fibrosis in the population of contaminated areas, by developing a mouse model of chronic co-exposure to chlordecone and a hepatotoxic agent, carbon tetrachloride (CCl₄). After repeated administrations of chlordecone and CCl₄ by gavage over a 12-week period, we checked for liver damage in the exposed mice, by determining serum liver transaminase (AST, ALT) levels, histological examinations of the liver and measuring the expression of genes encoding extracellular matrix components. The co-exposure of mice to CCl₄ and chlordecone resulted in significant increases in ALT and AST levels. Chlordecone also increased expression of the Col1A2, MMP-2, TIMP-1 and PAI-1 genes in CCl₄-treated mice. Finally, we demonstrated, by quantifying areas of collagen deposition and alpha-SMA gene expression, that chlordecone potentiated the hepatic fibrosis induced by CCl₄. In conclusion, our data suggest that chlordecone potentiates hepatic fibrosis in mice with CCl₄-induced chronic liver injury.
Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.KEYWORDS:

CCl4; Chlordecone; Collagen; Fibrosis; Kepone; Liver

PMID:

26853152

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Select item 268525918.

[Serum markers of fibrosis and endothelial dysfunction in patients with alcoholism, with varying degrees of liver fibrosis].

Panchenko LF, Terebilina NN, Pyrozhkov SV, Naumova TA, Baronets VY, Balashova AA, Garmash IV.

Patol Fiziol Eksp Ter. 2015 Jul-Sep;(3):18-27. Russian.
 Abstract

In the serum of patients with alcoholism with varying degrees of severity of liver fibrosis were studied the content markers of fibrosis, endothelial dysfunction and proinflammatory cytokines.
Concentration in blood indicators of fibrogenesis--collagen type 4, hyaluronic acid, TIMP-1, TIMP-2, YKL-40 and MMP-2 is considerably increased at the 4 degree of fibrosis and moderately increased at low and zero degrees of liver fibrosis. Similar results were obtained in respect of proinflammatory cytokines Il-6, IL-8, IL-12/p70 and IL-12/p40.  
The magnitude of endothelial dysfunc tion, calculated based on its content in the blood markers--VEGF-A, MCP-1, s-VCAM, s-ICAM and endothelin, was maximal at 4 degrees of fibrosis and less pronounced at low degrees of fibrosis.
Correlations between of the average degree of fibrosis, endothelial dysfunction, and blood levels of proinflammatory cytokines were installed. Close relation between the immune cells releasing stimulators of inflammation and fibrogenesis, perisinusoidal fat cells producing collagen, and endothelium secreting vasoconstrictors in the pathogenesis of alcoholic liver fibrosis and cirrhosis was installed.

PMID:

26852591

[PubMed - indexed for MEDLINE]

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Select item 268111029.

Bone marrow-derived mesenchymal stem cells effectively regenerate fibrotic liver in bile duct ligation rat model.

Mohamed HE, Elswefy SE, Rashed LA, Younis NN, Shaheen MA, Ghanim AM.

Exp Biol Med (Maywood). 2016 Mar;241(6):581-91. doi: 10.1177/1535370215627219. Epub 2016 Jan 24.Abstract

Mesenchymal stem cells (MSCs) have attracted lots of attention for the treatment of acute liver failure and end-stage liver diseases. This study aimed at investigating the fundamental mechanism by which bone marrow-derived MSCs (BM-MSCs) induce liver regeneration of fibrotic liver in rats.
Rats underwent bile duct ligation (BDL) surgery and four weeks later they were treated with either BM-MSCs (3 × 10(6) cells /rat, once, tail vein injection) or silymarin (100 mg/kg, daily, orally) for four weeks.
Liver function tests and hepatic oxidative stress were determined. Hepatic injury and fibrosis were assessed by H and E, Sirus red staining and immunohistochemical expression of α-smooth muscle actin (α-SMA). Hepatocyte growth factor (HGF) and the gene expression of cytokeratin-19 (CK-19) and matrix metalloproteinase-2 (MMP-2) in liver tissue were determined. BDL induced cholestatic liver injury characterized by elevated ALT and AST activities, bilirubin and decreased albumin. The architecture damage was staged as Metavir score: F3, A3. Fibrosis increased around proliferating bile duct as indicated by sirus red staining and α-SMA immunostaining. Fibrogenesis was favored over fibrolysis and confirmed by decreased HGF with increased expression of CK-19, but decreased MMP-2 expression. BM-MSCs treatment restored deteriorated liver functions and restored the histological changes, resolved fibrosis by improving liver regenerative capabilities (P < 0.001), increases in HGF and MMP-2 mRNA and downregulating CK-19 mRNA. Sliymarin, however, induced similar but less prominent effects compared to BM-MSCs. In conclusion, liver regenerative capabilities can be stimulated by BM-MSCs via augmentation of HGF that subsequently up-regulate MMP-2 mRNA while downregulating CK-19 mRNA.
© 2016 by the Society for Experimental Biology and Medicine. KEYWORDS: Bone marrow-derived mesenchymal stem cells; bile duct ligation; cytokeratin-19; hepatic regeneration; hepatocyte growth factor; matrix mettaloproteinase-2

PMID:

26811102

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Select item 2681057010.

Ameliorative effects of tannic acid on carbon tetrachloride-induced liver fibrosis in vivo and in vitro.

Chu X, Wang H, Jiang YM, Zhang YY, Bao YF, Zhang X, Zhang JP, Guo H, Yang F, Luan YC, Dong YS.

J Pharmacol Sci. 2016 Jan;130(1):15-23. doi: 10.1016/j.jphs.2015.12.002. Epub 2015 Dec 15. Abstract  We investigated the ameliorative effects and potential mechanisms of tannic acid (TA) in carbon tetrachloride (CCl4)-intoxicated mice and hepatic stellate cells (HSCs). Liver fibrosis was observed in CCl4 (800 ml/kg)-induced mice, and high viability was observed in CCl4 (10 mM)-intoxicated HSCs. Pre-treatment of mice with TA (25 or 50 g/kg/day) significantly ameliorated hepatic morphology and coefficient values and reduced the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), the concentrations of malondialdehyde (MDA) and serum levels of endothelin-1 (ET-1). In addition, TA increased the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and endothelial nitric oxide synthase (eNOS) and the serum level of NO. Moreover, TA reduced the expression of angiotensin II receptor-1 (ATR-1), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), caspase-3, c-fos, c-jun, the ratio of Bax/bcl-2, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TA increased matrix metal proteinase-9 (MMP-9), matrix metalloproteinase-1 (MMP-1). Furthermore, TA (0.01 μM, 0.1 μM or 1 μM) decreased the TIMP-1/MMP-1 ratio and reduced the viability of HSCs. These results indicated that TA exerts significant liver-protective effects in mice with CCl4-induced liver fibrosis. The potential mechanism may rely on the inhibition of collagen accumulation, oxidative stress, inflammation and apoptosis.

Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

KEYWORDS:

Anti-Apoptosis; Anti-Inflammation; Anti-fibrosis; Anti-oxidation; Tannic acid

PMID:

26810570

[PubMed - in process]

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PMID:

26810570

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Select item 2680719511.

Silybin-vitamin E-phospholipids complex reduces liver fibrosis in patients with chronic hepatitis C treated with pegylated interferon α and ribavirin.

Malaguarnera M, Motta M, Vacante M, Malaguarnera G, Caraci F, Nunnari G, Gagliano C, Greco C, Chisari G, Drago F, Bertino G.

Am J Transl Res. 2015 Nov 15;7(11):2510-8. eCollection 2015.

Abstract

Chronic hepatitis C is both a virologic and a fibrotic disease, with mortality resulting mainly from the complications of cirrhosis and HCC. The aim was to evaluate the impact on of supplementation with a new pharmaceutical complex of silybinvitamin E-phospholipids in patients with chronic hepatitis C treated with Pegylated-Interferon-α2b plus Ribavirin. In this prospective, randomized, placebo controlled, double blind clinical trial, 32 subjects with chronic hepatitis, received Pegylated-Interferon-α2b (1.5 mg/kg per week) plus Ribavirin and placebo, while 32 subjects received the same dosage of Pegylated-Interferon-α2b plus Ribavirin plus association of Silybin 47 mg + vitamin E 15 mg + phospholipids 97 mg in two pill for 12 months. Serum levels of the following markers of liver fibrosis were evaluated: transforming growth factor beta, hyaluronic acid, metalloproteinase 2, amino-terminal pro-peptide of type III procollagen, tissue inhibitor of matrix metalloproteinase type I. The comparison between group A and group B showed a significant difference in ALT (P<0 .001="" 12="" 6="" a="" activation="" after="" ameliorated="" ameliorative="" and="" antioxidants.="" at="" beta="" cells="" complex="" conclusion="" direct="" e-phosholipids="" effect="" fibrosis.="" follow="" hepatic="" in="" levels="" liver="" markers="" maybe="" mediated="" mmp-2="" months="" of="" on="" or="" p="" peg-ifn="" piiinp="" plus="" rbv="" reduced="" related="" response="" serum="" silybin-vitamin="" stellate="" supplementation="" tgf="" the="" timp-1="" to="" treatment="" up="" via="" viremia="" with="">

KEYWORDS:

Silybin; hepatitis C; interferons; liver fibrosis; ribavirin

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Select item 2673126212.

A New Signaling Pathway for HCV Inhibition by Estrogen: GPR30 Activation Leads to Cleavage of Occludin by MMP-9.

Ulitzky L, Lafer MM, KuKuruga MA, Silberstein E, Cehan N, Taylor DR.

PLoS One. 2016 Jan 5;11(1):e0145212. doi: 10.1371/journal.pone.0145212. eCollection 2016.

Abstract

Poor outcome in response to hepatitis C virus, including higher viral load, hepatocellular carcinoma and cirrhosis, is more associated with men and postmenopausal women than with premenopausal women and women receiving hormone replacement therapy, suggesting that β-estradiol plays an innate role in preventing viral infection and liver disease. Consequently, most research in the field has concluded that estrogen affects HCV replication through viral interactions with estrogen receptor-α. Previously, estrogen-like antagonists, including Tamoxifen, were shown to reduce HCV RNA production and prevent viral entry, although the authors did not identify host factors involved. Estrogen can act alternatively through the membrane-bound G-protein-coupled estrogen receptor, GPR30. Here, human hepatoma Huh7.5 cells were infected with HCV J6/JFH-1 and treated with estrogen or Tamoxifen, resulting in a marked decrease in detectable virus. The effect was mimicked by G1, a GPR30-specific agonist, and was reversed by the GPR30-specific antagonist, G15. While previous studies have demonstrated that estrogen down-regulated occludin in cervical cancer cells, its action on liver cells was unknown. Occludin is a tight junction protein and HCV receptor and here we report that activation and cellular export of MMP-9 led to the cleavage of occludin upon estrogen treatment of liver cells. This is the first report of the cleavage of an HCV receptor in response to estrogen. We also identify the occludin cleavage site in extracellular Domain D; the motif required for HCV entry and spread. This pathway gives new insight into a novel innate antiviral pathway and the suboptimal environment that estrogen provides for the proliferation of the virus. It may also explain the disparate host-virus responses to HCV demonstrated by the two sexes. Moreover, these data suggest that hormone replacement therapy may have beneficial antiviral enhancement properties for HCV-infected postmenopausal women and show promise for new antiviral treatments for both men and women.

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Select item 2669219413.

Can Chronic Nitric Oxide Inhibition Improve Liver and Renal Dysfunction in Bile Duct Ligated Rats?

Mahmoud MF, Zakaria S, Fahmy A.

Adv Pharmacol Sci. 2015;2015:298792. doi: 10.1155/2015/298792. Epub 2015 Nov 25.

Abstract

The aims of the present work were to study the effects of chronic NO inhibition on liver cirrhosis and to analyze its relationship with liver and kidney damage markers. Two inhibitors of NO synthesis (inducible NO synthase (iNOS) inhibitor, aminoguanidine (AG), and nonselective NOS inhibitor, L-nitroarginine methyl ester (L-NAME)) were administered for 6 weeks to bile duct ligated (BDL) rats 3 days after surgery. The present study showed that BDL was associated with liver injury and renal impairment. BDL increased liver NO content and myeloperoxidase (MPO) activity. This was corroborated by increased oxidative stress, TNF-α, TGF-1β, and MMP-13 genes overexpression. Although both drugs reduced NO synthesis and TNF-α gene overexpression, only AG improved renal dysfunction and liver damage and reduced liver oxidative stress. However, L-NAME exacerbated liver and renal dysfunction. Both drugs failed to modulate TGF-1β and MMP-13 genes overexpression. In conclusion, inhibition of NO production by constitutive nitric oxide synthase (cNOS) plays a crucial role in liver injury and renal dysfunction while inhibition of iNOS by AG has beneficial effect. TNF-α is not the main cytokine responsible for liver injury in BDL model. Nitric oxide inhibition did not stop the progression of cholestatic liver damage.

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Select item 2667029114.

Attrition of Hepatic Damage Inflicted by Angiotensin II with α-Tocopherol and β-Carotene in Experimental Apolipoprotein E Knock-out Mice.

Gopal K, Gowtham M, Sachin S, Ravishankar Ram M, Shankar EM, Kamarul T.

Sci Rep. 2015 Dec 16;5:18300. doi: 10.1038/srep18300.

Abstract

Angiotensin II is one of the key regulatory peptides implicated in the pathogenesis of liver disease. The mechanisms underlying the salubrious role of α-tocopherol and β-carotene on liver pathology have not been comprehensively assessed. Here, we investigated the mechanisms underlying the role of Angiotensin II on hepatic damage and if α-tocopherol and β-carotene supplementation attenuates hepatic damage. Hepatic damage was induced in Apoe(-/-)mice by infusion of Angiotensin II followed by oral administration with α-tocopherol and β-carotene-enriched diet for 60 days. Investigations showed fibrosis, kupffer cell hyperplasia, hepatocyte degeneration and hepatic cell apoptosis; sinusoidal dilatation along with haemorrhages; evidence of fluid accumulation; increased ROS level and increased AST and ALT activities. In addition, tPA and uPA were down-regulated due to 42-fold up-regulation of PAI-1. MMP-2, MMP-9, MMP-12, and M-CSF were down-regulated in Angiotensin II-treated animals. Notably, α-tocopherol and β-carotene treatment controlled ROS, fibrosis, hepatocyte degeneration, kupffer cell hyperplasia, hepatocyte apoptosis, sinusoidal dilatation and fluid accumulation in the liver sinusoids, and liver enzyme levels. In addition, PAI-1, tPA and uPA expressions were markedly controlled by β-carotene treatment. Thus, Angiotensin II markedly influenced hepatic damage possibly by restraining fibrinolytic system. We concluded that α-tocopherol and β-carotene treatment has salubrious role in repairing hepatic pathology.

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Select item 2666783415.

The Effector Protein BPE005 from Brucella abortus Induces Collagen Deposition and Matrix Metalloproteinase 9 Downmodulation via Transforming Growth Factor β1 in Hepatic Stellate Cells.

Arriola Benitez PC, Rey Serantes D, Herrmann CK, Pesce Viglietti AI, Vanzulli S, Giambartolomei GH, Comerci DJ, Delpino MV.

Infect Immun. 2015 Dec 14;84(2):598-606. doi: 10.1128/IAI.01227-15.

Abstract

The liver is frequently affected in patients with active brucellosis. In the present study, we identified a virulence factor involved in the modulation of hepatic stellate cell function and consequent fibrosis during Brucella abortus infection. This study assessed the role of BPE005 protein from B. abortus in the fibrotic phenotype induced on hepatic stellate cells during B. abortus infection in vitro and in vivo. We demonstrated that the fibrotic phenotype induced by B. abortus on hepatic stellate (LX-2) cells was dependent on BPE005, a protein associated with the type IV secretion system (T4SS) VirB from B. abortus. Our results indicated that B. abortus inhibits matrix metalloproteinase 9 (MMP-9) secretion through the activity of the BPE005-secreted protein and induces concomitant collagen deposition by LX-2 cells. BPE005 is a small protein containing a cyclic nucleotide monophosphate binding domain (cNMP) that modulates the LX-2 cell phenotype through a mechanism that is dependent on the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway. Altogether, these results indicate that B. abortus tilts LX-2 cells to a profibrogenic phenotype employing a functional T4SS and the secreted BPE005 protein through a mechanism that involves the cAMP and PKA signaling pathway.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.

PMID:

26667834

[PubMed - in process]

PMCID:

PMC4730569

[Available on 2016-07-25]

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Select item 2666301416.

An immortalized rat pancreatic stellate cell line RP-2 as a new cell model for evaluating pancreatic fibrosis, inflammation and immunity.

Piao RL, Xiu M, Brigstock DR, Gao RP.

Hepatobiliary Pancreat Dis Int. 2015 Dec;14(6):651-9.

Abstract

BACKGROUND:

Pancreatic stellate cells (PSCs) play a critical role in the pathogenesis of pancreatic fibrosis and have emerging functions as progenitor cells, immune cells or intermediaries in pancreatic exocrine secretion. Increasing evidence has shown that desmin as an exclusive cytoskeleton marker of PSC is only expressed in part of these cells. This study was to establish a desmin-positive PSC cell line and evaluate its actions on pancreatic fibrosis, inflammation and immunity.

METHODS:

The presence of cytoskeletal proteins, integrin alpha5beta1 or TLR4, was determined by immunocytochemistry while the production of desmin, collagen I, MMP-1, MMP-2, TIMP-2, or CD14 was evaluated by Western blotting. The levels of desmin, collagen I, IL-1 and IL-6 mRNA were determined by real-time quantitative PCR. The secretion of cytokines was detected by ELISA. Cell function was assessed using adhesion, migration, or proliferation assays.

RESULTS:

A stable activated rat PSC cell line (designated as RP-2) was established by RSV promoter/enhancer-driven SV40 large T antigen expression. RP-2 cells retained typical PSC properties, exhibited a myofibroblast-like phenotype and persistently produced desmin. The cells produced collagen I protein, matrix metalloproteinases and inhibitors thereof. RP-2 cells demonstrated typical PSC functions, including proliferation, adherence, and migration, the latter two of which occurred in response to fibronectin and were mediated by integrin alpha5beta1. TLR4 and its response genes including proinflammatory cytokines (IL-1, IL-6, TNF-alpha) and chemotactic cytokines (MCP-1, MIP-1alpha, Rantes) were produced by RP-2 cells and activated by LPS. LPS-induced IL-1 or IL-6 mRNA expression in this cell line was fully blocked with MyD88 inhibitor.

CONCLUSION:

RP-2 cells provide a novel tool for analyzing the properties and functions of PSCs in the pathogenesis of fibrosis, inflammation and immunity in the pancreas.

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Select item 2664109617.

AIH: Which Alternative for Difficult-to-Treat Patients?

Sebode M, Schramm C.

Dig Dis. 2015;33 Suppl 2:83-7. doi: 10.1159/000440752. Epub 2015 Dec 7.

Abstract

BACKGROUND:

Oftentimes we are expected to make difficult decision when patients with autoimmune hepatitis (AIH) present themselves before us. Among these cases, advanced liver cirrhosis, fulminant AIH with hepatic failure or pregnancy with highly active AIH will pose challenges on their own. In patients where standard treatment has failed, the risk of disease progression including liver transplantation has to be weighed against the risk of drug-related side effects, including infectious complications.

KEY MESSAGES:

Standard treatment of AIH includes the use of drugs like corticosteroids and usually azathioprine. However, up to 15% of patients will require second-line treatment. There are no prospective studies evaluating second- or third-line treatment regimens in AIH. In our opinion, it is essential to differentiate between those patients who are intolerant and those who do not respond sufficiently to standard treatment. For patients intolerant to prednisolone due to steroid-induced side effects, budesonide may be a feasible alternative, unless liver cirrhosis forbids its use. Our experience indicates that 6-mercaptopurine may be given as an alternative to azathioprine, especially in cases of gastrointestinal side effects, with good tolerance and response rates of up to 70%. As a more expensive alternative, mycophenolat mofetil (MMF) has been shown to effectively suppress disease activity in a majority of patients intolerant to azathioprine. Of note, MMF is contraindicated in pregnancy. In patients with insufficient response to azathioprine, the dose should be increased up to 2.5 mg/kg of body weight, and measurement of azathioprine metabolites (6TGN and MMP) may aid the optimal dosage. Several other immunosuppressive treatment strategies have been tested and published in small case series. These include the calcineurin inhibitors cyclosporine A and tacrolimus, mTOR inhibitors, anti-tumor necrosis factor α treatment with infliximab, rituximab as well as cyclophosphamide.

CONCLUSIONS:

It is difficult to tell whether 1 strategy is superior to another in the case of difficult-to-treat AIH patients. Intolerance should be differentiated from insufficient response to standard treatment. The choice of second- and third-line treatment will depend on the comorbidities, patient's choice after informed consent and also local expertise.

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Select item 2659954719.

Glycoprotein Nonmetastatic Melanoma B (Gpnmb)-Positive Macrophages Contribute to the Balance between Fibrosis and Fibrolysis during the Repair of Acute Liver Injury in Mice.

Kumagai K, Tabu K, Sasaki F, Takami Y, Morinaga Y, Mawatari S, Hashimoto S, Tanoue S, Kanmura S, Tamai T, Moriuchi A, Uto H, Tsubouchi H, Ido A.

PLoS One. 2015 Nov 23;10(11):e0143413. doi: 10.1371/journal.pone.0143413. eCollection 2015.

Abstract

BACKGROUND AND AIMS:

Glycoprotein nonmetastatic melanoma B (Gpnmb), a transmembrane glycoprotein that is expressed in macrophages, negatively regulates inflammation. We have reported that Gpnmb is strongly expressed in the livers of rats fed a choline-deficient, L-amino acid-defined (CDAA) diet. However, the role of macrophage-expressed Gpnmb in liver injury is still unknown. This study aimed to clarify the characteristics of infiltrating macrophages that express Gpnmb, and the involvement of Gpnmb in the repair process in response to liver injury.

METHODS:

C57BL/6J, DBA/2J [DBA] and DBA/2J-Gpnmb+ [DBA-g+] mice were treated with a single intraperitoneal injection of carbon tetrachloride (CCl4) at a dose of 1.0 mL/kg body weight. Mice were sacrificed at predetermined time points, followed by measurement of serum alanine aminotransferase (ALT) levels and histological examination. Expression of Gpnmb, pro-/anti-inflammatory cytokines, and profibrotic/antifibrotic factors were examined by quantitative RT-PCR and/or Western blotting. Immunohistochemistry, fluorescent immunostaining and flow cytometry were used to determine the expression of Gpnmb, CD68, CD11b and α-SMA, phagocytic activity, and the presence of apoptotic bodies. We used quantitative RT-PCR and ELISA to examine TGF-β and MMP-13 expression and the concentrations and supernatants of isolated infiltrating hepatic macrophages transfected with siGpnmb.

RESULTS:

In C57BL/6J mice, serum ALT levels increased at two days after CCl4 injection and decreased at four days. Gpnmb expression in the liver was stimulated four days after CCl4 injection. Histological examination and flow cytometry showed that Gpnmb-positive cells were almost positive for CD68-positive macrophages, contained engulfed apoptotic bodies and exhibited enhanced phagocytic activity. Isolated infiltrating hepatic macrophages transfected with siGpnmb showed high MMP-13 secretion. There was no significant difference in the magnitude of CCl4-induced liver injury between DBA-g+ and DBA mice. However, hepatic MMP-13 expression, as well as α-SMA expression and collagen production, increased significantly in DBA-g+ compared with DBA mice.

CONCLUSIONS:

Gpnmb-positive macrophages infiltrate the liver during the recovery phase of CCl4-induced acute liver injury and contribute to the balance between fibrosis and fibrolysis in the repair process following acute liver injury.

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