Limiting serine availability during tumor progression promotes muscle wasting in cancer cachexia.

Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of body weight occurring in about 80% of cancer patients, frequently representing the leading cause of death. Dietary intervention is emerging as a promising therapeutic strategy to counteract cancer-induced wasting. Serine is the second most-consumed amino acid (AA) by cancer cells and has emerged to be strictly necessary to preserve skeletal muscle structure and functionality.

Metabolic challengers selecting tumor-persistent cells.

Resistance to anticancer therapy still represents one of the main obstacles to cancer treatment. Numerous components of the tumor microenvironment (TME) contribute significantly to the acquisition of drug resistance. Microenvironmental pressures arising during cancer evolution foster tumor heterogeneity (TH) and facilitate the emergence of drug-resistant clones.

Oncostatin M: From Intracellular Signaling to Therapeutic Targets in Liver Cancer.

Primary liver cancers represent the third-most-common cause of cancer-related mortality worldwide, with an incidence of 80-90% for hepatocellular carcinoma (HCC) and 10-15% for cholangiocarcinoma (CCA), and an increasing morbidity and mortality rate. Although HCC and CCA originate from independent cell populations (hepatocytes and biliary epithelial cells, respectively), they develop in chronically inflamed livers. Evidence obtained in the last decade has revealed a role for cytokines of the IL-6 family in the development of primary liver cancers.

The protease-inhibitor SerpinB3 as a critical modulator of the stem-like subset in human cholangiocarcinoma.

Background And Aims: Cholangiocarcinoma (CCA) is a form of primary liver cancer with limited therapeutic options. Recently, cancer stem cells (CSCs) have been proposed as a driving force of tumour initiation and dissemination, thus representing a crucial therapeutic target. The protease inhibitor SerpinB3 (SB3) has been identified in several malignancies including hepatocellular carcinoma.

Analytical evaluation of direct bicarbonate measurement with the new gem premier chemstat in hemodialysis patients.

GEM Premier ChemSTAT is a whole-blood analyzer designed for providing a rapid basic metabolic panel, inclusive of creatinine and blood urea nitrogen, with the unique characteristic of providing measured bicarbonate (HCO) levels. The aim of this work was to evaluate the clinical performance of HCO assessment with this analyser in a real-life hemodialysis setting. Imprecision was calculated at different HCO levels, along with assay comparison with Gem Premier 4000 analysers.

Extracellular Signal-Regulated Kinase 5 Regulates the Malignant Phenotype of Cholangiocarcinoma Cells.

Background And Aims: Cholangiocarcinoma (CCA) is characterized by high resistance to chemotherapy and poor prognosis. Several oncogenic pathways converge on activation of extracellular signal-regulated kinase 5 (ERK5), whose role in CCA has not been explored. The aim of this study was to investigate the role of ERK5 in the biology of CCA.

Mitochondrial oxidative metabolism contributes to a cancer stem cell phenotype in cholangiocarcinoma.

Background & Aims: Little is known about the metabolic regulation of cancer stem cells (CSCs) in cholangiocarcinoma (CCA). We analyzed whether mitochondrial-dependent metabolism and related signaling pathways contribute to stemness in CCA.

Methods: The stem-like subset was enriched by sphere culture (SPH) in human intrahepatic CCA cells (HUCCT1 and CCLP1) and compared to cells cultured in monolayer.

PCSK9 rs11591147 R46L loss-of-function variant protects against liver damage in individuals with NAFLD.

Background And Aims: The proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis, and its inhibition represents an effective therapy to lower low-density lipoprotein cholesterol (LDL-C) levels. In this study, we examined the impact of the PCSK9 rs11591147 loss-of-function (LOF) variant on liver damage in a multicenter collection of patients at risk of nonalcoholic steatohepatitis (NASH), in clinical samples and experimental models.

Methods: We considered 1874 consecutive individuals at risk of NASH as determined by histology.

Role of Chemokines in the Biology of Cholangiocarcinoma.

Cholangiocarcinoma (CCA), a heterogeneous tumor with poor prognosis, can arise at any level in the biliary tree. It may derive from epithelial cells in the biliary tracts and peribiliary glands and possibly from progenitor cells or even hepatocytes. Several risk factors are responsible for CCA onset, however an inflammatory milieu nearby the biliary tree represents the most common condition favoring CCA development.

Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives.

Cholangiocarcinoma (CCA) is a deadly tumor without an effective therapy. Unique metabolic and bioenergetics features are important hallmarks of tumor cells. Metabolic plasticity allows cancer cells to survive in poor nutrient environments and maximize cell growth by sustaining survival, proliferation, and metastasis.

Design and evaluation of non-carboxylate 5-arylidene-2-thioxo-4-imidazolidinones as novel non-competitive inhibitors of protein tyrosine phosphatase 1B.

Protein tyrosine phosphatase 1B (PTP1B) acts as a negative regulator of insulin and leptin signalling and is crucially involved in the development of type 2 diabetes mellitus, obesity, cancer and neurodegenerative diseases. Pursuing our efforts to identify PTP1B inhibitors endowed with drug-like properties, we designed and evaluated 3-aryl-5-arylidene-2-thioxo-4-imidazolidinones (7) as a novel class of non-carboxylate PTP1B inhibitors. In agreement with our design, kinetic studies demonstrated that selected compounds 7 act as reversible, non-competitive inhibitors of the target enzyme at low micromolar concentrations.

Role of Myeloid-Epithelial-Reproductive Tyrosine Kinase and Macrophage Polarization in the Progression of Atherosclerotic Lesions Associated With Nonalcoholic Fatty Liver Disease.

Recent lines of evidence highlight the involvement of myeloid-epithelial-reproductive tyrosine kinase (MerTK) in metabolic disease associated with liver damage. MerTK is mainly expressed in anti-inflammatory M2 macrophages where it mediates transcriptional changes including suppression of proinflammatory cytokines and enhancement of inflammatory repressors. MerTK is regulated by metabolic pathways through nuclear sensors including LXRs, PPARs, and RXRs, in response to apoptotic bodies or to other sources of cholesterol.

CXCR7 contributes to the aggressive phenotype of cholangiocarcinoma cells.

Development of cholangiocarcinoma (CCA) is dependent on a cross-talk with stromal cells, which release different chemokines including CXCL12, that interacts with two different receptors, CXCR4 and CXCR7. The aim of the present study was to investigate the role of CXCR7 in CCA cells. CXCR7 is overexpressed by different CCA cell lines and in human CCA specimens.

LMW-PTP targeting potentiates the effects of drugs used in chronic lymphocytic leukemia therapy.

Background: Low molecular weight protein tyrosine phosphatase (LMW-PTP) is overexpressed in different cancer types and its expression is related to more aggressive disease, reduced survival rate and drug resistance. Morin is a natural polyphenol which negatively modulates, among others, the activity of LMW-PTP, leading to the potentiation of the effects of different antitumoral drugs, representing a potential beneficial treatment against cancer.

Methods: LMW-PTP levels were measured by immunoblot analysis both in CLL cells from patients and in chronic lymphocytic leukemia (CLL)-derived Mec-1 cells.

Morin-dependent inhibition of low molecular weight protein tyrosine phosphatase (LMW-PTP) restores sensitivity to apoptosis during colon carcinogenesis: Studies in vitro and in vivo, in an Apc-driven model of colon cancer.

LMW-PTP has been associated with the development of colorectal cancer (CRC) and with the resistance to chemotherapy in cancer cells. To clarify its role in vivo, we studied LMW-PTP expression in Pirc rats (F344/NTac-Apc ), genetically prone to CRC and resistant to apoptosis. In the morphologically normal mucosa (NM) of Pirc rats, a dramatic over-expression of LMW-PTP was found compared to wt rats (about 60 times higher).

Synthesis and evaluation of thiazolidine-2,4-dione/benzazole derivatives as inhibitors of protein tyrosine phosphatase 1B (PTP-1B): Antihyperglycemic activity with molecular docking study.

This work presents the synthesis of two hybrid compounds (1 and 2) with thiazolidine-2,4-dione structure as a central scaffold which were further screened in combo (in vitro as PTP-1B inhibitors, in vivo antihyperglycemic activity, in silico toxicological profile and molecular docking). Compound 1 was tested in the enzymatic assay showing an IC = 9.6 ± 0.

LMW-PTP modulates glucose metabolism in cancer cells.

Background: Low Molecular Weight Phosphotyrosine Protein Phosphatase (LMW-PTP) is an enzyme involved not only in tumor onset and progression but also in type 2 diabetes. A recent review shows that LMW-PTP acts on several RTK (receptor tyrosine kinase) such as PDGFR, EGFR, EphA2, Insulin receptor. It is well described also its interaction with cSrc.

Targeting LMW-PTP to sensitize melanoma cancer cells toward chemo- and radiotherapy.

Tumor resistance to apoptosis is one the main causes of anticancer treatment failure. Previous studies showed that LMW-PTP overexpression enhances resistance of cancer cells to traditional anticancer drugs. Today, the role of LMW-PTP in inducing resistance to apoptosis in melanoma cells remains to be elucidated.

Discovery of 4-[(5-arylidene-4-oxothiazolidin-3-yl)methyl]benzoic acid derivatives active as novel potent allosteric inhibitors of protein tyrosine phosphatase 1B: In silico studies and in vitro evaluation as insulinomimetic and anti-inflammatory agents.

New 4-{[5-arylidene-2-(4-fluorophenylimino)-4-oxothiazolidin-3-yl]methyl}benzoic acids (5) and 2-thioxo-4-thiazolidinone analogues (6) were synthesised as a part of a continuing search for new inhibitors of protein tyrosine phosphatase 1B (PTP1B), an enzyme which is implicated in metabolic disorders and inflammatory signaling. Most of the tested compounds were shown to be potent PTP1B inhibitors. Moreover, their inhibition mechanism was markedly influenced by the substituents in the positions 2 and 5, as kinetic studies indicated.