Colon cancer cell chemosensitisation by fish oil emulsion involves apoptotic mitochondria pathway

Adjuvant use of safe compounds with anti-tumour properties has been proposed to improve cancer chemotherapy outcome. We aimed to investigate the effects of fish oil emulsion (FOE) rich in n-3 PUFA with the standard chemotherapeutic agents 5-fluorouracil (5-FU), oxaliplatin (OX) or irinotecan (IRI) on two human colorectal adenocarcinoma cells with different genetic backgrounds. The HT-29 (Bax+/+) and LS174T (Bax−/−) cells were co-treated for 24-72h with 1μm-5-FU, 1μm-OX or 10μm-IRI and/or FOE dilution corresponding to 24μm-EPA and 20·5μm-DHA. Soyabean oil emulsion (SOE) was used as isoenergetic and isolipid control. Cell viability, apoptosis and nuclear morphological changes were evaluated by cytotoxic colorimetric assay, flow cytometry analysis with annexin V and 4′,6′-diamidino-2-phenylindole staining, respectively. A cationic fluorescent probe was used to evaluate mitochondrial dysfunction, and protein expression involved in mitochondrial apoptosis was determined by Western blot. In contrast to SOE, co-treatment with FOE enhanced significantly the pro-apoptotic and cytotoxic effects of 5-FU, OX or IRI in HT-29 but not in LS174T cells (two-way ANOVA, P<0·01). These results were confirmed by the formation of apoptotic bodies in HT-29 cells. A significant increase in mitochondrial membrane depolarisation was observed after the combination of 5-FU or IRI with FOE in HT-29 but not in LS174T cells (P<0·05). Co-administration of FOE with the standard agents, 5-FU, OX and IRI, could be a good alternative to increase the efficacy of chemotherapeutic protocols through a Bax-dependent mitochondrial pathwa

Direct In Vivo Cell Lineage Analysis in the Retrorsine and 2AAF Models of Liver Injury after Genetic Labeling in Adult and Newborn Rats

BACKGROUNDS AND AIMS:When hepatocyte proliferation is impaired, liver regeneration proceeds from the division of non parenchymal hepatocyte progenitors. Oval cells and Small Hepatocyte-like Progenitor Cells (SHPCs) represent the two most studied examples of such epithelial cells with putative stem cell capacity. In the present study we wished to compare the origin of SHPCs proliferating after retrorsine administration to the one of oval cells observed after 2-Acetyl-Amino fluorene (2-AAF) treatment. METHODOLOGY/PRINCIPAL FINDINGS:We used retroviral-mediated nlslacZ genetic labeling of dividing cells to study the fate of cells in the liver. Labeling was performed either in adult rats before treatment or in newborn animals. Labeled cells were identified and characterised by immunohistochemistry. In adult-labeled animals, labeling was restricted to mature hepatocytes. Retrorsine treatment did not modify the overall number of labeled cells in the liver whereas after 2-AAF administration unlabeled oval cells were recorded and the total number of labeled cells decreased significantly. When labeling was performed in newborn rats, results after retrorsine administration were identical to those obtained in adult-labeled rats. In contrast, in the 2-AAF regimen numerous labeled oval cells were present and were able to generate new labeled hepatocytes. Furthermore, we also observed labeled biliary tracts in 2-AAF treated rats. CONCLUSIONS:Our results strongly suggest that SHPCs are derived from hepatocytes and we confirm that SHPCs and oval cells do not share the same origin. We also show that hepatic progenitors are labeled in newborn rats suggesting future directions for in vivo lineage studies

Bone Marrow Transplant

Mucopolysaccharidosis type I-H (MPS I-H) is a rare lysosomal storage disorder caused by α-L-Iduronidase deficiency. Early haematopoietic stem cell transplantation (HSCT) is the sole available therapeutic option to preserve neurocognitive functions. We report long-term follow-up (median 9 years, interquartile range 8-16.5) for 51 MPS I-H patients who underwent HSCT between 1986 and 2018 in France. 4 patients died from complications of HSCT and one from disease progression. Complete chimerism and normal α-L-Iduronidase activity were obtained in 84% and 71% of patients respectively. No difference of outcomes was observed between bone marrow and cord blood stem cell sources. All patients acquired independent walking and 91% and 78% acquired intelligible language or reading and writing. Intelligence Quotient evaluation (n = 23) showed that 69% had IQ ≥ 70 at last follow-up. 58% of patients had normal or remedial schooling and 62% of the 13 adults had good socio-professional insertion. Skeletal dysplasia as well as vision and hearing impairments progressed despite HSCT, with significant disability. These results provide a long-term assessment of HSCT efficacy in MPS I-H and could be useful in the evaluation of novel promising treatments such as gene therapy

Angiogenesis as a potential target of pharmaconutrients in cancer therapy

PURPOSE OF REVIEW: The aim of this review is to provide insight into tumor angiogenesis inhibition by pharmaconutrients through description of the most relevant and recent findings in cancer research. RECENT FINDINGS: Cancer growth needs oxygen and nutrients supplied through blood vessels to the tumor site. New vessel formation named angiogenesis can be prevented to avoid cancer invasion. Epidemiological studies suggested that specific food intakes could decrease incidence of many cancers. Recently, scientists were interested in the potential antitumor effects of nutrients because of their safety and general acceptance. Many excellent publications demonstrated that a large class of natural compounds including pharmaconutrients exhibits antitumoral activities in selected cancer types. This review focuses on the antiangiogenic role of natural products in cancer treatment, used alone or in combination with conventional chemotherapy. SUMMARY: There is strong evidence that natural diets influence cancer development by modulating signaling pathways. Our goal is to highlight the specific impact of specific nutrients in the modulation of vascular network leading to tumor angiogenesis inhibition

Histological analysis of retrorsin and 2-AAF treated rat liver after genetic labeling of mature hepatocytes in adult animals.

<p><u>Retrorsin model</u>. (A) β-galactosidase positive cells gathered in clusters of small hepatocyte day 15. (B) same clusters at day 30 post hepatectomy. <u>2-AAF model.</u> Immunohistochemical detection of CKs (C), GGT (D), and β-catenin (E) expressed by oval cells. (F) Clusters of β-galactosidase positive hepatocyte observed in the 2-AAF model. All sections are hematoxylin counterstained. All magnifications: ×400 except ×200 B and F.</p

Histological analysis of the retrorsin model after genetic labeling of liver cells in newborn rats.

<p><u>Retrorsin model</u>. (A) Cluster of SHPCs positive for β-galactosidase. (B) Hematoxylin and eosin staining showing large number of merging clusters 30 days post hepatectomy. (C) Immunohistochemical detection of CKs day 30 post hepatectomy. Oval cells are not detected. Hematoxylin counterstain. Magnification: ×200 A–B: ×400 C.</p

Quantification of the number of β-galactosidase positive hepatocytes in the liver of rat labeled at adulthood and treated with Retrorsine (upper panel) or 2-AAF (lower panel).

<p>Quantification of the number of β-galactosidase positive hepatocytes in the liver of rat labeled at adulthood and treated with Retrorsine (upper panel) or 2-AAF (lower panel).</p

Schematic diagrams of retrorsine and 2-AAF treatments.

<p>Schematic diagrams of retrorsine and 2-AAF treatments.</p

Histological analysis of 2-AAF model after genetic labeling of liver cells in newborn rats.

<p>(A) Detection of β-galactosidase positives oval cells. (B1) Immunofluorescent staining of CK in oval cells appearing in red (B2) colocalisation of CK with β-galactosidase appearing in green. (C) Detection of β-galactosidase positive cells in the biliary cell population (arrows). (D) Detection of a positive cells (arrow) near the Hering canal. Hematoxylin counterstain for A, C, D, Magnification: ×400 except for B: ×1000.</p

Quantification of β-galactosidase positive hepatocytes and clones in the liver of adult-labeled rats treated with retrorsine.

<p>Quantification of β-galactosidase positive hepatocytes and clones in the liver of adult-labeled rats treated with retrorsine.</p