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The cyclic adenosine monophosphate (cAMP) signalling pathway plays an important role in the regulation of the development and pathogenicity of filamentous fungi. cAMP-dependent protein kinase A (PKA) is the conserved element downstream of cAMP, and its diverse mechanisms in multiple filamentous fungi are not well known yet. In the present study, gene knockout mutants of two catalytic subunits of PKA (PKA-C) in Setosphaeria turcica were created to illustrate the regulatory mechanisms of PKA-Cs on the development and pathogenicity of S. turcica. As a result, StPkaC2 was proved to be the main contributor of PKA activity in S. turcica. In addition, it was found that both StPkaC1 and StPkaC2 were necessary for conidiation and invasive growth, while only StPkaC2 played a negative role in the regulation of filamentous growth. We reveal that only StPkaC2 could interact with the transcription factor StEfg1, and it inhibited the transcription of StRAB1, a Rab GTPase homologue coding gene in S. turcica, whereas StPkaC1 could specifically interact with a transcriptional regulator StFlo8, which could rescue the transcriptional inhibition of StEfg1 on StRAB1. We also demonstrated that StRAB1 could positively influence the biosynthesis of chitin in hyphae, thus changing the filamentous growth. Our findings clarify that StPkaC2 participates in chitin biosynthesis to modulate mycelium development by targeting the Efg1-mediated transcription of StRAB1, while StFlo8, interacting with StPkaC1, acts as a negative regulator during this process.

Liver regeneration requires intrahepatic and extrahepatic metabolic reprogramming to meet the high hepatic bioenergy demand for liver cell repopulation. This study aims to elucidate how pyruvate dehydrogenase kinase 4 (PDK4), a critical regulator of glucose and lipid metabolism, coordinates metabolic regulation with efficient liver growth. We found that hepatic Pdk4 expression was elevated after two‐thirds partial hepatectomy (PHx). In Pdk4 −/− PHx mice, the liver/body weight ratio was more rapidly restored, accompanied by more aggressive hepatic DNA replication; however, Pdk4 −/− mice developed more severe hypoglycemia. In Pdk4 −/− PHx livers, the pro‐regenerative insulin signaling was potentiated, as demonstrated by early peaking of the phosphorylation of insulin receptor, more remarkable induction of the insulin receptor substrate proteins, IRS1 and IRS2, and more striking activation of Akt. The hepatic up‐regulation of CD36 contributed to the enhanced transient regeneration‐associated steatosis in Pdk4 −/− PHx mice. Notably, CD36 overexpression in mice promoted the recovery of liver/body weight ratio and elevated intrahepatic adenosine triphosphate after PHx. CD36 expression was transcriptionally suppressed by FOXO1 (forkhead box protein O1), which was stabilized and translocated to the nucleus following AMPK (adenosine monophosphate–activated protein kinase) activation. PHx remarkably induced AMPK activation, which became incompetent to respond in Pdk4 −/− livers. Moreover, we defined that PDK4‐regulated AMPK activation directly depended on intracellular adenosine monophosphate in vitro and in regenerative livers. Conclusion: PDK4 inhibition reprograms glucose and lipid metabolism to promote liver regeneration by enhancing hepatic insulin/Akt signaling and activating an AMPK/FOXO1/CD36 regulatory axis of lipid. These findings may lead to potential therapeutic strategies to prevent hepatic insufficiency and liver failure., In this study, we tested our hypothesis that PDK4‐mediated metabolic reprogramming energizes efficient liver growth. We elucidated the role of PDK4 in liver regeneration using the PHx model, defined PDK4 regulation of hepatic insulin signaling in regenerative livers and unraveled PDK4 as a critical mediator of hepatic lipid metabolism through regulating a novel AMPK/FOXO1/CD36 axis to promote LR efficiency.

Liver ageing not only damages liver function but also harms systemic metabolism. To better understand the mechanisms underlying liver ageing, we transplanted the livers of young rats to young and old rats and performed untargeted metabolomics to detect changes in the metabolites in the liver tissues and sera. A total of 153 metabolites in the livers and 83 metabolites in the sera were different between the old and young rats that did not undergo liver transplantation; among these metabolites, 7 different metabolites were observed in both the livers and sera. Five weeks after liver transplantation, the levels of 25 metabolites in the young donor livers were similar to those in the old rats, and this result probably occurred due to the effect of the whole‐body environment of the older recipients on the young livers. The 25 altered metabolites included organic acids and derivatives, lipids and lipid‐like molecules, etc. In the sera, the differences in 78 metabolites, which were significant between the young and old rats, were insignificant in the old recipient rats and made the metabolic profile of the old recipients more similar to that of the young recipients. Finally, combining the above metabolomic data with the transcriptomic data from the GEO, we found that the altered metabolites and genes in the liver were enriched in 9 metabolic pathways, including glycerophospholipid, arachidonic acid, histidine and linoleate. Thus, this study revealed important age‐related metabolites and potential pathways as well as the interaction between the liver and the whole‐body environment., Aging is related to metabolic disorder. To better understand the underlying mechanisms, we transplanted livers of young rats to young and old rats. Analyses of differential metabolites in the livers and sera revealed that while the young donor livers underwent aging in the old recipients, they could benefit the old recipients through circulation. Integrated metabolomic and transcriptomic profiles suggested altered metabolic pathways during liver aging.

Li C, Li Y, Wang X, Wang Z, Cai J, Wang L, Zhao Y, Song H, Meng X, Ning X, Xu C, Lin M, Li L & Geng J (2012) Histopathology 60, 953–963 Elevated expression of astrocyte elevated gene-1 (AEG-1) is correlated with cisplatin-based chemoresistance and shortened outcome in patients with stages III–IV serous ovarian carcinoma Aims: To correlate astrocyte elevated gene-1 (AEG-1) expression with the clinicopathological features and outcome of patients with stages III–IV ovarian serous carcinoma, and to clinically assess the involvement of AEG-1 in acquired cisplatin resistance. Methods and results: The frequency and intensity of immunohistochemical AEG-1 expression increased in a step-wise fashion from normal to chemosensitive to chemoresistant tissues. These observations were confirmed by Western blot analysis. AEG-1 expression level was correlated with lymph nodal metastasis, histological differentiation, residual tumour size and response to primary chemotherapy. Five-year progression-free survival (PFS) and overall survival (OS) rates were lower in the high-expression group than that in the low-expression group. AEG-1 overexpression was an independent but poor prognostic factor in the OS and PFS of these patients, as determined by multivariate Cox regression analysis. Multivariate logistic regression analysis revealed that the presence of cisplatin-based chemoresistance was significantly associated with expression level of AEG-1 and the degree of residual disease (P = 0.0001 and P = 0.0027, respectively). Conclusion: Our findings indicate that tumour AEG-1 overexpression is associated with poor prognosis and cisplatin resistance in advanced serous ovarian cancer.

Eur J Clin Invest 2011; 41 (11): 1245–1253 Abstract Background Recent studies have shown that microRNAs (miRNA) could play a potential role as diagnostic and prognostic biomarkers of cancers. The aim of this meta-analysis is to summarize the global predicting role of miR-21 for survival in patients with a variety of carcinomas. Design Eligible studies were identified and assessed for quality through multiple search strategies. Data were collected from studies comparing overall, relapse-free or cancer-specific survival (CSS) in patients with cancer having higher miR-21 expression with those having lower levels. Pooled hazard ratios (HRs) of miR-21 for survival were calculated. Results A total of 17 studies dealing with various carcinomas were included for this global meta-analysis. For overall survival (OS), the pooled hazard ratio (HR) of higher miR-21 expression in cancerous tissue was 1·69 (95% CI: 1·33–2·16, P

Purpose Our study is to examine astrocyte-elevated gene-1 (AEG-1) expression in triple-negative breast cancer and to determine whether it is associated with vascular endothelial growth factor (VEGF), microvessel density (MVD), clinicopathological parameters and poor survival. Methods Specimens from 125 patients with triple-negative breast cancers were investigated by immunohistochemistry for MVD, AEG-1 and VEGF expression. Correlations between the expression of AEG-1, VEGF, MVD, and various clinicopathological factors including survival status were studied. Results AEG-1 and VEGF were highly expressed in 56.8% and 52.8% of triple-negative breast cancer patients, respectively. The intensity of AEG-1 was gradually up-regulated from VEGF−MVD−low, VEGF−high, or MVD−high to VEGF−MVD−high tissues using Western blot analysis. Statistically significant correlation was found among AEG-1 and VEGF, and MVD. Moreover, AEG-1 expression was correlated with clinical stage, lymphatic venous invasion, lymph nodal metastasis, tumor size, Ki67, and recurrence. Patients with AEG-1 high-expression showed far lower disease-free survival (DFS) and overall survival (OS) rates than those with AEG-1 low-expression. For VEGF and MVD, there were similar results in these patients. Only AEG-1 expression and tumor size were independent prognostic factors for both DFS and OS by multivariate analysis. However, the prognostic impact of tumor size was not as strong as that of AEG-1. Conclusions AEG-1 expression may be related with tumor angiogenesis and progression and is a valuable prognostic factor in patients with triple-negative breast cancer. J. Surg. Oncol. 2011; 103:184–192. © 2010 Wiley-Liss, Inc.

ING4, as a novel candidate tumor suppressor gene, has been implicated in several human malignances by tumor growth inhibition and apoptosis enhancement. The mechanism of ING4 remains largely unknown. The purpose of this study was to investigate the inhibitory tumor growth effects of ING4 on lung adenocarcinoma, and its mechanism, by ING4 cDNA transduction into A549 cells. Furthermore, the expression level of ING4 in lung adenocarcinoma tissues was examined. The expression of ING4 was markedly reduced in human lung adenocarcinoma tissues. Overexpression of ING4 can induce growth inhibition in A549 cells both in vitro and in vivo, and also induce up-regulation of p27, down-regulation of cyclinD1, SKP2, and Cox2, and inactivation of the Wnt-1/beta-catenin pathway. Moreover, overexpression of ING4 can enhance the sensitivity of A549 cells to radiotherapy and chemotherapy. Thus, ING4 may play an inhibitory role on A549 cell proliferation and tumor growth in lung adenocarcinoma by up-regulation or down-regulation of cell proliferation-regulating proteins such as p27, cyclinD1, SKP2, and Cox2 by means of inactivation of Wnt-1/beta-catenin signaling.