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J K Reddy

Publications and source records attributed to J K Reddy.

At least 127 records · Page 7Linked to original sources
PubMed1989

In vivo distribution of a carcinogenic hepatic peroxisome proliferator: whole-body autoradiography of [14C]ciprofibrate in the mouse.

The distribution of radiolabel in male mice was studied by whole-body autoradiography at intervals after oral administration of [14C]ciprofibrate, a carcinogenic hepatic peroxisome proliferator. Radioactivity was rapidly taken up by the liver and to a lesser extent by the brown fat within 9 h after oral dosing of ciprofibrate. The radioactivity levels in blood, interstitial fluid and fat decreased during the first 3 days after dosing, but the liver remained densely labeled. Between 3 and 27 days after dosing, liver exhibited a stippled pattern as a result of heavier labeling apparently around the central veins. The relatively low levels of radiolabel in extra-hepatic tissues observed after oral dosing, together with the prolonged retention in this region of the liver, is consistent with the hepatotropic effects (i.e. hepatic peroxisome proliferation and development of liver tumors) exerted by this compound.

Administration, Oral↗
PubMed1989

gamma-Glutamyltranspeptidase-negative phenotypic property of preneoplastic and neoplastic liver lesions induced by ciprofibrate does not change following 2-acetylaminofluorene administration.

Preneoplastic and neoplastic lesions induced by peroxisome proliferators in the livers of rats and mice do not express gamma-glutamyltranspeptidase (GGT). Previous studies have shown that the absence of GGT is not due to the toxic effect of peroxisome proliferators or due to the presence of inactive enzyme. The present experiment was designed to examine whether the GGT-negative property of these lesions is stable and irreversible or whether these lesions can be modulated to express GGT by 2-acetylaminofluorene (AAF). Hepatic lesions were induced in F-344 rats by feeding ciprofibrate (0.025%) in diet for 60 or 84 weeks. These rats were then administered AAF in diet (0.02%) for 5 weeks and the altered areas (AAs), neoplastic nodules (NNs) and hepatocellular carcinomas were analyzed for the expression of GGT. Ninety per cent of carcinomas, 90-100% of NNs and greater than 60% AAs were negative for GGT following AAF treatment. These results are very similar to the phenotypic features observed in the livers of rats treated with ciprofibrate alone. The results of this study suggest that the GGT-negative property of ciprofibrate-induced lesions is stable and not modulatable by AAF.

2-Acetylaminofluorene↗
PubMed1989

Comparison of the peroxisome proliferator-induced pleiotropic response in the liver of nine strains of mice.

We have investigated the hepatic effect of ciprofibrate, a potent peroxisomal proliferator, in 9 strains of mice to ascertain whether all strains show similar peroxisome proliferation or if there are any that are resistant to the induction of peroxisome proliferation. Dietary feeding of ciprofibrate at 2 concentrations (0.0125% or 0.025% w/w) for 2 weeks resulted in a significant increase in liver weight (170 to 200%) and a 7- to 11-fold increase in volume density of peroxisomes. Catalase and peroxisomal beta-oxidation enzymes increased by 1.7- to 2.7- and 1.9- to 9.3-fold, respectively, over the controls. SDS-polyacrylamide slab gel electrophoresis of post-nuclear fractions of livers showed a marked increase in 80,000-mol. wt. polypeptide. Immunocytochemical studies, as expected, revealed higher levels of PBE. Ciprofibrate treatment also induced hepatic DNA synthesis in all strains as determined by [3H]thymidine incorporation and autoradiography. Dot blot analysis of total RNA from livers of ciprofibrate-treated mice (5 strains) showed a significant increase in peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase bifunctional enzyme (PBE) mRNA. When the 9 strains were ranked for each parameter, CBA/Ca was the least responsive mouse strain and the B6C3F1 was the most responsive. However, the results of this study indicate that there is no significant interstrain difference in rankings across strains to ciprofibrate-induced hepatic pleiotropic response.

Animals↗
PubMed1988

Almost total conversion of pancreas to liver in the adult rat: a reliable model to study transdifferentiation.

Study of transdifferentiation provides an excellent opportunity to investigate various factors and mechanisms involved in repression of activated genes and derepression of inactivated genes. Here we describe a highly reproducible in vivo model, in which hepatocytes are induced in the pancreas of adult rats that were maintained on copper-deficient diet containing a relatively non-toxic copper-chelating agent, triethylenetetramine tetrahydrochloride (0.6% w/w) for 7-9 weeks and then returned to normal rat chow. This dietary manipulation resulted in almost complete loss of pancreatic acinar cells at the end of copper-depletion regimen, and in the development of multiple foci of hepatocytes during recovery phase. In some animals, liver cells occupied more than 60% of pancreatic volume within 6-8 weeks of recovery. Northern blot analysis of total RNA obtained from the pancreas of these rats revealed the expression of albumin mRNA. Albumin was demonstrated in these pancreatic hepatocytes by immunofluorescence. The advantages of this model over the previously described models are: a) low mortality (10%), b) depletion of acinar cells, and c) development of multiple foci of hepatocytes in 100% of rats.

Animals↗
PubMed1988

Comparison of constitutive and inducible levels of expression of peroxisomal beta-oxidation and catalase genes in liver and extrahepatic tissues of rat.

Previous studies from our laboratories have shown that carcinogenic peroxisome proliferators significantly increase the mRNA levels of peroxisomal beta-oxidation genes in the rat liver by enhancing the transcriptional activity. Because of a good correlation between the inducibility of peroxisome proliferation and carcinogenicity of this class of xenobiotics, we proposed that sustained induction of peroxisomal beta-oxidation system and the resultant oxidative stress form the basis for carcinogenesis. Since this concept implies that tumors should develop only in tissues which display maximal peroxisome proliferation, we have now assessed the degree to which catalase and the three beta-oxidation genes are expressed in liver and 12 extrahepatic tissues of adult rats fed for 2 weeks a diet containing 0.025% ciprofibrate (w/w), a peroxisome proliferator. In the ciprofibrate-treated rats, the levels of catalase mRNA increased to less than 2-fold in liver, kidney, intestine, and heart, but no change was detected in other tissues. The mRNA levels of the three genes of beta-oxidation system in the liver of adult rats treated with ciprofibrate increased greater than 20-fold. In contrast, in the kidney, small intestine, and heart the increases in the mRNA levels of all three beta-oxidation genes were small and varied from 2- to 4-fold following ciprofibrate treatment. Ciprofibrate did not significantly increase the levels of these mRNAs in the other nine tissues. These results correlated well with the levels of peroxisomal beta-oxidation activity, peroxisome volume density, and the immunologically quantified proteins in various tissues. These results provide evidence for the presence of beta-oxidation enzymes in peroxisomes of many tissues of rat and for tissue (cell)-specific differences in the inducibility of mRNAs of these beta-oxidation genes. The marked inducibility of beta-oxidation genes in liver and subsequent development of liver tumors support the hypothesis that tumors develop in tissues that show inducibility of peroxisome proliferation vis a vis beta-oxidation system following exposure to peroxisome proliferators.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1988

Lack of expression of glutathione-S-transferase P, gamma-glutamyl transpeptidase, and alpha-fetoprotein messenger RNAs in liver tumors induced by peroxisome proliferators.

Many structurally unrelated nonmutagenic peroxisome proliferators induce altered areas, neoplastic nodules, and hepatocellular carcinomas in rats. Unlike the lesions induced by genotoxic hepatocarcinogens, these lesions do not stain positively for the phenotypic markers gamma-glutamyl transpeptidase (GGT) and glutathione-S-transferase P (GST-P). To ascertain whether the absence of immunocytochemically detectable GST-P and GGT proteins in peroxisome proliferator-induced neoplastic lesions is due to the absence of specific mRNAs, we analyzed the total RNA isolated from hepatocellular carcinomas induced by three different peroxisome proliferators (ciprofibrate, Wy-14643, and BR-931) and the genotoxic carcinogens, 2-acetylaminofluorene and aflatoxin B1 (AFB), for the presence of GST-P, GGT, and alpha-fetoprotein (AFP) mRNAs. Northern and dot blot analysis of total RNA isolated from liver tumors induced by three different peroxisome proliferators revealed no detectable GST-P, GGT, and AFP mRNAs. GST-P mRNA was also not detected in a transplantable hepatocellular carcinoma established from a liver tumor induced by ciprofibrate. In contrast, GST-P mRNA levels were high in primary liver tumors induced by both 2-acetylaminofluorene and AFB and the two transplantable hepatocellular carcinomas established from such tumors. By immunoblot method, GST-P protein was found to be abundant in both primary and transplantable liver tumors induced by genotoxic carcinogens but not in those derived from peroxisome proliferator treatment. The GGT and AFP mRNAs were also not found in all 18 liver tumors induced by peroxisome proliferators that were analyzed and also in the ciprofibrate-derived transplantable liver tumor. The expression of GGT and AFP genes in liver tumors induced by 2-acetylaminofluorene and AFB was variable. These studies with peroxisome proliferators show that the GST-P and GGT gene derepression is not essential for the hepatocarcinogenesis or successful tumor transplantation. Further characterization of the molecular basis for the differential expression, particularly of the GST-P gene in liver tumors, may help identification of the critical event(s) in hepatocarcinogenesis by genotoxic carcinogens and nongenotoxic peroxisome proliferators.

Animals↗
PubMed1988

Induction of peroxisome proliferation and hepatic tumours in C57BL/6N mice by ciprofibrate, a hypolipidaemic compound.

The hepatic effects of ciprofibrate, a potent peroxisome proliferator, were evaluated in male C57BL/6N mice, a mouse strain with very low incidence of spontaneous liver tumour development. Dietary feeding of ciprofibrate (0.0125% or 0.025% w/w) for 2 weeks resulted in a marked proliferation of peroxisomes (9-fold increase) and several-fold increase (8- to 10-fold) in the activity of peroxisomal beta-oxidation enzymes. Feeding ciprofibrate at 0.025% concentration for 15 months followed by a 0.0125% for 6 months led to the development of hepatic adenomas in 8/14 (57%) and hepatocellular carcinomas (HCC) in 3/14 (21%) mice. In mice given 0.0125% ciprofibrate for 18 months 5 of 8 (62%) and 3 of 8 (37%) developed adenomas and HCC respectively. Similar to the findings observed in rats, both the adenomas and HCC were negative for gamma-glutamyltranspeptidase. These results in C57BL/6N mice of hepatocarcinogenic effect of ciprofibrate, a non-genotoxic chemical, indicate that peroxisome proliferation can be used as a reliable parameter to evaluate the carcinogenicity of hypolipidaemic compounds.

Adenoma↗
PubMed1988

Immunocytochemical localization of urate oxidase, fatty acyl-CoA oxidase, and catalase in bovine kidney peroxisomes.

We investigated the localization of urate oxidase, peroxisomal fatty acyl-CoA oxidase, and catalase in bovine kidney by immunoblot analysis and protein A-gold immunocytochemistry, using the respective polyclonal monospecific antibodies raised against the enzymes purified from rat liver. By immunoblot analysis, these three proteins were detected in bovine kidney and bovine liver homogenates. Subcellular localization of these three enzymes in kidney was ascertained by protein A-gold immunocytochemical staining of Lowicryl K4M-embedded tissue. Peroxisomes in bovine kidney cortical epithelium possessed crystalloid cores or nucleoids, which were found to be the exclusive sites of urate oxidase localization. The limiting membrane, the marginal plate, and the matrix of renal peroxisomes were negative for urate oxidase staining. In contrast, catalase and fatty acyl-CoA oxidase were found in the peroxisome matrix. These results demonstrate that, unlike rat kidney peroxisomes which lack urate oxidase, peroxisomes of bovine kidney contain this enzyme as well as peroxisomal fatty acyl-CoA oxidase.

Acyl-CoA Oxidase↗
PubMed1988

Immunocytochemical localization of liver-specific proteins in pancreatic hepatocytes of rat.

Hepatocytes are induced in the pancreas of rats maintained first on a copper-deficient diet for 8 weeks and then on normal rat chow. These cells are morphologically identical to parenchymal cells of the liver. These hepatocytes contain two liver-specific proteins: carbamyl phosphate synthetase I, a mitochondrial matrix protein that participates in the conversion of ammonia to carbamyl phosphate; and urate oxidase, an enzyme that catalyzes the oxidation of uric acid to allantoin. In addition, we also present evidence indicating that dietary administration of ciprofibrate induces peroxisomal beta-oxidation pathway enzymes, while the levels of catalase are unaltered in pancreatic hepatocytes. These observations along with the previously published results further establish the identity of pancreatic hepatocytes to parenchymal cells of liver and clearly indicate that transdifferentiation of pancreatic cells to hepatocytes is associated with activation of several liver-specific genes.

Animals↗
PubMed1988

Tissue specificity and species differences in the distribution of urate oxidase in peroxisomes.

The localization of urate oxidase in different tissues of rat and in the livers of selected mammalian species was investigated by immunoblot analysis and protein A-gold immunoelectron microscopy. Urate oxidase was purified from rat liver and used as an antigen to generate polyclonal antibodies in the rabbit. The antibodies were found to be monospecific by immunodiffusion and immunoblot analyses. By immunoblot analysis, urate oxidase was detected in the livers of rat, two strains of mice, hamster, dog, cat, and cow, but not in the Cynomolgus monkey and human liver. Urate oxidase was not detected by immunoblot method in rat kidney, jejunal mucosa, adrenal gland, testis, and pancreas. The subcellular localization of urate oxidase was ascertained by the protein A-gold immunocytochemical staining of the Lowicryl K4M embedded tissues. Urate oxidase was localized exclusively in the crystalloid core of the peroxisome in hepatic parenchymal cells of rat, mouse, hamster, dog, cat, and cow. The limiting membrane and the matrix of hepatic peroxisomes in these species were negative for the staining. The marginal plates of feline, canine, and bovine hepatic peroxisomes were also negative for urate oxidase. This enzyme was also not detected within the peroxisomes of human and monkey livers by the immunocytochemical technique. Peroxisomes (microperoxisomes) in extrahepatic rat tissues did not stain positively for urate oxidase by the protein A-gold immunocytochemical method, although they were positive for catalase. Fatty acyl-CoA oxidase was present in peroxisomes of jejunal mucosa, Leydig cells of test-is and pancreas but not in adrenal gland. Administration of a hepatic peroxisome proliferator, ciprofibrate or Wy-14643, failed to induce urate oxidase in rat liver. These results indicate that urate oxidase is a liver specific protein in rat and its localization within the liver peroxisomes of six mammals, excluding man and a nonhuman primate, and that its localization is limited exclusively to the crystalloid core. Unlike fatty acyl-CoA oxidase, urate oxidase does not appear to be inducible significantly by peroxisome proliferator treatment in the rat liver.

Animals↗
PubMed1987

Myosin from pancreatic acinar carcinoma cells. Isolation, characterization and demonstration of heavy- and light-chain phosphorylation.

Myosin has been identified in a variety of non-muscle cells, and is believed to play a role in maintenance of cell shape, locomotion, cytokinesis, exocytosis and other cellular functions. In this paper we describe the purification of myosin from a pancreatic acinar-cell carcinoma of the rat which forms solid tumours, but retains many differentiated functions. The purified myosin was composed of a 200,000 Da heavy chain and two or three classes of light chains. Electron-microscopic examination of rotary-shadowed preparations revealed that individual molecules had two globular heads and a long tail measuring approx. 149 nm. The myosin was soluble in high-salt buffers and became sedimentable as the ionic strength was lowered. Examination of negative-stained preparations showed that this sedimentable myosin consisted of short, bipolar, thick filaments which had a strong tendency to aggregate in a head-to-head manner. The ATPase activity of the purified myosin was stimulated by EDTA or Ca2+, but not by Mg2+. In low ionic strength the Mg2+-dependent ATPase activity was activated by muscle f-actin. The pancreatic myosin bound to actin and could be dissociated by the addition of MgATP. Myosin purified from cells cultured in media containing [32P]Pi was phosphorylated on one of the light chains as well as the heavy chain. Thus pancreatic acinar cells contain a typical non-muscle myosin, and the subunits of this molecule are subject to post-translational modification by phosphorylation.

Actins↗
PubMed1987

Purification and characterization of alpha-amylase from rat pancreatic acinar carcinoma. Comparison with pancreatic alpha-amylase.

alpha-Amylase was purified to apparent homogeneity from normal pancreas and a transplantable pancreatic acinar carcinoma of the rat by affinity chromatography on alpha-glucohydrolase inhibitor (alpha-GHI) bound to aminohexyl-Sepharose 4B. Recovery was 95-100% for both pancreas and tumour alpha-amylases. They were monomeric proteins, with Mr approx. 54000 on SDS/polyacrylamide-gel electrophoresis. Isoelectric focusing of both normal and tumour alpha-amylases resolved each into two major isoenzymes, with pI 8.3 and 8.7. Tumour-derived alpha-amylase contained two additional minor isoenzymes, with pI 7.6 and 6.95 respectively. All four tumour isoenzymes demonstrated amylolytic activity when isoelectric-focused gels were treated with starch and stained with iodine. Two-dimensional electrophoresis, on SDS/10-20%-polyacrylamide-gradient gels after isoelectric focusing, separated each major isoenzyme into doublets of similar Mr values. Pancreatic and tumour-derived alpha-amylases had similar Km and Ki (alpha-GHI) values, but the specific activity of the tumour alpha-amylase was approximately two-thirds that of the normal alpha-amylase. Although amino acid analysis and peptide mapping with the use of CNBr, N-chlorosuccinimide or Staphylococcus aureus V8 proteinase gave comparable profiles for the two alpha-amylases, tryptic-digest fingerprint patterns were different. Antibodies raised against the purified pancreatic alpha-amylase and tumour alpha-amylase respectively showed only one positive band on immunoblotting after gel electrophoresis of crude extracts of rat pancreas and carcinoma, at the same position as that of the purified enzyme. More than 95% of the alpha-amylase activity in the pancreas and in the tumour was absorbed by an excess amount of either antibody, indicating that normal and tumour alpha-amylases are immunologically identical. The presence of additional isoenzymes in the carcinoma, and dissimilarity of tryptic-digest patterns, may reflect an alteration in gene expression or in the post-translational modification of this protein in this heterogeneously differentiated transplantable pancreatic acinar carcinoma.

Amino Acids↗
PubMed1987

Tannic acid-induced nucleolar changes in hepatocytes transplanted into syngeneic or xenogeneic host and in hepatocytes maintained in primary culture.

In this study we have investigated the effect of a single dose of tannic acid, administered s.c., on the nucleolar ultrastructure of hepatocytes transplanted into a syngeneic or xenogeneic host in order to evaluate the validity of our hepatocyte transplantation system as an in vivo alternative to the use of whole animals to test for species and strain differences to the effects of hepatotoxins. Within 4-6 h following tannic acid injection, rat hepatocytes transplanted into the anterior chamber of eye and inguinal fat pads of rat and athymic nude mouse, showed changes of nucleolar components, with separation of ribonucleoprotein containing granules into discrete dark zones. These dark areas were surrounded by light areas consisting of granular and fibrillar components of the nucleolus. These changes were identical to tannic acid-induced nucleolar alterations in the homotopic liver. Hamster and rat hepatocytes xenotransplanted into athymic nude mice also displayed prominent nucleolar alterations in response to tannic acid. The similarity and extent of nucleolar alterations observed in transplanted hepatocytes and the in situ homotopic liver cells attest to the usefulness of the hepatocyte transplantation system for the evaluation of species differences in biological response to toxic/carcinogenic effects of xenobiotics.

Animals↗
PubMed1987

Beta-oxidation of 2-ethyl-5-carboxypentyl phthalate in rodent liver.

[7-14C]-2-Ethyl-5-carboxypentyl phthalate was isolated and purified from urine of rats given [7-14C]-di-(2-ethylhexyl) phthalate. This metabolite was shown to serve as a precursor for 2-ethyl-3-carboxypropyl phthalate in vivo. 2-Ethyl-5-carboxypentyl phthalate was oxidized to 2-ethyl-3-carboxypropyl phthalate in liver slices from control or, much more rapidly, from clofibrate-pretreated rats. Inhibition by KCN in liver slices from untreated rats, and strong inhibition by acrylate, suggested that formation of 2-ethyl-3-carboxypropyl phthalate involved mitochondrial beta-oxidation. The strong enhancement of the production of this compound by clofibrate (a very weak inducer for mitochondrial dehydrogenases), and strong inhibition by chlorpromazine suggested that peroxisomes may also be able to oxidize 2-ethyl-5-carboxypentyl phthalate. We were able to detect beta-oxidation of 2-ethyl-5-carboxypentyl phthalate to 2-ethyl-3-carboxypropyl phthalate using purified mitochondria, but strong phthalate monoester hydrolase activity observed during incubation of the former compound with purified peroxisomes made it impossible to determine whether 2-ethyl-3-carboxypropyl phthalate could be produced in the latter organelle or not. 2-Ethyl-5-carboxypentyl phthalate was such an inefficient substrate for beta-oxidation compared to palmitic acid that it is unlikely that it contributes significantly to the production of H2O2 in rats chronically exposed to di-(2-ethylhexyl) phthalate. Normal fatty acids are most likely to serve as the dominant substrates for peroxisomal beta-oxidase.

Animals↗
PubMed1987

Xenobiotic-induced peroxisome proliferation: role of tissue specificity and species differences in response in the evaluation of the implications for human health.

Significant increases in the number of peroxisomes and in the activity of H2O2 generating peroxisomal fatty acid beta-oxidation enzyme system occur in liver parenchymal cells of mice, rats and certain other species exposed to several structurally dissimilar hypolipidemic drugs and certain phthalate-ester plasticizers. These agents, referred to as peroxisome proliferators, are considered as novel hepatocarcinogenic agents in view of their non-mutagenic and non-genotoxic nature. The lack of mutagenicity of these agents combined with consistent coupling of proliferation of H2O2 generating peroxisomes led to the hypothesis that persistent proliferation of peroxisomes serves as an endogenous initiator of neoplastic transformation by inducing oxidative stress. The mechanism by which oxidative stress leads to neoplastic transformation is, however, not clear. This postulated link between peroxisome proliferation and carcinogenicity implies that tumors should develop only in organs displaying profound peroxisome proliferation. Current evidence indicates that maximal peroxisome proliferation is a tissue-specific phenomenon, restricted largely to the hepatocyte. This tissue-specific biological response suggests that interaction of these structurally dissimilar xenobiotics with a receptor(s) might be the mechanism responsible for peroxisome proliferation and the selective increase in the rate of transcription of peroxisomal fatty acid beta-oxidation enzyme genes without significantly affecting the transcriptional rate of peroxisomal marker enzyme catalase gene. Identification and molecular characterization of peroxisome proliferator specific receptor(s) and elucidation of the mechanisms responsible for the differences in interspecies responses will be necessary for the evaluation of the implications for human health, since the carcinogenicity is not directly attributable to the chemical but to the adaptive responses of the host.

Animals↗
PubMed1987

Pancreatic acinar cell regeneration following copper deficiency-induced pancreatic necrosis.

Rats maintained on a diet deficient in copper for up to 8-10 weeks exhibit marked necrosis and depletion of acinar cells in the pancreas. When these animals are subsequently fed a copper-supplemented diet, foci of hepatocyte differentiation emerge by about 12 weeks. The present study deals with pancreatic changes during copper depletion and determines the extent of regenerative capacity of the pancreas during the early phases of copper supplementation. During the period of copper depletion, the pancreas gradually decreased in size, and by eight weeks of deficiency weighed approx. 30% as much as the control pancreas. Light-microscopic examination showed focal necrosis of acinar cells at 4 weeks, loss of lobular architecture by six weeks and loss of 85-90% of acinar tissue by eight weeks. Regeneration of the pancreas was initiated by feeding copper-supplemented diet at the end of eight weeks of copper deficiency. The wet weight of the pancreas increased gradually, and by 17 days it weighed 50% more than on the first day of regeneration. Mitotic activity was observed mainly in the acinar cells, beginning at 24 h and reaching a maximum of 19 +/- 1/1000 acinar cells at 72 h, and decreasing steadily thereafter. [3H]Thymidine autoradiography showed a labeling index of 51 +/- 1.7/1000 acinar cell nuclei at 24 h, reaching a peak value of 261 +/- 5.5/1000 acinar cells at 96 h. By 17 days, pancreatic regeneration was only partially complete; however, the proliferative activity was still persistent, albeit at a slower pace. Morphometric analysis of the pancreas on the 17th day of regeneration showed that acinar tissue occupied only 37% of the volume, as compared to 84% in the normal pancreas. These studies clearly demonstrate that acinar tissue of the pancreas following copper deficiency is capable of regeneration, but that the recovery of the pancreas is only partial. Additional studies are necessary to establish the role of this early acinar cell regeneration in pancreatic hepatocyte differentiation.

Animals↗