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.
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. .
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
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
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 liverfibrosis
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
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
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 liverfibrosis
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, onliverfibrosiswere examined using carbon tetrachloride (CCl4)- or bile duct ligation (BDL)-induced mouse liverfibrosis
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 liverfibrosis, 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 liverfibrosis. KEYWORDS:
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
In the serum of patients with alcoholism with varying degrees of severity of liverfibrosis 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 andMMP-2 is considerably increased at the 4 degree of fibrosis and moderately increased at low and zero degrees of liverfibrosis.
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 liverfibrosis and cirrhosis was installed.
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). Liverfibrosis
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 liverfibrosis. The potential mechanism may rely on the inhibition of collagen accumulation, oxidative stress, inflammation and apoptosis.
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="">
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.
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.
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.
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.
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.
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.
