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Featured researches published by Peter Dietrich.


Best Practice & Research in Clinical Gastroenterology | 2014

Non-alcoholic fatty liver disease, obesity and the metabolic syndrome

Peter Dietrich; Claus Hellerbrand

Nonalcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. Its prevalence has increased to more than 30% of adults in developed countries and its incidence is still rising. The majority of patients with NAFLD have simple steatosis but in up to one third of patients, NAFLD progresses to its more severe form nonalcoholic steatohepatitis (NASH). NASH is characterized by liver inflammation and injury thereby determining the risk to develop liver fibrosis and cancer. NAFLD is considered the hepatic manifestation of the metabolic syndrome. However, the liver is not only a passive target but affects the pathogenesis of the metabolic syndrome and its complications. Conversely, pathophysiological changes in other organs such as in the adipose tissue, the intestinal barrier or the immune system have been identified as triggers and promoters of NAFLD progression. This article details the pathogenesis of NAFLD along with the current state of its diagnosis and treatment.


Gut | 2011

Amelioration of portal hypertension and the hyperdynamic circulatory syndrome in cirrhotic rats by neuropeptide Y via pronounced splanchnic vasoaction

Lukas Moleda; Jonel Trebicka; Peter Dietrich; Erwin Gäbele; Claus Hellerbrand; Rainer H. Straub; Tilman Sauerbruch; Juergen Schoelmerich; Reiner Wiest

Background Splanchnic vasodilation triggers the development of the hyperdynamic circulatory syndrome in portal hypertension. Neuropeptide Y (NPY), a sympathetic co-transmitter of norepinephrine, improves contractility in mesenteric arteries of pre-hepatic portal hypertensive rats. Therefore, we investigated the effect of NPY on mesenteric arterial contractility in vitro and in vivo in cirrhotic ascitic rats, as well as the vasoactive pathways involved. Methods All experiments were performed in CCl4-induced cirrhotic rats with ascites and compared to controls. In vivo haemodynamic characterisation was assessed before and after cumulative application of NPY i.v. using the microspheres technique. In vitro mesenteric arterial perfusion was used to analyse the effect of NPY on the response to α1-adrenergic, as well as nitrergic stimulation. The NPY effects on vasoactive pathways (RhoA/Rho-kinase and NOS/NO) were analysed by western blot in mesenteric arteries. Results NPY decreased portal-venous blood flow and reduced portal pressure in cirrhotic rats, without changes in mean arterial pressure. This was accompanied by decreased cardiac output and normalised systemic vascular resistance in cirrhotic rats. By contrast, no significant splanchnic or systemic haemodynamic effect of NPY was seen in controls. NPY enhanced arterial contractility in cirrhotic but not in control rats. Furthermore, NO-mediated vasodilation was reduced to a greater extent than in controls. These findings were paralleled by an increased expression and activity of the constrictive Rho-kinase pathway and decreased activation of vasodilating NOS/NO signalling after NPY administration in mesenteric arteries. Conclusions NPY exerts marked portal hypotensive effects and ameliorates the hyperdynamic circulation in cirrhotic ascitic rats. This is mediated mainly by a pronounced splanchnic vasoconstriction and reduction in splanchnic blood flow due to enhanced Rho-kinase expression and activity, as well as reduced NOS activation and NO effect.


Journal of Hepatology | 2013

Dysbalance in sympathetic neurotransmitter release and action in cirrhotic rats: Impact of exogenous neuropeptide Y

Peter Dietrich; Lukas Moleda; Frieder Kees; M. Müller; Rainer H. Straub; C Hellerbrand; Reiner Wiest

BACKGROUND & AIMS Splanchnic vasodilation is an essential disturbance in portal hypertension. Increased systemic sympathetic nerve activity is well known, but potential corresponding vascular desensitization is incompletely characterized. Release of splanchnic sympathetic neurotransmitters noradrenaline (NA) and co-transmitter neuropeptide Y (NPY) remains to be elucidated. Finally, the effects of exogenous NPY on these mechanisms are unexplored. METHODS Portal vein ligated cirrhotic, and control rats were used for in vitro perfusion of mesenteric arteries. Depletion of vascular pressure response was induced by repetitive electric sympathetic perivascular nerve stimulation (PNS) and performed in the absence and presence of exogenous NPY. Additionally, PNS-induced release of NA and NPY was measured. RESULTS Mesenteric PNS-induced pressure response was lower in portal hypertension. Depletion of the pressure response to PNS, representing the degree of desensitization, was enhanced in portal hypertension. NA release was elevated, whereas NPY release was attenuated in cirrhosis. Administration of exogenous NPY led to marked recovery from desensitization and vasoconstrictive improvement in cirrhotic rats, being associated with more pronounced decrease of NA release. CONCLUSIONS Pronounced depletion of splanchnic arterial pressure-response to repetitive sympathetic nerve stimulation in cirrhosis is partly attributable to altered NA release as well as to deficient NPY release. External NPY restores vascular contractility and attenuates pathologically elevated NA release in the portal hypertensive mesenteric vasculature, revealing post-, and prejunctional effects at the vascular smooth muscle motor endplate; therefore outlining encouraging therapeutic strategies.


Gut | 2017

ERK activation and autophagy impairment are central mediators of irinotecan-induced steatohepatitis.

A Mahli; M Saugspier; Andreas Koch; J Sommer; Peter Dietrich; Seren Lee; Reinhard M. K. Thasler; Jan Schulze-Luehrmann; Anja Luehrmann; Wolfgang E. Thasler; M Müller; A Bosserhoff; C Hellerbrand

Objective Preoperative chemotherapy with irinotecan is associated with the development of steatohepatitis, which increases the risk of perioperative morbidity and mortality for liver surgery. The molecular mechanisms of this chemotherapeutic complication are widely unknown. Design Mechanisms of irinotecan-induced steatohepatitis were studied in primary human hepatocytes in vitro, in mice treated with irinotecan and in liver specimens from irinotecan-treated compared with control patients. Results Irinotecan dose-dependently induced lipid accumulation and pro-inflammatory gene expression in hepatocytes. This was accompanied by an impairment of mitochondrial function with reduced expression of carnitine palmitoyltransferase I and an induction of acyl-coenzyme A oxidase-1 (ACOX1), oxidative stress and extracellular signal-regulated kinase (ERK) activation. ERK inhibition prevented irinotecan-induced pro-inflammatory gene expression but had only a slight effect on lipid accumulation. However, irinotecan also induced an impairment of the autophagic flux mediated by alkalisation of lysosomal pH. Re-acidification of lysosomal pH abolished irinotecan-induced autophagy impairment and lipid accumulation. Also in mice, irinotecan treatment induced hepatic ACOX1 expression, ERK phosphorylation and inflammation, as well as impairment of autophagy and significant steatosis. Furthermore, irinotecan-treated patients revealed higher hepatic ERK activity, expression of pro-inflammatory genes and markers indicative for a shift to peroxisomal fatty acid oxidation and an impaired autophagic flux. Pretreatment with the multityrosine kinase inhibitor sorafenib did not affect autophagy impairment and steatosis but significantly reduced ERK phosphorylation and inflammatory response in irinotecan-treated hepatocytes and murine livers. Conclusions Irinotecan induces hepatic steatosis via autophagy impairment and inflammation via ERK activation. Sorafenib appears as a novel therapeutic option for the prevention and treatment of irinotecan-induced inflammation.


Genes, Chromosomes and Cancer | 2015

Systematic investigation of CMTM family genes suggests relevance to glioblastoma pathogenesis and CMTM1 and CMTM3 as priority targets

Sabit Delic; Andreas Thuy; Markus Schulze; Martin Proescholdt; Peter Dietrich; Anja-Katrin Bosserhoff; Markus J. Riemenschneider

The novel CKLF‐like Marvel Transmembrane Domain‐containing gene family (CMTM) consists of 8 members (CMTM1–8). As little is known about the oncogenic impact of these genes, we aimed to systematically investigate the relevance of CMTMs to glioblastoma pathogenesis. We performed mRNA expression analyses and survival correlations in glioblastoma patients. Moreover, we analyzed the impact of RNAi‐based silencing and overexpression of CMTM family genes on tumor cell proliferation and invasion in vitro. CMTMs appeared to be widely regulated in the group of glioblastomas relative to non‐neoplastic brain (NB) tissue (significant upregulation for CMTM2, 3, and 6 and significant downregulation for CMTM 4 and 8). For CMTM1, 5 and 7, we found aberrant expression levels in individual tumors. Functionally, CMTM1, 3, and 7 promoted tumor cell invasion, while CMTM1 additionally enhanced cell proliferation. In a large clinically annotated dataset, higher CMTM1 and 3 expression was significantly correlated with shorter overall survival. Our data thus suggest CMTM1 and 3 as priority targets in glioblastomas. Using a human phosphokinase protein expression profiling assay, we can provide first insights into signalling of these two genes that might be conveyed by growth factor receptor, Src family kinase and WNT activation.


Liver International | 2015

Neuropeptide Y restores non‐receptor‐mediated vasoconstrictive action in superior mesenteric arteries in portal hypertension

Johannes Hartl; Peter Dietrich; Lukas Moleda; Martina Müller-Schilling; Reiner Wiest

Vascular hyporeactivity to vasoconstrictors contributes to splanchnic arterial vasodilatation and hemodynamic dysregulation in portal hypertension. Neuropeptide Y (NPY), a sympathetic cotransmitter, has been shown to improve adrenergic vascular contractility in portal hypertensive rats and markedly attenuate hyperdynamic circulation. To further characterize the NPY‐effects in portal hypertension, we investigated its role for non‐receptor‐mediated vasoconstriction in the superior mesenteric artery (SMA) of portal vein ligated (PVL) and sham‐operated rats.


Oncogene | 2018

Wild-type KRAS is a novel therapeutic target for melanoma contributing to primary and acquired resistance to BRAF inhibition

Peter Dietrich; Silke Kuphal; Thilo Spruss; C Hellerbrand; A Bosserhoff

Malignant melanoma reveals rapidly increasing incidence and mortality rates worldwide. By now, BRAF inhibition is the standard therapy for advanced melanoma in patients carrying BRAF mutations. However, only approximately 50% of melanoma patients harbor therapeutically attackable BRAF mutations, and overall survival after treatment with BRAF inhibitors is modest. KRAS (Kirsten Rat sarcoma) proteins are acting upstream of BRAF and have a major role in human cancer. Recent approaches awaken the hope to use KRAS inhibition (KRASi) as a clinical tool. In this study, we identified wild-type KRAS as a novel therapeutic target in melanoma. KRASi functions synergistically with BRAF inhibition to reduce melanoma proliferation and to induce apoptosis independently of BRAF mutational status. Moreover, acquired resistance to BRAF inhibitors in melanoma is dependent on dynamic regulation of KRAS expression with subsequent AKT and extracellular-signal regulated kinase activation and can be overcome by KRASi. This suggests KRASi as novel approach in melanoma—alone or in combination with other therapeutic regimes.


Gut | 2018

Wild type Kirsten rat sarcoma is a novel microRNA-622-regulated therapeutic target for hepatocellular carcinoma and contributes to sorafenib resistance

Peter Dietrich; Andreas Koch; Valerie Fritz; Arndt Hartmann; Anja-Katrin Bosserhoff; C Hellerbrand

Objective Sorafenib is the only effective therapy for advanced hepatocellular carcinoma (HCC). Combinatory approaches targeting mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)- and phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)/protein-kinase B(AKT) signalling yield major therapeutic improvements. RAS proteins regulate both RAF/MAPK and PI3K/AKT signalling. However, the most important RAS isoform in carcinogenesis, Kirsten rat sarcoma (KRAS), remains unexplored in HCC. Design Human HCC tissues and cell lines were used for expression and functional analysis. Sorafenib-resistant HCC cells were newly generated. RNA interference and the novel small molecule deltarasin were used for KRAS inhibition both in vitro and in a murine syngeneic orthotopic HCC model. Results Expression of wild type KRAS messenger RNA and protein was increased in HCC and correlated with extracellular-signal regulated kinase (ERK) activation, proliferation rate, advanced tumour size and poor patient survival. Bioinformatic analysis and reporter assays revealed that KRAS is a direct target of microRNA-622. This microRNA was downregulated in HCC, and functional analysis demonstrated that KRAS-suppression is the major mediator of its inhibitory effect on HCC proliferation. KRAS inhibition markedly suppressed RAF/ERK and PI3K/AKT signalling and proliferation and enhanced apoptosis of HCC cells in vitro and in vivo. Combinatory KRAS inhibition and sorafenib treatment revealed synergistic antitumorigenic effects in HCC. Sorafenib-resistant HCC cells showed elevated KRAS expression, and KRAS inhibition resensitised sorafenib-resistant cells to suppression of proliferation and induction of apoptosis. Conclusions KRAS is dysregulated in HCC by loss of tumour-suppressive microRNA-622, contributing to tumour progression, sorafenib sensitivity and resistance. KRAS inhibition alone or in combination with sorafenib appears as novel promising therapeutic strategy for HCC.


Pigment Cell & Melanoma Research | 2016

DNMT targets MiRacle torching TORCh.

Peter Dietrich; Anja-Katrin Bosserhoff

able for evaluation of novel treatment modalities (Gao et al., 2015). We have extensively implemented PDXs to test promising therapeutic regimens, including combination of mitotic inhibitors with MDM2 antagonist, as well as to study the outcome of therapy-induced senescence (Vilgelm et al., 2015, 2016). However, due to the expense, timing, and complexity of the assays, one can envision a series of preclinical studies linked to clinical trials to demonstrate whether each individual PDX can consistently predict response to secondline therapy. Obviously, this will add to the complexity of the path report needed to inform the oncologist. Currently, commercial companies, such as Champion Oncology are doing this type of study and patients pay out of pocket for the analysis. The type of study proposed here by Krepler et al., if tested in a broader context of a multiple arm clinical trial, might lead to the establishment of new guidelines for therapy which could be covered by insurance companies once proven beneficial. As the authors point out, the PDX models described in this article do not take into account the effects of the targeted therapy combinations on the antitumor immune response. Moreover, it is not useful for examining the effects of immunotherapy. Currently, checkpoint inhibitors and other immunotherapeutic treatments are showing considerable promise for treatment of metastatic cancers, so viable humanized mouse models will need to be developed to effectively utilize PDX models to predict response to immune therapies. Progress is being made in this area, but much more effort needs to be put forward to create a NSG mouse that produces the human cytokines needed for full differentiation of a human hematopoietic system from human CD34+ cells engrafted into the NSG mice. References


Pigment Cell & Melanoma Research | 2015

Modifying microRNAs--another piece of the melanoma puzzle.

Peter Dietrich; Anja-Katrin Bosserhoff

Since their first discovery in 1993, microRNAs have been shown to regulate processes as diverse as protein expression and nuclear functions inside cells, and to signal extracellularly to influence cell fate at a distance (Mione and Bosserhoff, 2015). The role of specific microRNAs in melanoma development and progression is addressed in many recent studies, and several reviews show the fast progress in this field (e.g., Mione and Bosserhoff, 2015). RNA editing is an extensively studied post-transcriptional modification which increases protein diversity from a limited set of genes and creates proteins with different functions from the same premessenger RNA. In cancer cells, this process can promote tumor growth and progression. The most common form of RNA editing is adenosine-to-inosine (A-to-I) editing, which is mediated by the action of ‘adenosine deaminase acting on RNA’ (ADAR) enzymes. However, ADAR-mediated RNA editing has been shown to occur also in regulatory RNAs such as microRNAs (miRNAs), and can interfere with miRNA biogenesis, alter their stability within the cell, or modify their target binding (e.g., Kawahara et al., 2007). In 2013, Nemlich et al. previously reported that loss of ADAR1 in melanoma contributes to melanoma growth by modulating the processing of several miRNAs independent of its RNA-editing activity (Nemlich et al., 2013). The same group extended these observations in a recent study which is covered in this article to demonstrate that loss of ADAR1 in metastatic melanoma cells causes reduced A-to-I microRNA editing, leading to changes in target mRNA selection. Therefore, RNA editing of microRNAs provides a mechanism for how post-transcriptional modification can further expand the already diverse functions of microRNAs in melanoma development and progression. In detail, Shoshan et al. confirmed that ADAR1 expression was significantly lower in highly metastatic melanoma cell lines compared with non-metastatic melanoma cells and melanocytes, concluding that ADAR1 expression decreases with melanoma progression. Interestingly, they revealed that ‘cAMP-responsive element-binding protein’ (CREB) acts as a repressor of ADAR1 expression in melanoma. CREB was identified as a regulator of ADAR1 by gene expression profiling due to an increase in ADAR1 expression after CREB silencing in metastatic melanoma cells. The group could further show that the loss of ADAR1 in metastatic melanoma cells leads to a decrease in A-to-I RNA editing. Subsequent in vivo experiments revealed that suppression of ADAR1 contributes to tumorigenicity and metastatic potential of melanoma cells, whereas overexpression of ADAR1 in metastatic melanoma cells led to a significant decrease in the median number of lung metastases. Subsequently, the group examined whether the effect of downregulated ADAR1 in metastatic melanoma cells affects A-to-I microRNA editing. After ADAR1 and CREB silencing, they saw respectively decreased and increased A-to-I microRNA editing in three microRNAs: miR378-3p, miR-324-5p, and miR-455-5p. They concentrated on the miR-455-5p as this microRNA contains two ADAR1mediated RNA-editing sites inside its target binding ‘seed’ sequence. After ADAR1 knockdown, RNA editing was decreased and overexpression of ADAR1 led to an increase in RNA editing. After the silencing of CREB, an increase in A-to-I RNA editing was observed, and rescue of CREB expression decreased RNA editing at these sites, providing evidence that ADAR1 and CREB (as a negative regulator of ADAR1 expression) affect A-to-I RNA editing of miR-455-5p in melanoma. In a subsequent set of experiments carried out to elucidate the effects of RNA editing on microRNA biogenesis, the group found that ADAR1-mediated A-to-I RNA editing reduced the ability of primary microRNA-455 to bind to the nuclear microRNA-processing enzyme Drosha, therefore influencing its further processing to mature miR-455-5p. This mechanism could lead to reduced levels of biologically active mature miR-455-5p in the presence of ADAR1; however, ADAR1 is decreased in metastatic melanoma. To compare the functions of wild-type and edited miR-455, a set of lentiviral expression vectors overexpressing either wild-type miR-455, miR455 edited at site 1 only, miR-455 edited at site 2 only, or miR-455 edited at both sites 1 and 2 as well as an ‘antagomir’ to silence miR-455 (anti-miR-455) was created. Subsequent in vitro experiments with ADAR1-overexpressing or ADAR1-knockdown melanoma cells demonstrated that wild-type but not RNA-edited miR-455-5p targets ‘cytoplasmic polyadenylation element-binding protein 10 (CPEB1), which has two binding sites for miR-455-5p in its 30UTR. Thus, the group concluded that the effect of the unedited (=wild-type) miR455-5p is mediated by its sequencedependent ability to target CPEB1. ADAR1 overexpression enhanced CPEB1 expression, and after ADAR1 silencing, CPEB1 expression was decreased by about 70% at the mRNA level and 80% at the protein level, confirming that ADAR1 affects CPEB1 expression. Subsequently, the group examined whether CPEB1 could function as a tumor suppressor (which is lost in metastatic melanoma) and found Coverage on: Shoshan E, Mobley AK, Braeuer RR, Kamiya T, Huang L, Vasquez ME, Salameh A, Lee HJ, Kim SJ, Ivan C, Velazquez-Torres G, Nip KM, Zhu K, Brooks D, Jones SJ, Birol I, Mosqueda M, Wen YY, Eterovic AK, Sood AK, Hwu P, Gershenwald JE, Robertson AG, Calin GA, Markel G, Fidler IJ, Bar-Eli M. (2015) Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis. Nat. Cell Biol. 17(3), 311–321. doi: 10.1038/ncb3110.

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C Hellerbrand

University of Erlangen-Nuremberg

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A Bosserhoff

University of Erlangen-Nuremberg

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Anja-Katrin Bosserhoff

University of Erlangen-Nuremberg

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K Freese

University of Erlangen-Nuremberg

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A Mahli

University of Erlangen-Nuremberg

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Lukas Moleda

University of Regensburg

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Silke Kuphal

University of Regensburg

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V Fritz

University of Erlangen-Nuremberg

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