Viability of Glioblastoma Cells and Fibroblasts in the Presence of Imidazole-Containing Compounds.

The naturally occurring dipeptide carnosine (β-alanyl--histidine) specifically attenuates tumor growth. Here, we ask whether other small imidazole-containing compounds also affect the viability of tumor cells without affecting non-malignant cells and whether the formation of histamine is involved. Patient-derived fibroblasts and glioblastoma cells were treated with carnosine, -alanyl--histidine (LA-LH), β-alanyl--alanine, -histidine, histamine, imidazole, β-alanine, and -alanine.

De novo variants in ATP2B1 lead to neurodevelopmental delay.

Calcium (Ca) is a universal second messenger involved in synaptogenesis and cell survival; consequently, its regulation is important for neurons. ATPase plasma membrane Ca transporting 1 (ATP2B1) belongs to the family of ATP-driven calmodulin-dependent Ca pumps that participate in the regulation of intracellular free Ca. Here, we clinically describe a cohort of 12 unrelated individuals with variants in ATP2B1 and an overlapping phenotype of mild to moderate global development delay.

RNA sequencing of glioblastoma tissue slice cultures reveals the effects of treatment at the transcriptional level.

One of the major challenges in cancer research is finding models that closely resemble tumors within patients. Human tissue slice cultures are a promising approach to provide a model of the patient's tumor biology ex vivo. Recently, it was shown that these slices can be successfully analyzed by whole transcriptome sequencing as well as automated histochemistry, increasing their usability as preclinical model.

Erythrocytes Prevent Degradation of Carnosine by Human Serum Carnosinase.

The naturally occurring dipeptide carnosine (β-alanyl-l-histidine) has beneficial effects in different diseases. It is also frequently used as a food supplement to improve exercise performance and because of its anti-aging effects. Nevertheless, after oral ingestion, the dipeptide is not detectable in human serum because of rapid degradation by serum carnosinase.

Surfactant protein C is associated with perineuronal nets and shows age-dependent changes of brain content and hippocampal deposits in wildtype and 3xTg mice.

Surfactant protein C (SP-C) modulates cerebrospinal fluid (CSF) rheology. During ageing, its declining levels are accompanied by an increased burden of white matter lesions. Pulmonary SP-C intermediates harbouring the BRICHOS-domain prevent protein misfolding in the lungs.

Antifibrotic Effects of Amyloid-Beta and Its Loss in Cirrhotic Liver.

The function and regulation of amyloid-beta (Aβ) in healthy and diseased liver remains unexplored. Because Aβ reduces the integrity of the blood-brain barrier we have examined its potential role in regulating the sinusoidal permeability of normal and cirrhotic liver. Aβ and key proteins that generate (beta-secretase 1 and presenilin-1) and degrade it (neprilysin and myelin basic protein) were decreased in human cirrhotic liver.

Deep sequencing and automated histochemistry of human tissue slice cultures improve their usability as preclinical model for cancer research.

Cancer research requires models closely resembling the tumor in the patient. Human tissue cultures can overcome interspecies limitations of animal models or the loss of tissue architecture in in vitro models. However, analysis of tissue slices is often limited to histology.

Carnosine increases efficiency of temozolomide and irradiation treatment of isocitrate dehydrogenase-wildtype glioblastoma cells in culture.

The naturally occurring dipeptide carnosine (CAR) has been considered for glioblastoma therapy. As CAR also protects against ionizing irradiation (IR), we investigated whether it may counteract standard therapy consisting of postsurgery IR and treatment with temozolomide (TMZ). Four isocitrate dehydrogenase-wildtype primary cell cultures were exposed to different doses of IR and different concentrations of TMZ and CAR.

The Chk1 inhibitor SAR-020106 sensitizes human glioblastoma cells to irradiation, to temozolomide, and to decitabine treatment.

Background: Glioblastoma is the most common and aggressive brain tumour in adults with a median overall survival of only 14 months after standard therapy with radiation therapy (IR) and temozolomide (TMZ). In a novel multimodal treatment approach we combined the checkpoint kinase 1 (Chk1) inhibitor SAR-020106 (SAR), disrupting homologue recombination, with standard DNA damage inducers (IR, TMZ) and the epigenetic/cytotoxic drug decitabine (5-aza-2'-deoxycitidine, 5-aza-dC). Different in vitro glioblastoma models are monitored to evaluate if the impaired DNA damage repair may chemo/radiosensitize the tumour cells.

Non-enzymatic reaction of carnosine and glyceraldehyde-3-phosphate accompanies metabolic changes of the pentose phosphate pathway.

Objectives: Carnosine (β-alanyl-l-histidine) is a naturally occurring dipeptide that selectively inhibits cancer cell growth, possibly by influencing glucose metabolism. As its precise mode of action and its primary targets are unknown, we analysed carnosine's effect on metabolites and pathways in glioblastoma cells.

Materials And Methods: Glioblastoma cells, U87, T98G and LN229, were treated with carnosine, and metabolites were analysed by gas chromatography coupled with mass spectrometry.

Carnosine inhibits glioblastoma growth independent from PI3K/Akt/mTOR signaling.

Glioblastoma is a high-grade glioma with poor prognosis even after surgery and standard therapy. Here, we asked whether carnosine (β-alanyl-L-histidine), a naturally occurring dipeptide, exert its anti-neoplastic effect on glioblastoma cells via PI3K/Akt/mTOR signaling. Therefore, glioblastoma cells from the lines U87 and T98G were exposed to carnosine, to the mTOR inhibitor rapamycin and to the PI3K inhibitor Ly-294,002.

The proton-coupled oligopeptide transporters PEPT2, PHT1 and PHT2 mediate the uptake of carnosine in glioblastoma cells.

The previous studies demonstrated that carnosine (β-alanyl-L-histidine) inhibits the growth of tumor cells in vitro and in vivo. Considering carnosine for the treatment of glioblastoma, we investigated which proton-coupled oligopeptide transporters (POTs) are present in glioblastoma cells and how they contribute to the uptake of carnosine. Therefore, mRNA expression of the four known POTs (PEPT1, PEPT2, PHT1, and PHT2) was examined in three glioblastoma cell lines, ten primary tumor cell cultures, in freshly isolated tumor tissue and in healthy brain.

Assessment of ApoC1, LuzP6, C12orf75 and OCC-1 in cystic glioblastoma using MALDI-TOF mass spectrometry, immunohistochemistry and qRT-PCR.

Mass spectrometric analysis of glioblastoma cyst fluids has disclosed a protein peak with m/z 6424-6433. Among the proteins, potentially generating this peak are ApoC1 and LuzP6. To further elucidate protein expression of glioblastoma cells, we analyzed MALDI-TOF results of cyst fluid, performed immunohistochemistry and mRNA analysis.

D,L-Methadone does not improve radio- and chemotherapy in glioblastoma in vitro.

Purpose: Glioblastoma (GBM) is the most common malignant tumor of the central nervous system. Median survival of glioblastoma patients under standard therapy including radiotherapy and chemotherapy using temozolomide (TMZ) is 14.6 months.

Carnosine's inhibitory effect on glioblastoma cell growth is independent of its cleavage.

The naturally occurring dipeptide carnosine (β-alanyl-L-histidine) inhibits the growth of tumor cells. As its component L-histidine mimics the effect, we investigated whether cleavage of carnosine is required for its antineoplastic effect. Using ten glioblastoma cell lines and cell cultures derived from 21 patients suffering from this malignant brain tumor, we determined cell viability under the influence of carnosine and L-histidine.

β-Catenin and Yes-Associated Protein 1 Cooperate in Hepatoblastoma Pathogenesis.

Hepatoblastoma (HB), the most common pediatric primary liver neoplasm, shows nuclear localization of β-catenin and yes-associated protein 1 (YAP1) in almost 80% of the cases. Co-expression of constitutively active S127A-YAP1 and ΔN90 deletion-mutant β-catenin (YAP1-ΔN90-β-catenin) causes HB in mice. Because heterogeneity in downstream signaling is being identified owing to mutational differences even in the β-catenin gene alone, we investigated if co-expression of point mutants of β-catenin (S33Y or S45Y) with S127A-YAP1 led to similar tumors as YAP1-ΔN90-β-catenin.

Carnosine selectively inhibits migration of IDH-wildtype glioblastoma cells in a co-culture model with fibroblasts.

Background: Glioblastoma (GBM) is a tumor of the central nervous system. After surgical removal and standard therapy, recurrence of tumors is observed within 6-9 months because of the high migratory behavior and the infiltrative growth of cells. Here, we investigated whether carnosine (β-alanine-l-histidine), which has an inhibitory effect on glioblastoma proliferation, may on the opposite promote invasion as proposed by the so-called "go-or-grow concept".

Carnosine influences transcription via epigenetic regulation as demonstrated by enhanced histone acetylation of the pyruvate dehydrogenase kinase 4 promoter in glioblastoma cells.

Carnosine (β-alanyl-L-histidine) affects a plethora of signaling pathways and genes in different biological systems. Although known as a radical scavenger, not all of these effects can simply be ascribed to its chemical nature. As previous experiments pointed towards the possibility that carnosine affects epigenetic regulation via histone acetylation, we investigated this hypothesis using the glioblastoma cell lines U87 and T98G in which carnosine's anti-neoplastic effect is accompanied by increased expression of pyruvate dehydrogenase kinase 4.

The Wnt/β-catenin pathway determines the predisposition and efficiency of liver-to-pancreas reprogramming.

Unlabelled: Transdifferentiation (TD) is the direct reprogramming of adult cells into cells of alternate fate and function. We have previously shown that liver cells can be transdifferentiated into beta-like, insulin-producing cells through ectopic expression of pancreatic transcription factors (pTFs). However, the efficiency of the process was consistently limited to <15% of the human liver cells treated in culture.

Phenotypic Screen Identifies a Small Molecule Modulating ERK2 and Promoting Stem Cell Proliferation.

Stem cells display a fundamentally different mechanism of proliferation control when compared to somatic cells. Uncovering these mechanisms would maximize the impact in drug discovery with a higher translational applicability. The unbiased approach used in phenotype-based drug discovery (PDD) programs can offer a unique opportunity to identify such novel biological phenomenon.

Analysis of cellular and molecular antitumor effects upon inhibition of SATB1 in glioblastoma cells.

Background: The Special AT-rich Sequence Binding Protein 1 (SATB1) regulates the expression of many genes by acting as a global chromatin organizer. While in many tumor entities SATB1 overexpression has been observed and connected to pro-tumorigenic processes, somewhat contradictory evidence exists in brain tumors with regard to SATB1 overexpression in glioblastoma and its association with poorer prognosis and tumor progression. On the functional side, initial data indicate that SATB1 may be involved in several tumor cell-relevant processes.

Modulation of GLO1 Expression Affects Malignant Properties of Cells.

The energy metabolism of most tumor cells relies on aerobic glycolysis (Warburg effect) characterized by an increased glycolytic flux that is accompanied by the increased formation of the cytotoxic metabolite methylglyoxal (MGO). Consequently, the rate of detoxification of this reactive glycolytic byproduct needs to be increased in order to prevent deleterious effects to the cells. This is brought about by an increased expression of glyoxalase 1 (GLO1) that is the rate-limiting enzyme of the MGO-detoxifying glyoxalase system.

Pyruvate attenuates the anti-neoplastic effect of carnosine independently from oxidative phosphorylation.

Here we analyzed whether the anti-neoplastic effect of carnosine, which inhibits glycolytic ATP production, can be antagonized by ATP production via oxidative phosphorylation fueled by pyruvate. Therefore, glioblastoma cells were cultivated in medium supplemented with glucose, galactose or pyruvate and in the presence or absence of carnosine. CPI-613 was employed to inhibit the entry of pyruvate into the tricarboxylic acid cycle and 2,4-dinitrophenol to inhibit oxidative phosphorylation.