Ghrelin's second life - World Journal of Gastroenterology

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liver and have potent proliferative activity. Ki67 nuclear accumulation increased constantly in hepatocytes after liver injury, reaching 23fold as compared with the basal level of controls at week 13, the end point of the study (Figure 8A and B). This finding means that the number of mature hepatocytes increased steadily and significantly after CCl4 injury, and indicates that mature hepatocytes also play a part in responding to CCl4-induced liver injury by increasing their proliferative activity. However, even after 1 wk of YGJ treatment, the number of Ki67 positive hepatocytes was dramatically reduced (P < 0.01), and by the 13th wk, the number accounted for only 12.6% of those in the CCl4 injection group at the same time point, which is a reduction of approximately 87% compared with the CCl4treated group (Figure 8A and B). These findings suggest that YGJ treatment significantly reduced the number of hepatocytes accumulated after CCl4 injury. Serum Alb concentration (34.5 ± 6.9 g/L, control group) decreased by week 7 after hepatic injury (29.4 ± 3.5 g/L), and continued to decrease steadily at week 8 (26.4 ± 4.5 g/L, P < 0.05), week 9 (25.3 ± 3.2 g/L, P < 0.01), week 10 (28.9 ± 2.2 g/L) and week 13 (25.5 ± 2.40 g/L, P < 0.01). However, in YGJtreated mice, the serum Alb concentration increased markedly compared with that at week 9 (P < 0.05) and week 13 (P < 0.01) (Figure 8). Similarly, Western blotting results of Alb also showed that Alb protein expression in injured livers continually declined and reached its lowest level by the end of the experiment, at only 64% of the basal level. In contrast, treatment with YGJ steadily enhanced its protein level so that it reached 90% of the basal level by the end of the experiment. During the process of liver regeneration after injury, liver epithelial progenitor cells were induced to proliferate to compensate for the missing number of parenchymal hepatocytes. Hence, hepatic expression of progenitor markers, such as AFP and PKM2 [17,18] , were used in our experiment to assess the proliferation of hepatic progenitor cells after liver injury. PKM2 expression increased steadily after CCl4 injection as shown by immunostaining and Western blotting analysis, spanning 6 time points over 13 wk. Our data revealed that after 7 wk of CCl4 injection, PKM2 expression increased significantly (P < 0.01) and thereafter remained at a high level throughout the entire experimental period (Figure 9A, B and D). These enhancements were accompanied by an increase in AFP expression (Figure 9C and E). Treatment with YGJ significantly attenuated the increase in the progenitor markers PKM2 and AFP (Figure 9). These findings support the concept that after CCl4 injection, hepatic injury promotes accumulation of liver progenitor cells. DISCUSSION YGJ can ameliorate chronic liver injury in some animal models of CCl4-induced liver damage in mice. In the course of the experiment, serum ALT activity, deposi- WJG|www.wjgnet.com Wang XL et al . YGJ decoction protects against hepatic injury tion of collagen fibers and Hyp content were continuously increased, and had formed pseudonodules by the end of the study. In contrast, all these markers decreased significantly after YGJ treatment. These results strongly suggest that YGJ can block CCl4-induced chronic liver injury and exhibit a favorable therapeutic effect in mice. Any etiologically chronic liver injury could result in activation of myofibroblasts, which are the main source of extracellular matix (ECM) and finally lead to fibrosis or cirrhosis. We consider myofibroblasts to be a target of therapeutic liver fibrosis because they play such a key role in liver fibrogenesis. In our mouse model, αSMA expression in mice increased in a dynamic manner after CCl4 injection, and reached a peak at week 13. In contrast, αSMA expression was remarkably and constantly suppressed after YGJ treatment. Because myofibroblasts are thought to be heterogeneous in origin, both intrahepatic and BMderived sources are important in the development of fibrosis [19] . To assess the function of the BM in supplying myofibroblasts in cases of chronic liver injury, we examined the formation of BMderived myofibroblasts and found that BMderived EGFPpositive cells timedependently increased over the course of the study, reaching a peak at week 13, and they were mainly localized along the fibrous septa, in accordance with the course of fibrogenesis. Furthermore, the number of EGFP and αSMA double positive cells increased timedependently and they were scattered at the fibrous septa. Therefore, we concluded that the EGFP and αSMA positive cells are of BM origin and that BM cells can migrate and differentiate into myofibroblasts in the damaged liver. On the other hand, the number of both EGFPpositive cells and the EGFPαSMA positive cells decreased steadily after YGJ treatment, which suggested that YGJ inhibited the migration and differentiation of BM cells into myofibroblasts. Kupffer cells facilitate liver fibrogenic processes either by secreting fibrotic factors or by increasing the production of tissue inhibitor of metalloproteinases to reduce ECM degradation [20] . The origin of Kupffer cells was thought to be recruitment from the bone marrow to the liver [12] or from intrahepatic precursor cells that exist in the liver [21] . However, only the former population can be recruited into inflammatory foci in response to inflammation [22] . Our results indicate that the number of EGFP and F4/80 double positive cells begins to increase after CCl4 injection, reaching a peak at week 13, and that the cells are distributed along the fibrotic septa. The number of EGFP and F4/80 double positive cells decreased significantly after YGJ treatment. This revealed that YGJ inhibited liver fibrogenesis by mediating BM differentiation into Kupffer cells in the liver. It has also been reported that various components of the bone marrow can differentiate into hepatocytelike cells, causing a decrease in liver fibrosis [23,24] . The results from previously published reports concerning whether hepatocytes were BMderived or not were conflicting. 3245 July 7, 2012|Volume 18|Issue 25|
A 8 wk 9 wk 10 wk 13 wk CCl4/YGJ CCl4 Control B Ki-67 (+) hepatocytes (fold change) D Wang XL et al . YGJ decoction protects against hepatic injury 30 25 20 15 10 5 0 Alb GAPDH CCl4 YGJ CCl4 CCl4 + YGJ b Figure 8 Hepatocyte function. A: Ki-67 immunostaining in liver tissues, × 200; B: Semi-quantification of Ki-67 staining, with the week 0 control group level as the basal level; C: Serum Alb content; D: Liver Alb Western blotting bands; E: Semi-quantification of Alb based on Western blotting results, with the week 0 control group level as the basal level. a P < 0.05, b P < 0.01 vs week 0 control group; c P < 0.05, d P < 0.01 vs the same time-point CCl4 group. Results are presented as mean ± SD. GAPDH: Glyceraldehydes-3-phosphate dehydrogenase; YGJ: Yiguanjian; Alb: Albumin. WJG|www.wjgnet.com b d 0 7 8 9 10 13 t /wk - + + + + + + + + + - - - + - + - + - + 7 wk 8 wk 9 wk 10 wk 13 wk b d b c b d C Serum Alb (g/L) E Alb content (fold change) 40 35 30 25 20 15 10 5 0 1.2 1.0 0.8 0.6 0.4 0.2 0 CCl4 CCl4 + YGJ a 0 7 8 9 10 13 t /wk CCl4 CCl4 + YGJ 0 7 8 9 10 13 t /wk 3246 July 7, 2012|Volume 18|Issue 25| c b d b c a
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World Journal of Gastroenterology W
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Phillip S Oates, Perth Ross C Smith
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Deepak N Amarapurkar, Mumbai Abhiji
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Trine Olsen, Tromsø Eyvind J Pauls
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Conor P Delaney, Cleveland Sharon D
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S Contents EDITORIAL TOPIC HIGHLIGH
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Contents ACKNOWLEDGMENTS APPENDIX A
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Verhulst PJ et al . Ghrelin and glu
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Page 25 and 26: Verhulst PJ et al . Ghrelin and glu
Page 27: Online Submissions: http://www.wjgn
Page 31: Ishikawa T. Zinc during interferon
Page 35 and 36: Sitarz R et al . Gastroenterostoma
Page 37 and 38: Sitarz R et al . Gastroenterostoma
Page 39 and 40: Morais TC et al . Gastrointestinal
Page 47 and 48: Song MJ et al . Usefulness of PET/C
Page 49 and 50: A Sensitivity B Sensitivity C Sensi
Page 55 and 56: Bae GS et al . Anti-inflammatory ef
Page 59 and 60: B Myeloperoxidase activity (U/mg pr
Page 61 and 62: A Time (h) - 1 3 6 NJ4 B Relative H
Page 63 and 64: A C Time (h) - 1 3 6 NJ4-2 B Relati
Page 70 and 71: A Collagen staining (fold change) C
Page 72 and 73: CCl4/YGJ CCl4-13 wk CCl4-7 wk Contr
Page 74 and 75: CCl4/YGJ CCl4-13 wk CCl4-7 wk Contr
Page 78 and 79: A 8 wk 9 wk 10 wk 13 wk CCl4/YGJ CC
Page 80 and 81: Cheng JC. A Chinese Herbal Decoctio
Page 82 and 83: Singh R, Neo EN, Nordeen N, Shanmug
Page 84 and 85: etter patient tolerance with regard
Page 86: Key words: Intestinal alkaline phos
Page 89 and 90: Molnár K et al . iAP in pediatric
Page 97 and 98: Chung WC et al . Ulcer after gastre
Page 99: Yang HY et al . Early resection of
Page 102 and 103: indicate a later timing for radical
Page 104 and 105: Zhao WC, Zhang HB, Yang N, Fu Y, Qi
Page 106 and 107: level, or rapid enlargement of lesi
Page 108 and 109: Table 3 Area under the receiver ope
Page 111 and 112: Zhao WC et al . Prognostic factors
Page 113 and 114: Online Submissions: http://www.wjgn
Page 116 and 117: mV 0 2 4 6 8 cpm FD patients are sh
Page 118 and 119: COMMENTS Background Gastric motilit
Page 120 and 121: thirds partial hepatectomy (PH) in
Page 122: A Serum ALT (U/L) C Serum alkaline
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REFERENCES 1 Schibler U. Circadian
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positive patients were found to hav
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Online Submissions: http://www.wjgn
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21 Tosolini M, Kirilovsky A, Mlecni
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Diao TJ et al . NO and hepatopulmon
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Gallegos M et al . Lymphogranuloma
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Gallegos M et al . Lymphogranuloma
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A Hadžić N et al . Diagnosis in B
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Hadžić N et al . Diagnosis in BAA
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A B Chung HJ et al . Choledocholith
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Chung HJ et al . Choledocholithiasi
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Instructions to authors ISSN and EI
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Instructions to authors AIM (no mor
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Instructions to authors Guidelines
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