Transcription factor p53 exhibits increased binding to the A2-macroglobulin gene promoter and decreased glycosylation in fetal and adult rat liver during the acute-phase response

The binding affinity of p53 for the MG promoter was assessed by DNA-affinity chromatography with the extended α2-macroglobulin (MG) gene promoter (-852/+12) and immunoblot analysis. During the increased MG gene transcription observed in the fetus and the acute-phase (AP) response in both the fetus and the adult, p53 exhibited increased binding to the MG promoter. This increase was accompanied by decreased O-linked N-acetyl glucosamine glycosylation of p53. We suggest that the enzymatic removal of sugar moieties in vivo serves to activate the MG gene promoter binding potential of p53 and its participation in upregulated MG gene transcription.DNK afinitetna hromatografija, sa promotorskim regionom gena za alfa2-makroglobulin (MG) (-852/+12), i imunoblot analiza su pokazale povećan afinitet vezivanja p53 za promotorski region gena za MG u kontrolnoj jetri fetusa, kao i ulogup53 u transkripcionoj regulaciji gena za MG i u fetalnoj i adultnoj jetri tokom akutno-faznog odgovora (AFO). Povećanje vezivanja p53 za promotorski region gena za MG je praćeno smanjenjem stepena glikozilacije p53. Rezultati sugerišu da u in vivo uslovima uklanjanje šećernih ostataka sa p53 omogućava njegovo vezivanje za promotorski region MG gena, kao i ulogu u transkripcionoj aktivaciji ispitivanog gena tokom AFO.Projekat ministarstva br. 143002

The effect of chronic food restriction on liver acute phase protein response in female and male Wistar rats

The acute inflammatory response of the liver associated with chronic food restriction was examined in adult female and male Wistar rats. The changes in the levels of serum markers of liver injury, AST and ALT and the appearance of a serum marker of inflammation, the acute phase protein (APP) haptoglobin (Hp) were assessed following turpentine treatment of well-nourished (WN) controls and undernourished (UN) rats. Undernutrition was induced by food restriction during a six week period by offering chow equivalent to 50% of the normal food intake. In the female rats undernutrition significantly potentiated liver injury and increased their sensitivity to the toxic effects of turpentine, which was opposite to the results obtained for males. Differences in the basal levels of AST, ALT and Hp between females and males imply that the effects of chronic food restriction on protein synthesis in the liver are gender related.Ispitivan je akutni inflamatorni odgovor jetre odraslih ženki i mužjaka Wistar pacova u uslovima hroničnog izgladnjivanja. Praćene su promene koncentracije AST-a i ALT-a kao serumskih markera povrede jetre, i prisustvo akutno faznog proteina haptoglobina-serumskog markera inflamacije, nakon tretiranja normalno hranjenih (WN) i neuhranjenih pacova (UN) terpentinom. Neuhranjenost je bila indukovana restrikcijom hrane u periodu od šest nedelja količinom koja je za 50% bila manja od one koja se normalno uzima. Kod ženki pacova neuhranjenost je značajno potencirala inflamaciju jetre i povećava senzitivnost na toksične efekte terpentina što je suprotno od onog dobijenog za mužjake. Razlike u bazalnim nivoima AST-a, ALT-a i haptoglobina između ženki i mužjaka ukazuju da su efekti hroničnog izgladnjivanja na sistem za proteinsku sintezu u jetri specifični za pol.nul

The effect of nutritional status on the magnitude of acute phase protein response in female rats

In response to inflammation, infection and tissue injury, the sequence of events known as acute-phase (AP) response is induced and a number of plasma proteins, called acute-phase proteins (APPs) are synthesized in the liver as a part of the host defense mechanism. Any condition which impairs acute phase protein response (APPR) and hence organism's ability to restore homeostasis may limit its survival in various stress circumstances. Malnutrition is well-known causes of several metabolic, immune and neuroendocrine dysfunctions and this study was aimed at investigating its effect on the magnitude of normal APPR and in relation to turpentine injury. Malnutrition in female Wistar rats was induced by food restriction during six weeks period until they riched and kept body weight to 50% of that of ad libitum fed mates. Results of rocket immunoelectrophoresis revealed that malnutrition alone or in conjunction with turpentine was capable of elevating an expression of one of APPs, haptoglobin (Hp). Based on the studies of liver-specific regulatory proteins that bind to hormone regulatory elements of Hp gene and thus determine its expression we found that malnutrition probably modulated Hp response by changing the expression of active members of C/EBP, STAT and NF-kB transcription factor families.U odgovoru na inflamaciju, infekciju i povredu tkiva, kao sastavni deo odbrambenih mehanizama u organizmu se pokreće sled događaja poznat kao akutno-fazni odgovor (AFO) u okviru koga se u jetri sintetiše grupa proteina plazme označena kao akutno fazni proteini (AFP). Svako stanje koje narušava akutno fazni proteinski odgovor organizma (AFPO), a time i njegovu sposobnost da ponovo uspostavi homeostazu može da deluje ograničavajuće na njegovo preživljavanje u uslovima različitih vrsta stresa. Izgladnjivanje je dobro poznat uzrok nekoliko metaboličkih, imunih i neuroendokrinih poremećaja te je ovaj rad imao za cilj da ispita uticaj neuhranjenosti na nivo normalnog AFPO-a i onog izazvanog akutnom povredom. Ženke pacova soja Wistar su izgladnjivane tokom perioda od šest nedelja sve do dostizanja telesne mase koja predstavlja 50% telesne mase ženki pacova koje su se u istom periodu hranile normalno. Rezultati "roket" imunoelektroforeze su pokazali da je izgladnjivanje, samo ili u sprezi sa terpentinskom povredom dovelo do uvecanja ekspresije jednog od AFP-a, haptoglobina (Hp). Izučavanjem za jetru specifičnih regulatornih proteina koji se vezuju za hormon regulatorne elemente gena Hp i time određuju nivo njegove ekspresije zaključili smo da izgladnjivanje najverovatnije moduliše odgovor Hp-a tako što menja ekspresiju aktivnih članova C/EBP, STAT and NF-kB familija transkripcionih faktora.nul

The effect of nutritional status on the magnitude of acute phase protein response in female rats

In response to inflammation, infection and tissue injury, the sequence of events known as acute-phase (AP) response is induced and a number of plasma proteins, called acute-phase proteins (APPs) are synthesized in the liver as a part of the host defense mechanism. Any condition which impairs acute phase protein response (APPR) and hence organism's ability to restore homeostasis may limit its survival in various stress circumstances. Malnutrition is well-known causes of several metabolic, immune and neuroendocrine dysfunctions and this study was aimed at investigating its effect on the magnitude of normal APPR and in relation to turpentine injury. Malnutrition in female Wistar rats was induced by food restriction during six weeks period until they riched and kept body weight to 50% of that of ad libitum fed mates. Results of rocket immunoelectrophoresis revealed that malnutrition alone or in conjunction with turpentine was capable of elevating an expression of one of APPs, haptoglobin (Hp). Based on the studies of liver-specific regulatory proteins that bind to hormone regulatory elements of Hp gene and thus determine its expression we found that malnutrition probably modulated Hp response by changing the expression of active members of C/EBP, STAT and NF-kB transcription factor families.U odgovoru na inflamaciju, infekciju i povredu tkiva, kao sastavni deo odbrambenih mehanizama u organizmu se pokreće sled događaja poznat kao akutno-fazni odgovor (AFO) u okviru koga se u jetri sintetiše grupa proteina plazme označena kao akutno fazni proteini (AFP). Svako stanje koje narušava akutno fazni proteinski odgovor organizma (AFPO), a time i njegovu sposobnost da ponovo uspostavi homeostazu može da deluje ograničavajuće na njegovo preživljavanje u uslovima različitih vrsta stresa. Izgladnjivanje je dobro poznat uzrok nekoliko metaboličkih, imunih i neuroendokrinih poremećaja te je ovaj rad imao za cilj da ispita uticaj neuhranjenosti na nivo normalnog AFPO-a i onog izazvanog akutnom povredom. Ženke pacova soja Wistar su izgladnjivane tokom perioda od šest nedelja sve do dostizanja telesne mase koja predstavlja 50% telesne mase ženki pacova koje su se u istom periodu hranile normalno. Rezultati "roket" imunoelektroforeze su pokazali da je izgladnjivanje, samo ili u sprezi sa terpentinskom povredom dovelo do uvecanja ekspresije jednog od AFP-a, haptoglobina (Hp). Izučavanjem za jetru specifičnih regulatornih proteina koji se vezuju za hormon regulatorne elemente gena Hp i time određuju nivo njegove ekspresije zaključili smo da izgladnjivanje najverovatnije moduliše odgovor Hp-a tako što menja ekspresiju aktivnih članova C/EBP, STAT and NF-kB familija transkripcionih faktora.nul

Transcription factor p53 exhibits increased binding to the A2-macroglobulin gene promoter and decreased glycosylation in fetal and adult rat liver during the acute-phase response

The binding affinity of p53 for the MG promoter was assessed by DNA-affinity chromatography with the extended α2-macroglobulin (MG) gene promoter (-852/+12) and immunoblot analysis. During the increased MG gene transcription observed in the fetus and the acute-phase (AP) response in both the fetus and the adult, p53 exhibited increased binding to the MG promoter. This increase was accompanied by decreased O-linked N-acetyl glucosamine glycosylation of p53. We suggest that the enzymatic removal of sugar moieties in vivo serves to activate the MG gene promoter binding potential of p53 and its participation in upregulated MG gene transcription.DNK afinitetna hromatografija, sa promotorskim regionom gena za alfa2-makroglobulin (MG) (-852/+12), i imunoblot analiza su pokazale povećan afinitet vezivanja p53 za promotorski region gena za MG u kontrolnoj jetri fetusa, kao i ulogup53 u transkripcionoj regulaciji gena za MG i u fetalnoj i adultnoj jetri tokom akutno-faznog odgovora (AFO). Povećanje vezivanja p53 za promotorski region gena za MG je praćeno smanjenjem stepena glikozilacije p53. Rezultati sugerišu da u in vivo uslovima uklanjanje šećernih ostataka sa p53 omogućava njegovo vezivanje za promotorski region MG gena, kao i ulogu u transkripcionoj aktivaciji ispitivanog gena tokom AFO.Projekat ministarstva br. 143002

Induction of acute phase reaction and suppression of the immune system in the paraoxon-intoxicated rats

Widespread use of organophosphates, especially in agriculture, led us to study their toxic effects. Our investigations were focused on paraoxon an oxygenated analog of a phosphothionate pesticide. This points to an analogy between the response to organophosphate intoxication and the acute phase reaction to injury. The capacity of paraoxon to elicit the acute phase response was assessed by studying two major processes characteristic of acute inflammation, the expression of acute phase proteins (APP) and the immunosuppressive activity of serum. After an LDso paraoxon administration to rats, the serum APP levels increased with time reaching a maximal level at the 24 h time point. The several-fold increases of AGP, MG, Hp and TST concentrations in the circulation of intoxicated rats, as well as a significant immunosuppressive activity of examined animal serum, pointed to the role of APP, especially AGP and MG, as immune modulators. These processes are analog to those observed during the acute phase response to injury and aimed at reestablishing homeostasis.Široka upotreba organofosfatnih jedinjenja u industriji, a posebno u poljoprivredi, navela nas je da ispitujemo njihove toksične efekte. Istraživanja su bila fokusirana ka paraoksonu, kiseoničnom analogu fosfotionatnog pesticida, sa ciljem da se utvrdi analogija između odgovora organizma na intoksikaciju paraoksonom i akutno fazne reakcije na povredu. Sposobnost paraoksona da indukuje akutno fazni odgovor analizirana je ispitivanjem dva glavna procesa karakteristična za inflamaciju: ekspresije akutno faznih proteina i imunosupresivne aktivnosti seruma. Nakon ubrizgavanja LDso paraoksona u pacove, nivo akutno faznih proteina u serumu životinja se povećava dostižući maksimalni nivo u 24 satu. Višestruko povećanje koncentracije al- kiselog glikoproteina (AGP), a2-makroglobulina (MG), haptoglobina i tiostatina u cirkulaciji tretiranih pacova kao i značajna imunosupresivna aktivnost seruma tretiranih životinja ukazali su na ulogu ovih proteina, naročito AGP i MG, kao finih modulatora imunološkog odgovora. Ovi procesi su analogni procesima tokom akutno faznog odgovora organizma na povredu i odvijaju se u cilju uspostavljanja fiziološke ravnoteže.nul

The effect of chronic food restriction on liver acute phase protein response in female and male Wistar rats

The acute inflammatory response of the liver associated with chronic food restriction was examined in adult female and male Wistar rats. The changes in the levels of serum markers of liver injury, AST and ALT and the appearance of a serum marker of inflammation, the acute phase protein (APP) haptoglobin (Hp) were assessed following turpentine treatment of well-nourished (WN) controls and undernourished (UN) rats. Undernutrition was induced by food restriction during a six week period by offering chow equivalent to 50% of the normal food intake. In the female rats undernutrition significantly potentiated liver injury and increased their sensitivity to the toxic effects of turpentine, which was opposite to the results obtained for males. Differences in the basal levels of AST, ALT and Hp between females and males imply that the effects of chronic food restriction on protein synthesis in the liver are gender related.Ispitivan je akutni inflamatorni odgovor jetre odraslih ženki i mužjaka Wistar pacova u uslovima hroničnog izgladnjivanja. Praćene su promene koncentracije AST-a i ALT-a kao serumskih markera povrede jetre, i prisustvo akutno faznog proteina haptoglobina-serumskog markera inflamacije, nakon tretiranja normalno hranjenih (WN) i neuhranjenih pacova (UN) terpentinom. Neuhranjenost je bila indukovana restrikcijom hrane u periodu od šest nedelja količinom koja je za 50% bila manja od one koja se normalno uzima. Kod ženki pacova neuhranjenost je značajno potencirala inflamaciju jetre i povećava senzitivnost na toksične efekte terpentina što je suprotno od onog dobijenog za mužjake. Razlike u bazalnim nivoima AST-a, ALT-a i haptoglobina između ženki i mužjaka ukazuju da su efekti hroničnog izgladnjivanja na sistem za proteinsku sintezu u jetri specifični za pol.nul

Modulation of diabetes-related liver injury by the HMGB1/TLR4 inflammatory pathway.

Chronic inflammation plays an essential role in the development of diabetic complications. Understanding the molecular mechanisms that support inflammation is a prerequisite for the design of novel anti-inflammatory therapies. These would take into consideration circulating levels of cytokines and damage-associated molecular patterns (DAMPs) that include the high mobility group box 1 (HMGB1) protein which, in part, promotes the inflammatory response through TLR4 signaling. The liver, as the source of circulating cytokines and acute-phase proteins, contributes to the control of systemic inflammation. We previously found that liver injury in streptozotocin-induced diabetic rats correlated with the level of oxidative stress, increased expression of HMGB1, and with the activation of TLR4-mediated cell death pathways. In the present work, we examined the effects of ethyl pyruvate (EP), an inhibitor of HMGB1 release/expression, on the modulation of activation of the HMGB1/TLR4 inflammatory cascade in diabetic liver. We observed that increased expression of inflammatory markers, TNF-α, IL-6, and haptoglobin in diabetic liver was associated with increased HMGB1/TLR4 interaction, activation of MAPK (p38, ERK, JNK)/NF-κB p65 and JAK1/STAT3 signaling pathways, and with decreased expression of Nrf2-regulated antioxidative enzymes. The reduction in HMGB1 expression as the result of EP administration reduced the pro-inflammatory activity of HMGB1 and exerted a protective effect on diabetic liver, which was observed as improved liver histology and antioxidant and inflammatory statuses. Our results suggest that prevention of HMGB1 release and blockage of the HMGB/TLR4 axis represents a potentially effective therapeutic strategy aimed at ameliorating diabetes-induced inflammation and ensuing liver injury.This is a post-peer-review, pre-copyedit version of an article published in Journal of Physiology and Biochemistry. The final authenticated version is available online at: [http://dx.doi.org/10.1007/s13105-018-0626-0

Effets motivationnels et sommatifs de l'évaluation par réussite-échec à paliers

Résumé à la fin des ptiesÉgalement disponible en version papierTitre de l'écran-titre (visionné le 3 mars. 2010)Comprend des bibliogr

Expression of CYP1A in the hepatopancreas of Merluccius merluccius, Trigla lucerna, and Liza ramada (pisces) in the wider vicinity of Bar harbor Montenegro

The expression of CYP1A, a biomarker for the presence of xenobiotic compounds, was examined in three fish species from the wider vicinity of Bar harbor in winter and spring. Induction of CYP1A was observed in winter and increased further in spring. Several PCBs were found in seawater in winter. They decreased below the limit of detection in spring, when the PAH fluorene was detected. It is concluded that the constant presence of CYP1A expression is probably due to pollutants in the environment, whereas increased expression of CYP1A in spring results from exposure of the fish to fluorene.Ekspresija CYP1A, biomarkera na prisustvo ksenobiotika, posmatrana je u tri vrste riba ulovljenih sa šireg lokaliteta barske luke tokom zime i proleća. Indukcija CYP1A koja je uočena u zimskom periodu, dodatno je uvećana u prolećnom. Nekoliko PCB koji su pronađeni u morskoj vodi tokom zime, nije detektovano u proleće kada je otkriven PAH fluoren. Zaključeno je da je stalno prisustvo ekspresije CYP1A najverovatnije posledica prisustva polutanata u životnoj sredini; dodatno uvećanje ekspresije CYP1A u proleće posledica je izlaganja riba fluorenu.nul