Visualizing fixed cells and tissues only gives snapshots of cellular processes. To have a better insight into dynamic events ocurring in the cells or to vizualize interactions between various cellular components in real time (e.g., proteins, organelles, second messengers…), powerful microscopic approaches have been developed over the past decade. This post will review the recent live cell imaging probes developed by Goryo Chemicalsand available in Europe through tebu-bio.
The Murphy Roths Large-MRL engineered mouse strain spontaneously regenerates ears and even heart tissue. Such a regenerative process is known for amphibians; mammals generally forming scar tissue during the process of wound repair. The groups of Ellen Heber-Katz (The Wistar Institute, Philadelphia, PA) and Phillip B. Messersmith (Northwestern University, Evanston, IL) discovered these exceptional capabilities a few years ago. By using this unique model, the scientists have recently shown that Hypoxia-Inducible Factor-1 alpha (HIF-1alpha) is involved in mammalian tissue regeneration (Zhang Y. et al. “Drug-induced regeneration in adult mice”(2015) Sci. Transl. Med. DOI: 10.1126/scitranslmed.3010228).
A recent review by Nadim et al. casts some light on a Cosmetology and Dermatology, where circulating biomarkers, though studied to a certain extent so far, are yet unknown for many skin models. (1) A first element to have in mind when considering the skin-related experimental model is the “Oxygen level”. Oxygen levels may contribute to different findings, and the in vitro models used so far may not be so physiologically relevant as initially thought.
Today, I’d like to invite you to take a look at the 5 posts describing a pathway that saw the most visits on our blog in 2014.
Just follow the links if you haven’t read them yet (or if you want to browse them again, feel free!).
In a recent publication, Mennesson E. et al. have developped a smart approach to perform both adipokine protein and miRNA profilings in in vitro adipocyte models mimicking the physiological state of adipose tissues. Adipokines and miRNAs are now known to be involved in adipose tissue metabolism in obesity during which hypoxic adipose tissue development is seen due to tissue mass expansion. Such Cytokine and miRNA profilings are thus needed to better decipher the physiopathology of obesity and to identify new biomarkers.
Cell culture under oxygen controlled conditions: an improvement towards more predictive results
Oxygen concentration in tissues is a key factor for cell and organ survival. In normal conditions, partial oxygen pressure (pO2) results in the balance between oxygen delivery and its consumption. Oxygen is transported, in mammals, by circulating red blood cells. Partial oxygen pressure in tissues varies widely, depending on their respective metabolic requirements and their functional status. In normal physiological conditions, partial oxygen pressure is called physioxia. Any alteration of tissue environment leading to a decrease in partial oxygen pressure is called hypoxia. Hypoxic conditions have been observed in many different pathological situations like tumor development, obesity or transcient ischemia. [Read more…]
The cellular and physiological effects resulting from hypoxia-dependent networks have been clearly shown to impact a number of human pathological states, including ischemic disease, diabetes, pulmonary disease and, perhaps most notably, cancer. Thus, further research into the biomedical effects of hypoxia could lead to novel therapeutic approaches for these diseases.
Hypoxia in tumors is closely associated with tumor aggressiveness and resistance to radio- and chemotherapeutic treatment. Therefore, reliable markers for hypoxia represent both valuable diagnostic markers and potential targets for investigation.
Hypoxia has important effects on chemosensitivity of cancer cells and the synthetic lethal effects of drugs.
In a recent work presented during the “Experimental and Molecular Therapeutics” sessions at the AACR 2014, Claudine Kiéda’s and Nadia Normand’s teams showed that PARP inhibitors are less synthetically lethal in hypoxic conditions with increased IC50 and survival percentage at higher concentrations.
Synthetic Lethality (SL) is defined as when loss of two genes independently has no effect on viability, but simultaneous loss of both genes causes cell death.
In cancer research and drug discovery, SL is observed when the cancer mutation and the drug simultaneously inhibit two otherwise independent pathways, leading to cell death. The best known SL relationship is between BRCA1/2 mutation (tumors deficient in Homologous Recombination (HR) DNA Repair pathway) and PARP inhibitors (affecting the Base Excision Repair (BER) DNA Repair pathway).
In their work, Dr Kiéda and Dr Normand used already published in vitro stable BRCA1- and BRCA2-KD cell lines (SilenciX® technology) to measure the synthetic lethal efficiency of PARP inhibitors (Olaparib, Veliparib and Rucaparib) in both normoxic and hypoxic conditions. They demonstrate that the BRCA-KD SilenciX® cell lines are effective and convenient in vitro cellular models to design new cancer drug candidates through the SL approach in oxygen-controlled conditions to better mimick physioxia seen in solid tumors.
Low oxygen tension, or Hypoxia, regulates numerous cellular and tissular functions. In cancer research, hypoxia is a key regulator of tumor development, aggressiveness and therapy resistance by acting on malignant cells and their microenvironment. Hypoxia is also involved in age-related diseases and acts through intracellular and intercellular cascade of events (exosomes, paracrine loops, angiogenesis…) (1-2). [Read more…]