scholarly journals Different Calculation Strategies Are Congruent in Determining Chemotherapy Resistance of Brain Tumors In Vitro

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2689
Author(s):  
Igor Fischer ◽  
Ann-Christin Nickel ◽  
Nan Qin ◽  
Kübra Taban ◽  
David Pauck ◽  
...  
Keyword(s):  
Drug Response ◽  
Therapeutic Potential ◽  
Chemotherapy Resistance ◽  
Area Under The Curve ◽  
Growth Curves ◽  
In Vitro Models ◽  
Cell Phenotype ◽  
Cancer Pharmacology ◽  
Clinical Drugs

In cancer pharmacology, a drug candidate’s therapeutic potential is typically expressed as its ability to suppress cell growth. Different methods in assessing the cell phenotype and calculating the drug effect have been established. However, inconsistencies in drug response outcomes have been reported, and it is still unclear whether and to what extent the choice of data post-processing methods is responsible for that. Studies that systematically examine these questions are rare. Here, we compare three established calculation methods on a collection of nine in vitro models of glioblastoma, exposed to a library of 231 clinical drugs. The therapeutic potential of the drugs is determined on the growth curves, using growth inhibition 50% (GI50) and point-of-departure (PoD) as the criteria. An effect is detected on 36% of the drugs when relying on GI50 and on 27% when using PoD. For the area under the curve (AUC), a threshold of 9.5 or 10 could be set to discriminate between the drugs with and without an effect. GI50, PoD, and AUC are highly correlated. The ranking of substances by different criteria varies somewhat, but the group of the top 20 substances according to one criterion typically includes 17–19 top candidates according to another. In addition to generating preclinical values with high clinical potential, we present off-target appreciation of top substance predictions by interrogating the drug response data of non-cancer cells in our calculation technology.

scholarly journals Enhanced Therapeutic Potential of the Secretome Released from Adipose-Derived Stem Cells by PGC-1α-Driven Upregulation of Mitochondrial Proliferation

2019 ◽  
Vol 20 (22) ◽  
pp. 5589
Author(s):  
Jaeim Lee ◽  
Ok-Hee Kim ◽  
Sang Chul Lee ◽  
Kee-Hwan Kim ◽  
Jin Sun Shin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Liver Injury ◽  
Therapeutic Potential ◽  
Tissue Expression ◽  
In Vitro Models ◽  
Peroxisome Proliferator ◽  
Adipose Derived Stem Cells ◽  
Peroxisome Proliferator Activated Receptor

Peroxisome proliferator activated receptor λ coactivator 1α (PGC-1α) is a potent regulator of mitochondrial biogenesis and energy metabolism. In this study, we investigated the therapeutic potential of the secretome released from the adipose-derived stem cells (ASCs) transfected with PGC-1α (PGC-secretome). We first generated PGC-1α-overexpressing ASCs by transfecting ASCs with the plasmids harboring the gene encoding PGC-1α. Secretory materials released from PGC-1α-overexpressing ASCs were collected and their therapeutic potential was determined using in vitro (thioacetamide (TAA)-treated AML12 cells) and in vivo (70% partial hepatectomized mice) models of liver injury. In the TAA-treated AML12 cells, the PGC-secretome significantly increased cell viability, promoted expression of proliferation-related markers, such as PCNA and p-STAT, and significantly reduced the levels of reactive oxygen species (ROS). In the mice, PGC-secretome injections significantly increased liver tissue expression of proliferation-related markers more than normal secretome injections did (p < 0.05). We demonstrated that the PGC-secretome does not only have higher antioxidant and anti-inflammatory properties, but also has the potential of significantly enhancing liver regeneration in both in vivo and in vitro models of liver injury. Thus, reinforcing the mitochondrial antioxidant potential by transfecting ASCs with PGC-1α could be one of the effective strategies to enhance the therapeutic potential of ASCs.

In Vitro Study of Peritoneal Fibrosis

2007 ◽  
Vol 27 (2_suppl) ◽  
pp. 72-75
Author(s):  
Kuan-Yu Hung ◽  
Kuan-Dun Wu ◽  
Tun-Jun Tsai
Keyword(s):  
Therapeutic Potential ◽  
In Vitro Study ◽  
In Vitro Models ◽  
Drop Out ◽  
Clinical Implications ◽  
Peritoneal Fibrosis ◽  
Asian Studies ◽  
Peritoneal Tissue ◽  
Matrix Accumulation

Peritoneal fibrosis (PF) is an important issue in peritoneal dialysis (PD) because it remains one of the leading causes of patient drop-out from PD. In this review, we focus on in vitro approaches to the pathogenesis and therapeutic potential of PF and on associated clinical implications. Representative Asian studies, initiated since mid-1990s, that have investigated matrix accumulation in peritoneal tissue possibly leading to PF in the PD population will be highlighted as examples to learn how to apply this research tool. As compared with data from well-designed clinical trials, observations from in vitro models may be far from becoming solid evidence; however, they do cast new light on options for investigations into therapeutic pharmaceuticals.

scholarly journals A Context-Dependent Role for MiR-124-3p on Cell Phenotype, Viability and Chemosensitivity in Neuroblastoma in vitro

2020 ◽  
Vol 8 ◽  
Author(s):  
John C. Nolan ◽  
Manuela Salvucci ◽  
Steven Carberry ◽  
Ana Barat ◽  
Miguel F. Segura ◽  
...  
Keyword(s):  
Cell Lines ◽  
Epithelial To Mesenchymal Transition ◽  
Neuroblastoma Cell ◽  
Chemotherapy Resistance ◽  
Cellular Transformation ◽  
Cell Phenotype ◽  
Drug Resistant ◽  
Mesenchymal Transition ◽  
Neuroblastoma Cell Lines

Neuroblastoma (NB) is a neural crest-derived tumor, which develops before birth or in early childhood, with metastatic dissemination typically preceding diagnosis. Tumors are characterized by a highly heterogeneous combination of cellular phenotypes demonstrating varying degrees of differentiation along different lineage pathways, and possessing distinct super-enhancers and core regulatory circuits, thereby leading to highly varied malignant potential and divergent clinical outcomes. Cytoskeletal reorganization is fundamental to cellular transformations, including the processes of cellular differentiation and epithelial to mesenchymal transition (EMT), previously reported by our lab and others to coincide with chemotherapy resistance and enhanced metastatic ability of tumor cells. This study set out to investigate the ability of the neuronal miR-124-3p to reverse the cellular transformation associated with drug resistance development and assess the anti-oncogenic role of this miRNA in in vitro models of drug-resistant adrenergic (ADRN) and mesenchymal (MES) neuroblastoma cell lines. Low expression of miR-124-3p in a cohort of neuroblastomas was significantly associated with poor overall and progression-free patient survival. Over-expression of miR-124-3p in vitro inhibited cell viability through the promotion of cell cycle arrest and induction of apoptosis in addition to sensitizing drug-resistant cells to chemotherapeutics in a panel of morphologically distinct neuroblastoma cell lines. Finally, we describe miR-124-3p direct targeting and repression of key up-regulated cytoskeletal genes including MYH9, ACTN4 and PLEC and the reversal of the resistance-associated EMT and enhanced invasive capacity previously reported in our in vitro model (SK-N-ASCis24).

scholarly journals Antistaphylococcal Effect Related to the Area under the Curve/MIC Ratio in an In Vitro Dynamic Model: Predicted Breakpoints versus Clinically Achievable Values for Seven Fluoroquinolones

2005 ◽  
Vol 49 (7) ◽  
pp. 2642-2647 ◽  
Author(s):  
Alexander A. Firsov ◽  
Irene Y. Lubenko ◽  
Sergey N. Vostrov ◽  
Yury A. Portnoy ◽  
Stephen H. Zinner
Keyword(s):  
In Vitro Model ◽  
Therapeutic Potential ◽  
Area Under The Curve ◽  
Antimicrobial Effect ◽  
Clinical Isolates ◽  
Clinical Settings ◽  
Time Curve ◽  
Concentration Time ◽  
Vitro Model

ABSTRACT Prediction of the relative efficacies of different fluoroquinolones is often based on the ratios of the clinically achievable area under the concentration-time curve (AUC) to the MIC, usually with incorporation of the MIC50 or the MIC90 and with the assumption of antibiotic-independent patterns of the AUC/MIC-response relationships. To ascertain whether this assumption is correct, the pharmacodynamics of seven pharmacokinetically different quinolones against two clinical isolates of Staphylococcus aureus were studied by using an in vitro model. Two differentially susceptible clinical isolates of S. aureus were exposed to two 12-h doses of ciprofloxacin (CIP) and one dose of gatifloxacin (GAT), gemifloxacin (GEM), grepafloxacin (GRX), levofloxacin (LVX), moxifloxacin (MXF), and trovafloxacin (TVA) over similar AUC/MIC ranges from 58 to 932 h. A specific bacterial strain-independent AUC/MIC relationship with the antimicrobial effect (IE ) was associated with each quinolone. Based on the IE -log AUC/MIC relationships, breakpoints (BPs) that are equivalent to a CIP AUC/MIC ratio of 125 h were predicted for GRX, MXF, and TVA (75 to 78 h), GAT and GEM (95 to 103 h) and LVX (115 h). With GRX and LVX, the predicted BPs were close to those established in clinical settings (no clinical data on other quinolones are available in the literature). To determine if the predicted AUC/MIC BPs are achievable at clinical doses, i.e., at the therapeutic AUCs (AUCthers), the AUCther/MIC50 ratios were studied. These ratios exceeded the BPs for GAT, GEM, GRX, MXF, TVA, and LVX (750 mg) but not for CIP and LVX (500 mg). AUC/MIC ratios above the BPs can be considered of therapeutic potential for the quinolones. The highest ratios of AUCther/MIC50 to BP were achieved with TVA, MXF, and GEM (2.5 to 3.0); intermediate ratios (1.5 to 1.6) were achieved with GAT and GRX; and minimal ratios (0.3 to 1.2) were achieved with CIP and LVX.

Establishment of in-vitro models of chemotherapy resistance

2007 ◽  
Vol 18 (7) ◽  
pp. 749-754 ◽  
Author(s):  
Mark B. Watson ◽  
Michael J. Lind ◽  
Lynn Cawkwell
Keyword(s):  
Chemotherapy Resistance ◽  
In Vitro Models

scholarly journals 3D Co-Culture model of Endothelial Colony Forming Cells (ECFCs) Reverses Late Passage Adipose-derived Stem Cell Senescence for Wound Healing

2020 ◽  
Author(s):  
Wansheng Hu ◽  
Shengqian Zhu ◽  
Mimi Lalrimawii Fanai ◽  
Jing Wang ◽  
Junrong cai ◽  
...  
Keyword(s):  
Stem Cell ◽  
Single Cell ◽  
Culture System ◽  
Therapeutic Potential ◽  
Cell Phenotype ◽  
Angiogenic Growth Factors ◽  
Endothelial Colony Forming Cells ◽  
Culture Model ◽  
Late Passage

Abstract Background Extensive passage of adipose-derived stem cells (ASCs) in vitro leads to loss of function. Endothelial colony forming cells (ECFCs) can be isolated from adult peripheral blood. A 3D co-culture system may rescue in vitro ASC senescence.Methods A 3D co-culture model was successfully established using hyaluronic acid (HA) gel and a 10:1 ratio of late-passage ASCs and ECFCs. Cell density and culture conditions were optimized. Stem cell phenotype was characterized by flow cytometry. ELISA was used to measure the trophic effect of angiogenic growth factors and compare the effects of these factors between the 3-D co-culture and single cell culture. Therapeutic potential of ASC/ECFC 3-D co-cultures was evaluated in a mouse chronic injury model.Results Following incubation in a HA substrate 3D co-culture system, ASC morphology, phenotype, secretory profile and differentiation capacity was restored. The ASC/ECFC co-culture increased the secretion of cytokines, such as hepatocyte growth factor, compared with single cell 3D culture or monolayer culture. Mice radiation-ulcer wounds treated with ASC/ECFC 3-D co-cultures (spheroids) showed epithelialization and improved healing compared with wounds treated with ASCs or ECFCs alone. Further, transplanted ASC/ECFC spheroids exhibited superior angiogenic potential due to the ability of the ASCs to transdifferentiate into pericytes.Conclusion 3D co-culture of ECFCs and ASCs in vitro restored native ASC properties by reversing cellular senescence and loss of trophic function. Transplant of ASC/ECFC 3D spheroids in vivo demonstrated pro-angiogenic capacity with improved therapeutic potential.

scholarly journals Queuine, a bacterial derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration

2021 ◽  
Author(s):  
Patricia Richard ◽  
Xavier Manière ◽  
Lucie Kozlowski ◽  
Hélène Guillorit ◽  
Patrice Garnier ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Therapeutic Potential ◽  
Mrna Translation ◽  
Alpha Synuclein ◽  
In Vitro Models ◽  
Wobble Position ◽  
Mitochondrial Defects ◽  
Alpha Synuclein Aggregation ◽  
The Brain

AbstractGrowing evidence suggests that human gut bacteria, comprising the microbiome that communicates with the brain through the so-called ‘gut-brain-axis’, are linked to neurodegenerative disorders. Imbalances in the microbiome of Parkinson’s disease (PD) and Alzheimer’s disease (AD) patients have been detected in several studies. Queuine is a hypermodified nucleobase enriched in the brain and exclusively produced by bacteria and salvaged by humans through their gut epithelium. Queuine replaces guanine at the wobble position of tRNAs with GUN anticodons and promotes efficient cytoplasmic and mitochondrial mRNA translation.To elucidate whether queuine could facilitate protein folding and prevent aggregation and mitochondrial defects, hallmarks of neurodegenerative disorders, we tested the effect of chemically synthesized queuine, STL-101, in several in vitro models of neurodegeneration. Treatment with STL-101 led to increased neuronal survival as well as a significant decrease in hyper-phosphorylated alpha-synuclein, a marker of alpha-synuclein aggregation in a PD model and a decrease in tau hyperphosphorylation in an AD model. Our work has identified a new role for queuine in neuroprotection uncovering a therapeutic potential for STL-101 in neurological disorders.

scholarly journals Distinct Effects of Inflammation on Cytochrome P450 Regulation and Drug Metabolism: Lessons from Experimental Models and a Potential Role for Pharmacogenetics

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1509
Author(s):  
Laura M. de Jong ◽  
Wim Jiskoot ◽  
Jesse J. Swen ◽  
Martijn L. Manson
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Drug Response ◽  
Genetic Factors ◽  
Potential Role ◽  
In Vitro Models ◽  
Experimental Models ◽  
Individual Variability ◽  
The Individual

Personalized medicine strives to optimize drug treatment for the individual patient by taking into account both genetic and non-genetic factors for drug response. Inflammation is one of the non-genetic factors that has been shown to greatly affect the metabolism of drugs—primarily through inhibition of cytochrome P450 (CYP450) drug-metabolizing enzymes—and hence contribute to the mismatch between the genotype predicted drug response and the actual phenotype, a phenomenon called phenoconversion. This review focuses on inflammation-induced drug metabolism alterations. In particular, we discuss the evidence assembled through human in-vitro models on the effect of inflammatory mediators on clinically relevant CYP450 isoform levels and their metabolizing capacity. We also present an overview of the current understanding of the mechanistic pathways via which inflammation in hepatocytes may modulate hepatic functions that are critical for drug metabolism. Furthermore, since large inter-individual variability in response to inflammation is observed in human in-vitro models and clinical studies, we evaluate the potential role of pharmacogenetic variability in the inflammatory signaling cascade and how this can modulate the outcome of inflammation on drug metabolism and response.

Repetitive Transcranial Magnetic Stimulation of the Brain

2016 ◽  
Vol 23 (1) ◽  
pp. 82-94 ◽  
Author(s):  
Alexander Tang ◽  
Gary Thickbroom ◽  
Jennifer Rodger
Keyword(s):  
Transcranial Magnetic Stimulation ◽  
Magnetic Stimulation ◽  
Therapeutic Potential ◽  
Repetitive Transcranial Magnetic Stimulation ◽  
Experimental Studies ◽  
Basic Research ◽  
In Vitro Models ◽  
In Vivo Studies

Since the development of transcranial magnetic stimulation (TMS) in the early 1980s, a range of repetitive TMS (rTMS) protocols are now available to modulate neuronal plasticity in clinical and non-clinical populations. However, despite the wide application of rTMS in humans, the mechanisms underlying rTMS-induced plasticity remain uncertain. Animal and in vitro models provide an adjunct method of investigating potential synaptic and non-synaptic mechanisms of rTMS-induced plasticity. This review summarizes in vitro experimental studies, in vivo studies with intact rodents, and preclinical models of selected neurological disorders—Parkinson’s disease, depression, and stroke. We suggest that these basic research findings can contribute to the understanding of how rTMS-induced plasticity can be modulated, including novel mechanisms such as neuroprotection and neurogenesis that have significant therapeutic potential.

scholarly journals Nestin+ Mesenchymal Precursors Generate Distinct Spleen Stromal Cell Subsets and Have Immunomodulatory Function

2021 ◽  
Author(s):  
Jing Huang ◽  
Minrong Li ◽  
Ronghai Deng ◽  
Weiqiang Li ◽  
Meihua Jiang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Cell Phenotype ◽  
Therapeutic Effects ◽  
Inflammatory Bowel ◽  
Inflammatory Milieu

Abstract Background Mesenchymal stromal cells (MSCs) are known to be widespread in many tissues and possess a broad spectrum of immunoregulatory properties. They have been used in the treatment of a variety of inflammatory diseases; however, the therapeutic effects are still inconsistent owing to their heterogeneity. Spleen stromal cells have evolved to regulate the immune response at many levels as they are bathed in a complex inflammatory milieu during infection. Therefore, it is unknown whether they have stronger immunomodulatory effects than their counterparts derived from other tissues. Methods Here, using a transgenic mouse model expressing GFP driven by the Nestin (Nes) promoter, Nes-GFP+ cells from bone marrow and spleen were collected. Artificial lymphoid reconstruction in vivo was performed. Cell phenotype, inhibition of T cell inflammatory cytokines, and in vivo therapeutic effects were assessed. Results We observed Nes-GFP+ cells colocalized with splenic stromal cells and further demonstrated that these Nes-GFP+ cells had the ability to establish ectopic lymphoid-like structures in vivo. Moreover, we showed that the Nes-GFP+ cells possessed the characteristics of MSCs. Spleen-derived Nes-GFP+ cells exhibited greater immunomodulatory ability in vitro, and more remarkable therapeutic efficacy in inflammatory diseases, especially inflammatory bowel disease (IBD) than bone marrow-derived Nes-GFP+ cells. Conclusions Overall, our data showed that Nes-GFP+ cells contributed to subsets of spleen stromal populations and possessed the biological characteristics of MSCs with a stronger immunoregulatory function and therapeutic potential than bone marrow-derived Nes-GFP+ cells.

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