scholarly journals Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

2017 ◽  
Vol 41 (5) ◽  
pp. 1801-1829 ◽  
Author(s):  
Antônio F. Silva-filho ◽  
Wanessa L.B. Sena ◽  
Luiza R.A. Lima ◽  
Lidiane V.N. Carvalho ◽  
Michelly C. Pereira ◽  
...  
Keyword(s):  
Interaction Network ◽  
Cellular Respiration ◽  
Glycosylation Pattern ◽  
Cancer Models ◽  
Receptor Interactions ◽  
Molecular Machinery ◽  
Hypoxic Tumor ◽  
Intracellular Glucose

Post-translational and co-translational enzymatic addition of glycans (glycosylation) to proteins, lipids, and other carbohydrates, is a powerful regulator of the molecular machinery involved in cell cycle, adhesion, invasion, and signal transduction, and is usually seen in both in vivo and in vitro cancer models. Glycosyltransferases can alter the glycosylation pattern of normal cells, subsequently leading to the establishment and progression of several diseases, including cancer. Furthermore, a growing amount of research has shown that different oxygen tensions, mainly hypoxia, leads to a markedly altered glycosylation, resulting in altered glycan-receptor interactions. Alteration of intracellular glucose metabolism, from aerobic cellular respiration to anaerobic glycolysis, inhibition of integrin 3α1β translocation to the plasma membrane, decreased 1,2-fucosylation of cell-surface glycans, and galectin overexpression are some consequences of the hypoxic tumor microenvironment. Additionally, increased expression of gangliosides carrying N-glycolyl sialic acid can also be significantly affected by hypoxia. For all these reasons, it is possible to realize that hypoxia strongly alters glycobiologic events within tumors, leading to changes in their behavior. This review aims to analyze the complexity and importance of glycoconjugates and their molecular interaction network in the hypoxic context of many solid tumors.

The truncated somatostatin receptor sst5TMD4 stimulates the production of pro-angiogenic factors in in vitro and in vivo breast cancer models

2014 ◽  
Author(s):  
Raul M Luque ◽  
Mario Duran-Prado ◽  
David Rincon-Fernandez ◽  
Marta Hergueta-Redondo ◽  
Michael D Culler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Somatostatin Receptor ◽  
Angiogenic Factors ◽  
Cancer Models

scholarly journals The Revolutionary Roads to Study Cell–Cell Interactions in 3D In Vitro Pancreatic Cancer Models

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 930
Author(s):  
Donatella Delle Cave ◽  
Riccardo Rizzo ◽  
Bruno Sainz ◽  
Giuseppe Gigli ◽  
Loretta L. del Mercato ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Response ◽  
Three Dimensional ◽  
Cellular Models ◽  
Common Cancer ◽  
Cancer Models ◽  
Anti Cancer ◽  
Tumor Environment

Pancreatic cancer, the fourth most common cancer worldwide, shows a highly unsuccessful therapeutic response. In the last 10 years, neither important advancements nor new therapeutic strategies have significantly impacted patient survival, highlighting the need to pursue new avenues for drug development discovery and design. Advanced cellular models, resembling as much as possible the original in vivo tumor environment, may be more successful in predicting the efficacy of future anti-cancer candidates in clinical trials. In this review, we discuss novel bioengineered platforms for anticancer drug discovery in pancreatic cancer, from traditional two-dimensional models to innovative three-dimensional ones.

Meet me halfway: Are in vitro 3D cancer models on the way to replace in vivo models for nanomedicine development?

2021 ◽  
Author(s):  
Sabina Pozzi ◽  
Anna Scomparin ◽  
Sahar Israeli-Dangoor ◽  
Daniel Rodriguez ◽  
Paula Ofek ◽  
...  
Keyword(s):  
In Vivo Models ◽  
Cancer Models ◽  
The Way

scholarly journals Newly Developed Self-Assembling Antioxidants as Potential Therapeutics for the Cancers

2021 ◽  
Vol 11 (2) ◽  
pp. 92 ◽  
Author(s):  
Babita Shashni ◽  
Yukio Nagasaki
Keyword(s):  
Cancer Survival ◽  
Self Assembling ◽  
Therapeutic Regime ◽  
Cancer Models ◽  
Secondary Messengers ◽  
Potential Therapeutics ◽  
Target Effects ◽  
Tempo Radical

Elevated reactive oxygen species (ROS) have been implicated as significant for cancer survival by functioning as oncogene activators and secondary messengers. Hence, the attenuation of ROS-signaling pathways in cancer by antioxidants seems a suitable therapeutic regime for targeting cancers. Low molecular weight (LMW) antioxidants such as 2,2,6,6-tetramethylpyperidine-1-oxyl (TEMPO), although they are catalytically effective in vitro, exerts off-target effects in vivo due to their size, thus, limiting their clinical use. Here, we discuss the superior impacts of our TEMPO radical-conjugated self-assembling antioxidant nanoparticle (RNP) compared to the LMW counterpart in terms of pharmacokinetics, therapeutic effect, and adverse effects in various cancer models.

scholarly journals An In Vitro and In Vivo Investigation of the Antimetastatic Effects of a Chinese Medicinal Decoction, Erxian Decoction, on Human Ovarian Cancer Models

2012 ◽  
Vol 12 (4) ◽  
pp. 336-346 ◽  
Author(s):  
Ellie S. M. Chu ◽  
Stephen C. W. Sze ◽  
Ho P. Cheung ◽  
Qing Liu ◽  
Tzi B. Ng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Human Ovarian Cancer ◽  
Erxian Decoction ◽  
Cancer Models

scholarly journals In vivo reconstitution finds multivalent RNA-RNA interactions as drivers of mesh-like condensates

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Weirui Ma ◽  
Gang Zheng ◽  
Wei Xie ◽  
Christine Mayr
Keyword(s):  
Surface Area ◽  
Protein Trafficking ◽  
Rna Binding ◽  
Interaction Network ◽  
Large Surface Area ◽  
High Propensity ◽  
Membrane Protein Trafficking ◽  
Protein Components

Liquid-like condensates have been thought to be sphere-like. Recently, various condensates with filamentous morphology have been observed in cells. One such condensate is the TIS granule network that shares a large surface area with the rough endoplasmic reticulum and is important for membrane protein trafficking. It has been unclear how condensates with mesh-like shapes, but dynamic protein components are formed. In vitro and in vivo reconstitution experiments revealed that the minimal components are a multivalent RNA-binding protein that concentrates RNAs that are able to form extensive intermolecular mRNA-mRNA interactions. mRNAs with large unstructured regions have a high propensity to form a pervasive intermolecular interaction network that acts as condensate skeleton. The underlying RNA matrix prevents full fusion of spherical liquid-like condensates, thus driving the formation of irregularly shaped membraneless organelles. The resulting large surface area may promote interactions at the condensate surface and at the interface with other organelles.

scholarly journals Atovaquone-HSA nano-drugs enhance the efficacy of PD-1 blockade immunotherapy by alleviating hypoxic tumor microenvironment

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Simeng Wang ◽  
Xinrui Zhou ◽  
Zekun Zeng ◽  
Mengjun Sui ◽  
Lihong Chen ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Disulfide Bonds ◽  
Tumor Targeting ◽  
Tumor Hypoxia ◽  
Animal Experiments ◽  
Complex Iii ◽  
Mitochondrial Activity ◽  
Hypoxic Tumor

Abstract Background Hypoxia is inherent character of most solid malignancies, leading to the failure of chemotherapy, radiotherapy and immunotherapy. Atovaquone, an anti-malaria drug, can alleviate tumor hypoxia by inhibiting mitochondrial complex III activity. The present study exploits atovaquone/albumin nanoparticles to improve bioavailability and tumor targeting of atovaquone, enhancing the efficacy of anti-PD-1 therapy by normalizing tumor hypoxia. Methods We prepared atovaquone-loaded human serum albumin (HSA) nanoparticles stabilized by intramolecular disulfide bonds, termed HSA-ATO NPs. The average size and zeta potential of HSA-ATO NPs were measured by particle size analyzer. The morphology of HSA-ATO NPs was characterized by transmission electron microscope (TEM). The bioavailability and safety of HSA-ATO NPs were assessed by animal experiments. Flow cytometry and ELISA assays were used to evaluate tumor immune microenvironment. Results Our data first verified that atovaquone effectively alleviated tumor hypoxia by inhibiting mitochondrial activity both in vitro and in vivo, and successfully encapsulated atovaquone in vesicle with albumin, forming HSA-ATO NPs of approximately 164 nm in diameter. We then demonstrated that the HSA-ATO NPs possessed excellent bioavailability, tumor targeting and a highly favorable biosafety profile. When combined with anti-PD-1 antibody, we observed that HSA-ATO NPs strongly enhanced the response of mice bearing tumor xenografts to immunotherapy. Mechanistically, HSA-ATO NPs promoted intratumoral CD8+ T cell recruitment by alleviating tumor hypoxia microenvironment, thereby enhancing the efficacy of anti-PD-1 immunotherapy. Conclusions Our data provide strong evidences showing that HSA-ATO NPs can serve as safe and effective nano-drugs to enhance cancer immunotherapy by alleviating hypoxic tumor microenvironment. Graphic abstract

Carbon dioxide inhalation causes pulmonary inflammation

2009 ◽  
Vol 296 (4) ◽  
pp. L657-L665 ◽  
Author(s):  
Mohammad Abolhassani ◽  
Adeline Guais ◽  
Philippe Chaumet-Riffaud ◽  
Annie J. Sasco ◽  
Laurent Schwartz
Keyword(s):  
Carbon Dioxide ◽  
Nuclear Translocation ◽  
Rnase Protection Assay ◽  
Airway Hyperreactivity ◽  
Cellular Respiration ◽  
Rnase Protection ◽  
Monocyte Chemoattractant Protein 1 ◽  
Enhanced Production

The aim of this study was to assess whether one of the most common poisons of cellular respiration, i.e., carbon dioxide, is proinflammatory. CO2 is naturally present in the atmosphere at the level of 0.038% and involved in numerous cellular biochemical reactions. We analyzed in vitro the inflammation response induced by exposure to CO2 for 48 h (0–20% with a constant O2 concentration of 21%). In vivo mice were submitted to increasing concentrations of CO2 (0, 5, 10, and 15% with a constant O2 concentration of 21%) for 1 h. The exposure to concentrations above 5% of CO2 resulted in the increased transcription (RNase protection assay) and secretion (ELISA) of proinflammatory cytokines [macrophage inflammatory protein-1α (MIP-1α), MIP-1β, MIP-2, IL-8, IL-6, monocyte chemoattractant protein-1, and regulated upon activation, normal T cell expressed, and, presumably, secreted (RANTES)] by epithelial cell lines HT-29 or A549 and primary pulmonary cells retrieved from the exposed mice. Lung inflammation was also demonstrated in vivo by mucin 5AC-enhanced production and airway hyperreactivity induction. This response was mostly mediated by the nuclear translocation of p65 NF-κB, itself a consequence of protein phosphatase 2A (PP2A) activation. Short inhibiting RNAs (siRNAs) targeted toward PP2Ac reversed the effect of carbon dioxide, i.e., disrupted the NF-κB activation and the proinflammatory cytokine secretion. In conclusion, this study strongly suggests that exposure to carbon dioxide may be more toxic than previously thought. This may be relevant for carcinogenic effects of combustion products.

scholarly journals Induction of idiotype-bearing, nuclease-specific helper T cells by in vivo treatment with anti-idiotype.

1981 ◽  
Vol 154 (1) ◽  
pp. 24-34 ◽  
Author(s):  
G G Miller ◽  
P I Nadler ◽  
Y Asano ◽  
R J Hodes ◽  
D H Sachs
Keyword(s):  
T Cells ◽  
Network Theory ◽  
Individual Cell ◽  
Binding Activity ◽  
Helper T Cells ◽  
Antigen Binding ◽  
Receptor Interactions ◽  
Detectable Antigen

Treatment of BALB/c mice with purified pig anti-(BALB/c anti-nuclease) anti-idiotypic antibodies has been found to induce the appearance of idiotype-bearing immunoglobulins (Id') in the serum of these mice in the absence of detectable antigen binding activity. This phenomenon appeared to require T cells in the hosts because no Id' was detected in the serum of nude mice similarly treated. Furthermore, the spleens of BALB/c mice treated with anti-idiotype were found to contain helper T cells capable of providing help in an in vitro plaque-forming cell response to trinitrophenyl-nuclease equivalent to that provided by helper T cells from the spleens of nuclease-primed animals. Helper T cells from both anti-idiotype-treated and nuclease-treated animals were found to be antigen-specific and to be similarly susceptible to elimination by treatment with anti-idiotype plus complement. Therefore, treatment with both antigen and anti-idiotype appeared to prime similar populations of antigen-specific helper T cells, while having different effects on the induction of antibody. These findings are consistent with the network theory of receptor interactions in the immune response, and may provide a means for studying individual cell populations involved in such interactions.

PRO-INFLAMMATORY MOLECULAR AND INFLAMMATORY MECHANISMS OF SULFUR METABOLISM IN IBD-RELEVANT CLOSTRIDIA SPECIES

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S30-S31
Author(s):  
Gabriel Suarez ◽  
Bo Liu ◽  
Jeremy Herzog ◽  
Ryan Sartor
Keyword(s):  
Sulfur Metabolism ◽  
Cellular Respiration ◽  
Bile Acid Metabolism ◽  
Bile Salt Hydrolase ◽  
Oxygen Binding ◽  
Bacterial Strains ◽  
Healthy Human ◽  
H2s Production

Abstract Sulfur metabolism is emerging as a signature of IBD gut microbiota. Overrepresentation of sulfur-reducing bacteria (SRB) in IBD results in SRB-derived epithelial toxic H2S production that can overwhelm the body’s detoxification capacity, leading to impaired cellular respiration by inhibiting oxygen binding to mitochondrial cytochrome-c-oxidase. Butyrate potently inhibits SRBs and H2S, yet IBD patients have reduced short chain fatty acid (SCFA) production. More critically, H2S blocks butyrate oxidation, the primary energy source of colonocytes; butyrate oxidation deficiency is a defining characteristic of IBD. Since cysteine is the preferred substrate for H2S production by SRBs, a cysteine-rich environment provided by either a high protein diet or local intestinal mucus degradation promotes ideal conditions for SRB establishment and proliferation. SRBs can catabolize other sulfur-containing compounds critical for immune homeostasis and cellular health, such as taurine-conjugated bile acids and the “master antioxidant” glutathione, leading to further toxic H2S production. However, the molecular underpinnings of sulfur metabolism by specific bacterial genera is understudied in IBD. Results: Using a combination of in-vivo and in-vitro screening to detect the relative induction of interleukin 10 (IL-10) and interferon g (IFNg) by 19 resident bacterial strains isolated from a healthy human donor, we identified 4 bacterial strains that induce a low IL-10/IFNg ratio. These 4 strains (low group), but not 3 bacterial strains that induce a high IL-10/IFNg ratio, induce colitis in selectively colonized gnotobiotic Il10-/- mice (Fig.1A). Two of these 4 disease-inducing strains, Clostridium perfringens (A12) and Clostridium bolteae (B6), produce high concentrations of H2S in monoassociated mice (Fig.1B). In-vitro H2S production by these strains is dependent on cysteine (Fig.1C). C. perfringens and C. bolteae each induce colitis in monoassociated Il10-/- mice (Fig.1D). We are dissecting the sulfur metabolic pathways in C. perfringens and C. bolteae and their contribution to inflammatory processes by interrupting key genes predicted to contribute to H2S production, cysteine catabolism and bile acid metabolism. We will use these mutants in both in-vitro and in-vivo Il10 -/- gnotobiotic mice models to characterize their metabolic and inflammatory profiles. We have created several mutants using Targetron gene editing, including the dissimilatory sulfate reductase (Δdsr), a putative sulfonate membrane transporter (ΔssuA), anaerobic sulfite reductase (ΔasrA) and bile salt hydrolase (Δbsh). Conclusions: H2S producing bacterial strains can induce experimental colitis. Our planned mechanistic studies will determine the metabolic routes for H2S production by specific aggressive bacteria to guide novel therapeutic or dietary interventions to improve IBD prognosis.

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