東華大學圖書館 |

語系: 繁體中文

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

Toxicodynamics of liver injury and r...

Dadhania, Vivekkumar P.

FindBook

Google Book

Amazon

博客來

Toxicodynamics of liver injury and repair.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Toxicodynamics of liver injury and repair./
作者:	Dadhania, Vivekkumar P.
面頁冊數:	229 p.
附註:	Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.
Contained By:	Dissertation Abstracts International77-10B(E).
標題:	Toxicology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10111795
ISBN:	9781339749723

Toxicodynamics of liver injury and repair.
Dadhania, Vivekkumar P.

Toxicodynamics of liver injury and repair. - 229 p.

Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.

Thesis (Ph.D.)--University of Louisiana at Monroe, 2016.

It has been long known that low doses of model hepatotoxicants cause minimal liver necrosis in experimental animals, but the initiated injury doesn't expand to cause the death of the animals due to stimulated compensatory tissue repair (CTR) response. At higher and lethal doses, however, the initiated liver injury expands causing liver failure and death of the animals. Following lethal dose of a liver toxicant, the expansion of injury continues even after the toxicant is completely eliminated from the body. The objectives of this research were to investigate, i) the mechanisms by which liver injury expands even in the absence of the offending toxicant in the body, ii) the mechanisms by which the pre-placed liver regeneration inhibits the expansion of liver injury following a lethal dose of hepatotoxicant like acetaminophen (APAP), and iii) mechanisms underlying the compensatory liver regeneration the engine that restores the healthy liver. We hypothesized that, i) expansion of liver injury is mediated through the destruction by the hydrolytic enzymes, such as protease calpain, secretory phospholipase A2 (sPLA2) and other lysosomal enzymes, which are spilt extracellularly from the dying hepatocytes during their lysis and highly activated by extracellular high Ca2+ (1.3 mM) (now termed as death proteins), ii) the regression of injury after a lethal dose of toxicant occurs when the death proteins are inhibited by the hepatic overexpression of their endogenous inhibitors during pre-placed CTR, and iii) timely activation and appropriate termination of the Wnt/beta-catenin pathway that drives the well-balanced compensatory liver regeneration in order to restore the healthy liver.

ISBN: 9781339749723Subjects--Topical Terms:

556884
Toxicology.

Toxicodynamics of liver injury and repair.
LDR:06002nmm a2200301 4500 001 2074326
005 20160926125813.5
008 170521s2016 ||||||||||||||||| ||eng d
020 $a 9781339749723
035 $a (MiAaPQ)AAI10111795
035 $a AAI10111795
040 $a MiAaPQ $c MiAaPQ
100 1 $a Dadhania, Vivekkumar P. $3 3189629
245 1 0 $a Toxicodynamics of liver injury and repair.
300 $a 229 p.
500 $a Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.
500 $a Adviser: Harihara M. Mehendale.
502 $a Thesis (Ph.D.)--University of Louisiana at Monroe, 2016.
520 $a It has been long known that low doses of model hepatotoxicants cause minimal liver necrosis in experimental animals, but the initiated injury doesn't expand to cause the death of the animals due to stimulated compensatory tissue repair (CTR) response. At higher and lethal doses, however, the initiated liver injury expands causing liver failure and death of the animals. Following lethal dose of a liver toxicant, the expansion of injury continues even after the toxicant is completely eliminated from the body. The objectives of this research were to investigate, i) the mechanisms by which liver injury expands even in the absence of the offending toxicant in the body, ii) the mechanisms by which the pre-placed liver regeneration inhibits the expansion of liver injury following a lethal dose of hepatotoxicant like acetaminophen (APAP), and iii) mechanisms underlying the compensatory liver regeneration the engine that restores the healthy liver. We hypothesized that, i) expansion of liver injury is mediated through the destruction by the hydrolytic enzymes, such as protease calpain, secretory phospholipase A2 (sPLA2) and other lysosomal enzymes, which are spilt extracellularly from the dying hepatocytes during their lysis and highly activated by extracellular high Ca2+ (1.3 mM) (now termed as death proteins), ii) the regression of injury after a lethal dose of toxicant occurs when the death proteins are inhibited by the hepatic overexpression of their endogenous inhibitors during pre-placed CTR, and iii) timely activation and appropriate termination of the Wnt/beta-catenin pathway that drives the well-balanced compensatory liver regeneration in order to restore the healthy liver.
520 $a Involvement of death protein secretory phospholipase A2 (sPLA 2), which is capable of breaching plasma membrane integrity by hydrolyzing its phospholipids in the process of expansion of APAP-induced liver injury was tested. We employed a heteroprotection model of hepatotoxicity in mice, where a small priming dose [40 mg/kg-bw in 10 ml distilled water (DW)/kg-bw, intraperitoneally, i.p.] of thioacetamide (TA) was administered to male Swiss-Webster (SW) mice at 36h before treating them with a lethal dose of APAP (600 mg/kg-bw in 10 ml 0.45% NaCl/kg-bw, pH 8.2, i.p.). TA-induced liver injury, CTR, and the expression of annexin A1 and A2 (ANX1 and ANX2), the endogenous inhibitors of the death protein sPLA2, were measured over a time course of 84h after TA-priming. Possible effect of TA-priming on hepatic microsomal CYP2e1 protein content was assessed by western blot (WB) analysis. Both centrilobular necrosis and CTR peaked at 36h after TA-priming, declining thereafter as indicated by significantly increased plasma alanine transaminase (ALT) and aspartate transaminase (AST) activities, liver histological findings, and hepatic expression of the cell cycle-regulating proteins such as cyclin D1, cyclin-dependent kinase (CDK)4, p21, p27, and phospho-retinoblastoma (p-Rb), and proliferating cell nuclear antigen (PCNA). TA-priming resulted in the hepatic overexpression of ANX1 and ANX2, the endogenous inhibitors of the sPLA2, at 36 to 84h and 12 to 60h, respectively, as examined by WB analysis. Both ANX1 and ANX2 were found to be overexpressed mainly in the plasma membrane of the dividing/divided hepatocytes as examined by immunohistochemical (IHC) analysis. TA-priming did not affect the hepatic microsomal Cyp2e1 level until about 24h after TA-priming, but a marginal decrease (&sim;25%) at 36h and dramatic decrease was observed thereafter.
520 $a TA-priming did not affect the rise in plasma ALT, AST, sPLA2 and arachidonic acid (AA) levels seen at 2h after the APAP overdose. Neither these biochemical parameters nor histology suggested any escalation of hepatic injury at later time points (12 and 24h after APAP overdose), consistent with 100% survival of the TA+APAP treated mice compared to DW+APAP treated mice which suffered 100% mortality. Inhibition of ANX1 and ANX2 biosynthesis using cycloheximide (40 mg/kg-bw in 5 ml distilled water/kg-bw, i.p.) administered at 1h before TA-priming abolished this heteroprotection. Whereas glutathione depletion was similar after APAP treatment in both the TA+APAP and DW+APAP groups, immediate but significantly lower activation of hepatic c-Jun N-terminal kinases (JNKs) was observed in TA+APAP treated mice compared to its late and remarkably high expression in the DW+APAP treated mice. Robust liver regeneration in TA+APAP treated mice was secondary to the activation of Wnt/beta-catenin pathway as evidenced by the increased activated beta-catenin and upregulation of its target gene axis inhibition protein 2 (AXIN2), which was absent in the DW+APAP group. In conclusion, TA-priming substantially mitigated the expansion of liver injury due to hepatic overexpression of ANX1 and ANX2. Complimentary actions of the JNK and beta-catenin resulted in well-balanced liver regeneration leading to the restoration of liver functions in TA+APAP treated mice when a lethal dose of APAP was given at 24h after TA-priming. (Abstract shortened by UMI.).
590 $a School code: 1352.
650 4 $a Toxicology. $3 556884
650 4 $a Pharmaceutical sciences. $3 3173021
690 $a 0383
690 $a 0572
710 2 $a University of Louisiana at Monroe. $b Pharmacy. $3 3189630
773 0 $t Dissertation Abstracts International $g 77-10B(E).
790 $a 1352
791 $a Ph.D.
792 $a 2016
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10111795