scholarly journals Mechanical Stimulation: A Crucial Element of Organ-on-Chip Models

2020 ◽  
Vol 8 ◽  
Author(s):  
Clare L. Thompson ◽  
Su Fu ◽  
Martin M. Knight ◽  
Stephen D. Thorpe
Keyword(s):  
Drug Development ◽  
Cellular Response ◽  
The Body ◽  
Drug Candidate ◽  
Great Promise ◽  
Mechanical Stimuli ◽  
Health And Disease ◽  
Biomechanical Stimuli ◽  
On Chip

Organ-on-chip (OOC) systems recapitulate key biological processes and responses in vitro exhibited by cells, tissues, and organs in vivo. Accordingly, these models of both health and disease hold great promise for improving fundamental research, drug development, personalized medicine, and testing of pharmaceuticals, food substances, pollutants etc. Cells within the body are exposed to biomechanical stimuli, the nature of which is tissue specific and may change with disease or injury. These biomechanical stimuli regulate cell behavior and can amplify, annul, or even reverse the response to a given biochemical cue or drug candidate. As such, the application of an appropriate physiological or pathological biomechanical environment is essential for the successful recapitulation of in vivo behavior in OOC models. Here we review the current range of commercially available OOC platforms which incorporate active biomechanical stimulation. We highlight recent findings demonstrating the importance of including mechanical stimuli in models used for drug development and outline emerging factors which regulate the cellular response to the biomechanical environment. We explore the incorporation of mechanical stimuli in different organ models and identify areas where further research and development is required. Challenges associated with the integration of mechanics alongside other OOC requirements including scaling to increase throughput and diagnostic imaging are discussed. In summary, compelling evidence demonstrates that the incorporation of biomechanical stimuli in these OOC or microphysiological systems is key to fully replicating in vivo physiology in health and disease.

scholarly journals UPLC-MS/MS Method for Analysis of Endocannabinoid and Related Lipid Metabolism in Mouse Mucosal Tissue

2021 ◽  
Vol 12 ◽  
Author(s):  
Mark B. Wiley ◽  
Pedro A. Perez ◽  
Donovan A. Argueta ◽  
Bryant Avalos ◽  
Courtney P. Wood ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
The Body ◽  
Mucosal Tissues ◽  
Degradative Enzymes ◽  
Health And Disease ◽  
Amide Hydrolase

The endocannabinoid system is expressed in cells throughout the body and controls a variety of physiological and pathophysiological functions. We describe robust and reproducible UPLC-MS/MS-based methods for analyzing metabolism of the endocannabinoids, 2-arachidonoyl-sn-glycerol and arachidonoyl ethanolamide, and related monoacylglycerols (MAGs) and fatty acid ethanolamides (FAEs), respectively, in mouse mucosal tissues (i.e., intestine and lung). These methods are optimized for analysis of activity of the MAG biosynthetic enzyme, diacylglycerol lipase (DGL), and MAG degradative enzymes, monoacylglycerol lipase (MGL) and alpha/beta hydrolase domain containing-6 (ABHD6). Moreover, we describe a novel UPLC-MS/MS-based method for analyzing activity of the FAE degradative enzyme, fatty acid amide hydrolase (FAAH), that does not require use of radioactive substrates. In addition, we describe in vivo pharmacological methods to inhibit MAG biosynthesis selectively in the mouse small-intestinal epithelium. These methods will be useful for profiling endocannabinoid metabolism in rodent mucosal tissues in health and disease.

scholarly journals Development of fluorescence/MR dual-modal manganese-nitrogen-doped carbon nanosheets as an efficient contrast agent for targeted ovarian carcinoma imaging

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Cuiping Han ◽  
Ting Xie ◽  
Keying Wang ◽  
Shang Jin ◽  
Ke Li ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Colloidal Stability ◽  
The Body ◽  
Carcinoma Cells ◽  
Great Promise ◽  
Carbon Nanosheets ◽  
Nitrogen Doped ◽  
Ovarian Carcinoma Cells ◽  
Nitrogen Doped Carbon

Abstract Background Development of sensitive and specific imaging approaches for the detection of ovarian cancer holds great promise for improving the therapeutic efficacy and the lifespan of the patients. Results In this study, manganese-nitrogen doped carbon nanosheets (Mn-N-CNSs) coupled with Anti-HE4 monoclonal antibody (Mn-N-CNSs@Anti-HE4) were synthesized for the specific and targeted fluorescence/MR dual-modal imaging of ovarian carcinoma. The prepared Mn-N-CNSs revealed excellent aqueous dispersity, good colloidal stability, great optical properties and high longtudinal relaxivity rate (r1 = 10.30 mM−1 s−1). Encouraged by the tunable photoluminiscence of the nanoprobe and Anti-HE4 targeting ligand, the ovarian carcinoma cells were specifically labeled by the Mn-N-CNSs@Anti-HE4 nanoprobe with multi-color fluorescences. Benefiting from the high r1 relaxivity, the nanoprobe exhibited targeted and enhanced MR contrast effect in the ovarian carcinoma cells and tumor bearing mice model. Besides, the high biocompatibility and easy excretion from the body of the nanoprobe were further confirmed in vivo. Conclusion The prepared Mn-N-CNSs@Anti-HE4 with excellent biocompatibility, high-performance and superior tumor-targeting ability provides a novel fluorescence/MR dual-modal nanoprobe for specific labeling and detection of ovarian carcinoma cells in vitro and in vivo.

scholarly journals Hibrid képalkotás: klinikai evidenciák, lehetőségek

2015 ◽  
Vol 156 (52) ◽  
pp. 2110-2115
Author(s):  
György Trencsényi ◽  
Sándor Kristóf Barna ◽  
Ildikó Garai
Keyword(s):  
Computed Tomography ◽  
Hybrid Imaging ◽  
Single Photon ◽  
Photon Emission ◽  
Research Process ◽  
Clinical Diagnostics ◽  
The Body ◽  
Drug Candidate ◽  
Emission Computed Tomography

Nowadays the hybrid imaging technologies which combine the modern equipments of radiology and nuclear medicine play an important role in both the translational research process and clinical diagnostics. Among the routine diagnostic imaging procedures positron emission tomography and single photon emission computed tomography combined with computed tomography or magnetic resonance imaging currently belong to the most advanced techniques allowing that functional and morphological images can be superimposed on each other in the same position. The hybrid imaging equipments provide useful information about the pathological processes in the body due to their high sensibility and resolution. Furthermore, with the help of these imaging modalities we can get acquainted with the biochemical and pathobiochemical processes that are essential for understanding and treating diseases, or getting acquainted with the behaviour of a new drug candidate. With the help of the clinical and preclinical non-invasive in vivo molecular imaging systems the drug developing process can be shortened and its costs can be reduced. Orv. Hetil., 2015, 156(52), 2110–2115.

scholarly journals Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection

2017 ◽  
Vol 114 (28) ◽  
pp. 7426-7431 ◽  
Author(s):  
Nitin P. Kalia ◽  
Erik J. Hasenoehrl ◽  
Nurlilah B. Ab Rahman ◽  
Vanessa H. Koh ◽  
Michelle L. T. Ang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Development ◽  
Synthetic Lethality ◽  
Electron Flow ◽  
Clinical Stage ◽  
Atp Synthesis ◽  
Drug Candidate ◽  
Respiratory Oxidases ◽  
Host Infection

The recent discovery of small molecules targeting the cytochrome bc1:aa3 in Mycobacterium tuberculosis triggered interest in the terminal respiratory oxidases for antituberculosis drug development. The mycobacterial cytochrome bc1:aa3 consists of a menaquinone:cytochrome c reductase (bc1) and a cytochrome aa3-type oxidase. The clinical-stage drug candidate Q203 interferes with the function of the subunit b of the menaquinone:cytochrome c reductase. Despite the affinity of Q203 for the bc1:aa3 complex, the drug is only bacteriostatic and does not kill drug-tolerant persisters. This raises the possibility that the alternate terminal bd-type oxidase (cytochrome bd oxidase) is capable of maintaining a membrane potential and menaquinol oxidation in the presence of Q203. Here, we show that the electron flow through the cytochrome bd oxidase is sufficient to maintain respiration and ATP synthesis at a level high enough to protect M. tuberculosis from Q203-induced bacterial death. Upon genetic deletion of the cytochrome bd oxidase-encoding genes cydAB, Q203 inhibited mycobacterial respiration completely, became bactericidal, killed drug-tolerant mycobacterial persisters, and rapidly cleared M. tuberculosis infection in vivo. These results indicate a synthetic lethal interaction between the two terminal respiratory oxidases that can be exploited for anti-TB drug development. Our findings should be considered in the clinical development of drugs targeting the cytochrome bc1:aa3, as well as for the development of a drug combination targeting oxidative phosphorylation in M. tuberculosis.

scholarly journals The Progress of Intestinal Epithelial Models from Cell Lines to Gut-On-Chip

2021 ◽  
Vol 22 (24) ◽  
pp. 13472
Author(s):  
Shafaque Rahman ◽  
Mohammed Ghiboub ◽  
Joanne M. Donkers ◽  
Evita van de Steeg ◽  
Eric A. F. van Tol ◽  
...  
Keyword(s):  
Cell Lines ◽  
Ex Vivo ◽  
Ussing Chamber ◽  
Intestinal Epithelial ◽  
The Past ◽  
Health And Disease ◽  
Conventional Models ◽  
On Chip

Over the past years, several preclinical in vitro and ex vivo models have been developed that helped to understand some of the critical aspects of intestinal functions in health and disease such as inflammatory bowel disease (IBD). However, the translation to the human in vivo situation remains problematic. The main reason for this is that these approaches fail to fully reflect the multifactorial and complex in vivo environment (e.g., including microbiota, nutrition, and immune response) in the gut system. Although conventional models such as cell lines, Ussing chamber, and the everted sac are still used, increasingly more sophisticated intestinal models have been developed over the past years including organoids, InTESTine™ and microfluidic gut-on-chip. In this review, we gathered the most recent insights on the setup, advantages, limitations, and future perspectives of most frequently used in vitro and ex vivo models to study intestinal physiology and functions in health and disease.

scholarly journals In Vivo Electroporation of Plasmid DNA: A Promising Strategy for Rapid, Inexpensive, and Flexible Delivery of Anti-Viral Monoclonal Antibodies

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1882
Author(s):  
Silvere Pagant ◽  
Rachel A. Liberatore
Keyword(s):  
Monoclonal Antibodies ◽  
Plasmid Dna ◽  
Passive Immunization ◽  
The United States ◽  
Rapid Onset ◽  
The Body ◽  
Cold Chain ◽  
Great Promise ◽  
Therapeutic Antibodies

Since the first approval of monoclonal antibodies by the United States Food and Drug Administration (FDA) in 1986, therapeutic antibodies have become one of the predominant classes of drugs in oncology and immunology. Despite their natural function in contributing to antiviral immunity, antibodies as drugs have only more recently been thought of as tools for combating infectious diseases. Passive immunization, or the delivery of the products of an immune response, offers near-immediate protection, unlike the active immune processes triggered by traditional vaccines, which rely on the time it takes for the host’s immune system to develop an effective defense. This rapid onset of protection is particularly well suited to containing outbreaks of emerging viral diseases. Despite these positive attributes, the high cost associated with antibody manufacture and the need for a cold chain for storage and transport limit their deployment on a global scale, especially in areas with limited resources. The in vivo transfer of nucleic acid-based technologies encoding optimized therapeutic antibodies transform the body into a bioreactor for rapid and sustained production of biologics and hold great promise for circumventing the obstacles faced by the traditional delivery of antibodies. In this review, we provide an overview of the different antibody delivery strategies that are currently being developed, with particular emphasis on in vivo transfection of naked plasmid DNA facilitated by electroporation.

scholarly journals THE RESISTANCE TO A SPECIFIC HEMOLYSIN OF HUMAN ERYTHROCYTES IN HEALTH AND DISEASE

1909 ◽  
Vol 11 (6) ◽  
pp. 763-785 ◽  
Author(s):  
Peyton Rous
Keyword(s):  
High Temperature ◽  
Human Erythrocytes ◽  
The Body ◽  
Biological Reaction ◽  
Health And Disease

1. Phagocytosis of pneumococci in vitro runs parallel with phagocytosis in vivo. 2. Virulence depends not only on resistance to phagocytosis, but also on the ability to grow in the body of the animal. 3. The biological reaction of the pigeon to pneumococcus infection does not differ from that of the mouse. 4. The "immunity" of the pigeon to pneumococcus infection is due to its normal high temperature.

The emerging role of the peptidome in biomarker discovery and degradome profiling

2015 ◽  
Vol 396 (3) ◽  
pp. 185-192 ◽  
Author(s):  
Zon W. Lai ◽  
Agnese Petrera ◽  
Oliver Schilling
Keyword(s):  
Biomarker Discovery ◽  
Proteolytic Processing ◽  
The Body ◽  
Clinical Markers ◽  
Protein Fragments ◽  
Endogenous Peptides ◽  
Significant Research ◽  
Protease Substrate ◽  
Health And Disease

Abstract The peptidome represents the array of endogenous peptides that are present in both the intracellular and extracellular space of the body. Peptides are constantly generated in vivo by active synthesis, and by proteolytic processing of larger precursor proteins, often yielding protein fragments that mediate a variety of physiological functions. Given that aberrant proteolysis is a hallmark of various pathological diseases, many studies have now turned to the peptidome. Differential regulation of endogenous peptides may play a role in many pathological conditions. Mass spectrometry (MS) -based investigation of peptides in a system-wide manner is currently facilitating the identification of potential biomarkers. Furthermore, peptidomic approaches have provided major contributions to the identification of protease-substrate relationships; representing one of the major challenges in understanding and therapeutically exploiting protease function in health and disease. As such, degradomic studies looking for cleavage products via peptidomics in particular, have warranted a significant research interest in recent years. Given that substantial studies are accumulating in the field of peptidomics, this review highlights recent advances of MS-based peptidomic strategies in facilitating the identification of potential peptides as novel clinical markers and protease-substrate profiling.

scholarly journals In Vitro Immune Organs-on-Chip for Drug Development: A Review

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 278 ◽  
Author(s):  
Aya Shanti ◽  
Jeremy Teo ◽  
Cesare Stefanini
Keyword(s):  
Immune System ◽  
Drug Development ◽  
Attrition Rate ◽  
Human Immune System ◽  
Drug Candidates ◽  
Immune Organs ◽  
On Chip ◽  
High Attrition Rate

The current drug development practice lacks reliable and sensitive techniques to evaluate the immunotoxicity of drug candidates, i.e., their effect on the human immune system. This, in part, has resulted in a high attrition rate for novel drugs candidates. Organ-on-chip devices have emerged as key tools that permit the study of human physiology in controlled in vivo simulating environments. Furthermore, there has been a growing interest in developing the so called “body-on-chip” devices to better predict the systemic effects of drug candidates. This review describes existing biomimetic immune organs-on-chip, highlights their physiological relevance to drug development and discovery and emphasizes the need for developing comprehensive immune system-on-chip models. Such immune models can enhance the performance of novel drug candidates during clinical trials and contribute to reducing the high attrition rate as well as the high cost associated with drug development.

scholarly journals Gold Nanoclusters Display Low Immunogenic Effect in Microglia Cells

Nanomaterials ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 1066
Author(s):  
Joanna Sobska ◽  
Magdalena Waszkielewicz ◽  
Anna Podleśny-Drabiniok ◽  
Joanna Olesiak-Banska ◽  
Wojciech Krężel ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Interleukin 1 ◽  
Gold Nanoclusters ◽  
Biological Properties ◽  
The Body ◽  
Great Promise ◽  
Low Toxicity ◽  
Anti Inflammatory

Gold nanoparticles hold a great promise for both clinical and preclinical applications. The major factors impeding such applications are toxicity of new nanomaterials including e.g., pro-apoptotic activities or inflammatory effects, but also their potential to accumulate in the body or inadequate absorption, distribution, metabolism and excretion (ADME) profiles. Since such adverse effects depend on the size, form and coating of nanomaterials, the search for new, less toxic nanomaterials with low tendency to accumulate is highly active domain of research. Here, we describe optical and biological properties of Au18 gold nanoclusters (NCs), small gold nanoparticles composed of 18 atoms of gold and stabilized with glutathione ligands. These nanoclusters may be suitable for in vivo applications owing to their low toxicity and biodistribution profile. Specifically, using lactate dehydrogenase (LDH) test in P19 cell line we found that Au18 NCs display low toxicity in vitro. Importantly, using primary microglial cells we showed that at low concentrations Au18 NCs display anti-inflammatory signaling on evidence of reduced interleukin 1-β (IL1-β) levels and unchanged levels of tumor necrosis factor (TNF-α) or Ym1/2. Such effect was dose dependent as higher concentrations of Au18 NCs induced expression of pro-inflammatory cytokines and suppression of anti-inflammatory cytokine Ym1/2, pointing, thus, to global inflammatory activity. Finally, we also showed that within 3 days Au18 NCs can be completely eliminated from the liver reported as the major target organ for accumulation of gold nanoparticles. These data point to a potential of gold nanoparticles for further biomedical studies.

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