Resistance Modification by Cyclosporins is Time-Dependent In Vitro and In Vivo

1992 ◽  
pp. 439-445
Author(s):  
U. Fabry ◽  
P. Glatte ◽  
D. Soll ◽  
R. Osieka
Keyword(s):  
Time Dependent

scholarly journals Metformin Inhibited Growth, Invasion and Metastasis of Esophageal Squamous Cell Carcinoma in Vitro and in Vivo

2018 ◽  
Vol 51 (3) ◽  
pp. 1276-1286 ◽  
Author(s):  
Feng Liang ◽  
Yu-Gang Wang ◽  
Changcheng Wang
Keyword(s):  
Squamous Cell Carcinoma ◽  
Plasma Glucose Level ◽  
Caspase 3 ◽  
Time Dependent ◽  
Dependent Manner ◽  
Metformin Treatment ◽  
Invasion And Migration ◽  
And Migration

Background/Aims: This study aimed at investigating the effects of metformin on the growth and metastasis of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo. Methods: Two human ESCC cell lines EC9706 and Eca109 were selected and challenged with metformin in this study. Western blot assay was performed to detect th level of Bcl-2, Bax and Caspase-3. Scratch wound assay, transwell assay and Millicell invasion assay were used to assay the invasion and migration of EC9706 and Eca109 cells. Nude mice tumor models were used to assay the growth and lung metastasis of ESCC cells after metformin treatment. The plasma glucose level was also assayed. Results: We found that metformin significantly inhibited proliferation and induced apoptosis of both ESCC cell lines in a dose- and time-dependent manner, and the expression of Bcl-2 was down-regulated and Bax and Caspase-3 were up-regulated. Metformin significantly inhibited the invasion and migration of EC9706 and Eca109 cells (p < 0.05). mRNA and protein levels of MMP-2 and MMP-9 decreased significantly upon treatment with metformin of 10mM for 12, 24 and 48h in a time-dependent manner (p < 0.05). In line with in vitro results, in vivo experiments demonstrated that metformin inhibited tumorigenicity, inhibited lung metastasis and down-regulated the expression of MMP-2 and MMP-9. Moreover, we showed that metformin treatment did not cause significant alteration in liver and renal functions and plasma glucose level. Conclusion: Our study for the first time demonstrated the anti-invasive and anti-metastatic effects of metformin on human ESCC cells both in vitro and in vivo, which might be associated with the down-regulation of MMP-2 and MMP-9. As a whole, our results indicate the potential of metformin to be developed as a chemotherapeutic agent for patients with ESCC and might stimulate future studies on this area.

Abstract 344: FNDC5, a PGC1-a-Dependent Myokine, Increases Glucose Utilization and Fatty-Acid Oxidation by AMPK Signaling Pathway

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ling Tao ◽  
Yi Liu ◽  
Chao Xin ◽  
Weidong Huang ◽  
Lijian Zhang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Glucose Utilization ◽  
C2c12 Cells ◽  
Time Dependent ◽  
Acid Oxidation ◽  
Ampk Signaling

FNDC5 is a hormone secreted by myocytes that could reduce obesity and insulin resistance, However, the exact effect of FNDC5 on glucose and lipid metabolism remain poorly identified; More importantly, the signaling pathways that mediate the metabolic effects of FNDC5 is completely unknown. Here we showed that FNDC5 stimulates β-oxidation and glucose uptake in C2C12 cells in a dose- and time-dependent fashion in vitro (n=8, all P<0.01). In vivo study revealed that FNDC5 also enhanced glucose tolerance in diabetic mice and increased the glucose uptake evidenced by increased [18F] FDG accumulation in hearts by PET scan (n=6, all P<0.05). FNDC5 decreased the expression of gluconeogenesis related molecules (PEPCK and G6Pase) and increased the phosphorylation of ACC, a key modulator of fatty-acid oxidation, both in hepatocytes and C2C12 cells (n=3, all P<0.05). In parallel with its stimulation of β-oxidation and glucose uptake, FNDC5 increased the phosphorylation of AMPK both in hepatocytes and C2C12 cells in a dose- and time-dependent fashion in vitro and in vivo. More importantly, the β-oxidation and glucose uptake, the expression of PEPCK and G6Pase and the phosphorylation of ACC induced by FNDC5 were attenuated by AMPK inhibitor in hepatocytes and C2C12 cells (P<0.05). Most importantly, the FNDC5 induced glucose uptake and phosphorylation of ACC were attenuated in AMPK-DN mice (n=6, all P<0.05). The glucose-lowering effect of FNDC5 in diabetic mice was also attenuated by AMPK inhibitor. Our data presents the direct evidence that FNDC5 stimulates glucose utilization and fatty-acid oxidation by AMPK signaling pathway, suggesting that FNDC5 be a novel pharmacological approach for type 2 diabetes.

In vivo diffusion of immunoglobulin G in muscle: effects of binding, solute exclusion, and lymphatic removal

1997 ◽  
Vol 273 (6) ◽  
pp. H2783-H2793 ◽  
Author(s):  
Michael F. Flessner ◽  
Joanne Lofthouse ◽  
El Rasheid Zakaria
Keyword(s):  
Abdominal Wall ◽  
Immunoglobulin G ◽  
Diffusion Profile ◽  
Lymph Flow ◽  
Time Dependent ◽  
Concentration Profiles ◽  
Isotonic Solution ◽  
Cross Sectional

Previously, we demonstrated that immunoglobulin G (IgG), dissolved in an isotonic solution in the peritoneal cavity, transported rapidly into the abdominal wall when the intraperitoneal (ip) pressure was >2 cmH2O. We hypothesized that this was chiefly caused by convection and that diffusion of IgG was negligible. To investigate the role of diffusion, we dialyzed rats with no pressure gradient across the abdominal wall muscle for 2 or 6 h with an ip isotonic solution containing125I-labeled IgG. At the end of the experiment, the animal was euthanized and frozen and abdominal wall tissue was processed to produce cross-sectional autoradiograms. Quantitative densitometric analysis resulted in IgG concentration profiles with far lower magnitude than profiles from experiments in which convection dominated. In other in vivo experiments, we determined the lymph flow rate to be 0.8 × 10−4ml ⋅ min−1 ⋅ g−1and the fraction of extravascular tissue (θs) available to the IgG to be 0.041 ± 0.001. An in vitro binding assay was used to determine the time-dependent, nonsaturable binding constant: 0.0065 min−1 × duration of exposure. A non-steady-state diffusion model that included effects of θs, time-dependent binding, and lymph flow was fitted to the diffusion profile data, and the IgG diffusivity within the tissue void was estimated to be 2 × 10−7cm2/s, a value much higher than that published by other groups. We also demonstrate from our previous data that convection of IgG through tissue dominates over diffusion at ip pressures >2 cmH2O, but diffusion may not be negligible. Furthermore, nonsaturable binding must be accounted for in the interpretation of tissue protein concentration profiles.

scholarly journals Valproic acid causes dose- and time-dependent changes in nuclear structure in prostate cancer cells in vitro and in vivo

2009 ◽  
Vol 8 (4) ◽  
pp. 802-808 ◽  
Author(s):  
Madeleine S.Q. Kortenhorst ◽  
Sumit Isharwal ◽  
Paul J. van Diest ◽  
Wasim H. Chowdhury ◽  
Cameron Marlow ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Valproic Acid ◽  
Cancer Cells ◽  
Nuclear Structure ◽  
Time Dependent ◽  
Prostate Cancer Cells

Trajectory-Based Tissue Engineering for Cartilage Repair: Correlation Between Maturation Rate and Integration Capacity

2013 ◽  
Author(s):  
Matthew B. Fisher ◽  
Nicole Söegaard ◽  
David R. Steinberg ◽  
Robert L. Mauck
Keyword(s):  
Tissue Engineering ◽  
Time Course ◽  
Biomechanical Properties ◽  
Time Dependent ◽  
In Vivo Studies ◽  
Surgical Approaches ◽  
General Hypothesis ◽  
Vitro Assay

Given the limitations of current surgical approaches to treat articular cartilage injuries, tissue engineering (TE) approaches have been aggressively pursued over the past two decades. Although biochemical and biomechanical properties on the order of the native tissue have been achieved (1–5), several in-vitro and in-vivo studies indicate that increased tissue maturity may limit the ability of engineered constructs to remodel and integrate with surrounding cartilage, although results are highly variable (2, 6–8). Thus, “static” measures of construct maturity (e.g. compressive modulus) upon implantation may not be the best indicators of in-vivo success, which likely requires implanted TE constructs to mature, remodel, and integrate with the host over time to achieve optimal results. We recently introduced the concept of “trajectory-based” tissue engineering (TB-TE), which is based on the general hypothesis that time-dependent increases in construct maturation in-vitro prior to implantation (i.e. positive rates) may provide a better predictor of in-vivo success (9). As a first step in evaluating this concept, in the current study we hypothesized that time-dependent increases in equilibrium modulus (a metric of growth) would be correlated to ability of constructs to integrate to cartilage using an in-vitro assay. To test this hypothesis, the current objective was to determine and model the time course of maturation of TE constructs during in-vitro culture and to assess the ability of these constructs to integrate to cartilage at various points during their maturation.

CRM1/XPO1 Represents a Promising Therapeutic Target for Treatment of Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 232-232
Author(s):  
Rosa Lapalombella ◽  
Caroline Berglund ◽  
Emilia Mahoney ◽  
Katie Williams ◽  
Shruti Jha ◽  
...  
Keyword(s):  
Small Molecule ◽  
Cytotoxic Effect ◽  
Stromal Cell ◽  
Time Dependent ◽  
Dependent Manner ◽  
Spontaneous Apoptosis ◽  
Stromal Cell Line ◽  
Equity Ownership

Abstract Abstract 232 Exportin 1 (CRM1, XPO1) is a nuclear exporter that promotes the transit of tumor suppressor proteins (TSPs) including p53, I-κB, and FOXO3A out of the nucleus, thereby preventing their activity and contributing to disrupted apoptosis and enhanced proliferation. Recently, whole-genome sequencing in patients with CLL allowed the identification of recurrent mutations in a highly conserved region of CRM1 that can potentially affects its gene function, suggesting a direct role for CRM1 in the pathogenesis of CLL (Puente XS, et al: Nature 75:101, 2011). However the role of CRM1 and the consequences of its mutation in the development of CLL have yet to be explored. CRM1 has been shown to be up-regulated in hematologic and various solid tumors, making it a highly attractive molecular target impacting multiple pro apoptotic pathways. KPT-SINEs are new, potent and irreversible small molecule selective inhibitors of nuclear export developed by Karyopharm that specifically and irreversibly bind to CRM1 and block the function of this protein. CLL is characterized by disrupted apoptosis caused both by co-dependent stromal elements and aberrant activation of several survival-promoting signaling/transcriptional pathways including PI3K/Akt, NF-kB, and p53. Because of the distinct subtypes of CLL and multiple signaling pathways dysregulated, a therapeutic agent targeting a single biological pathway is unlikely to be effective. Thus, pursuit of CRM1 inhibition as a novel strategy aimed to restore multiple death pathways is crucial and has broad implications for many types of patients. Our preliminary work demonstrated CRM1 is over-expressed in CLL cells compared to normal B cells at a protein (3 fold, p<0.005) and mRNA level (2.6 fold p=0.014). Inhibition of CRM1 by KPT-185 induced apoptosis in primary patient CLL cells in a dose and time dependent manner (EC50<500nM) while limited cytotoxicity against normal PBMC and isolated B, NK and T cells was observed (EC50 values >20 μM). Additionally, KPT-185 treatment of NK cells had no effect on their function as measured by ability of NK cells to mediate antibody dependent (ADCC) as wekk as direct cytotoxicity. The effect of KPT-185 on T function is currently under evaluation. Nuclear accumulation of FOXO3, p53 and IkB was also observed in primary CLL cells in a time dependent manner as shown by western blot and confocal microscopy. The evaluation of activated target genes is currently ongoing. Given the importance of microenvironmental stimuli on survival of CLL cells and response to therapy, we evaluated the ability of KPT-185 to induce cytotoxicity of CLL cells in the presence or absence of soluble factors such as CPG, CD40L, BAFF, TNF-α, IL-6, or IL-4, which are known to reduce the spontaneous apoptosis associated with CLL cells. KPT-185 treatment abrogated the protection induced by each of these factors suggesting that KPT-SINEs can disrupt signaling from the microenvironment that lead to in vivo CLL cell survival and potentially drug resistance. Interestingly the cytotoxic effect elicited by KPT-185 was enhanced in CPG activated cells (p=0.02). We also tested the ability of KPT-185 to kill CLL cells under coculture conditions with Hs5 stromal cell line. Coculture of CLL cells alone for 48 hours on the Hs5 stromal cell line resulted in a marked reduction of spontaneous apoptosis suggesting a strong protective effect elicited (P<0.001) by the stromal cells. Interestingly the cytotoxic effect mediated by KPT-185 was enhanced under coculture conditions (p=0.013). KPT-185 was also proven to be effective on murine TCL1+ cells (EC50<500nM) in vitro. The in vivo efficacy of this compound and other structurally related analogs is currently being assessed in an ongoing study in theTCL1 mouse model of CLL. In conclusion CRM1 represents a novel target that has not been adequately explored in CLL. KPT-SINEs are a class of promising therapeutic agents with proven selective in vitro activity in CLL cells providing the rationale for developing small molecule, drug-like CRM1 inhibitors for the treatment of this disease. Disclosures: Sandanayaka: Karyopharm Therapeutics: Employment. Shechter:Karyopharm Therapeutics: Employment. McCauley:Karyopharm Therapeutics: Employment. Shacham:Karyopharm: Equity Ownership. Kauffman:Karyopharm: Equity Ownership.

scholarly journals A New Parasiticidal Compound inT. soliumCysticercosis

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Romel Hernández-Bello ◽  
Galileo Escobedo ◽  
Julio Cesar Carrero ◽  
Claudia Cervantes-Rebolledo ◽  
Charles Dowding ◽  
...  
Keyword(s):  
Taenia Solium ◽  
Time Dependent ◽  
Splenocyte Proliferation

The effect of 16α-bromoepiandrosterone (EpiBr), a dehydroepiandrosterone (DHEA) analogue, was tested on the cysticerci ofTaenia solium, bothin vitroandin vivo.In vitrotreatment ofT. soliumcultures with EpiBr reduced scolex evagination, growth, motility, and viability in dose- and time-dependent fashions. Administration of EpiBr prior to infection withT. soliumcysticerci in hamsters reduced the number and size of developed taenias in the intestine, compared with controls. These effects were associated to an increase in splenocyte proliferation in infected hamsters. These results leave open the possibility of assessing the potential of this hormonal analogue as a possible antiparasite drug, particularly in cysticercosis and taeniosis.

scholarly journals Decreased liver cytochrome P-450 in rats caused by norethindrone or ethynyloestradiol

1977 ◽  
Vol 166 (1) ◽  
pp. 57-64 ◽  
Author(s):  
I N H White ◽  
U Muller-Eberhard
Keyword(s):  
Marked Effect ◽  
Enzyme System ◽  
Time Dependent ◽  
Female Rats ◽  
Liver Cytochrome ◽  
Mixed Function Oxidases ◽  
Green Pigments ◽  
Cytochrome P 450

1. 19-Nor-17alpha-pregna-1,3,5(10)-trien-20-yne-3,17-diol (ethynyloestradiol) or 17beta-hydroxy-19-nor-17alpha-pregn-4-en-20-yn-3-one (norethindrone) but not 17alpha-ethyl-17beta-hydroxy-19-norandrost-4-en-3-one (norethandrolone) caused a time-dependent loss of cytochrome P-450 when incubated in vitro with rat liver microsomal fractions and NADPH-generating systems. 2. The enzyme system catalysing the norethindrone-mediated loss of cytochrome P-450 had many characteristics of the microsomal mixed-function oxidases. It required NADPH and air, and was inhibited by Co. However, it was unaffected by 1 mM-compound SKF 525A. 3. In microsomal fractions from phenobarbitone-pretreated rats the norethindrone-mediated loss of cytochrome P-450 was increased relative to controls. The norethindrone-mediated cytochrome P-450 loss was less pronounced when the animals were pretreated with 3beta-hydroxy-pregn-5-en-2-one 16alpha-carbonitrile (pregnenolone 16alpha-carbonitrile). Pretreatment with 3-methylcholanthrene rendered the animals resistant to the norethindrone effect. 4. Administration in vivo [100mg/kg, intraperitoneally] of norethindrone or ethinyl oestradiol also produced a time-dependent loss of liver cytochrome P-450. Norethandrolone had a similar, though much less-marked, effect. All three steroids lead to an induction of 5-aminolaevulinate synthase and an accumulation of porphyrins in the liver. 5. The loss of cytochrome P-450 and the accumulation of porphyrins in the liver 2 h after the administration of norethindrone to female rats was similar to that seen in males. 6. Rats pretreated with phenobarbitone and given norethindrone or ethynyloestradiol (100mg/kg, intraperitoneally) formed green pigments in their livers. These had characteristics similar to the green pigments produced in the livers of rats after the administration of 2-allyl-2-isopropylacetamide. No green pigments could be extracted from the livers of control rats or those given norethandrolone, oestradiol or progesterone.

scholarly journals Time-dependent Photodynamic Therapy for Multiple Targets: A Highly Efficient AIE-active Photosensitizer for Selective Bacterial Elimination and Cancer Cell Ablation

2019 ◽  
Author(s):  
Qiyao Li ◽  
Ying Li ◽  
Tianliang Min ◽  
Junyi Gong ◽  
Lili Du ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Reactive Oxygen Species Generation ◽  
Emission Feature ◽  
Time Dependent ◽  
Organic Salt ◽  
Antibacterial Performance ◽  
Cell Ablation ◽  
External Conditions

Pathogen infection and cancer are the two major human health problems. In this work, we achieved an organic salt photosensitizer (PS), called 4TPA-BQ with aggregation-induced emission feature <i>via</i> one-step reaction. Owing to the aggregation-induced reactive oxygen species generation effect and sufficient small ΔE<sub>ST</sub>, 4TPA-BQ shows a satisfactorily high <sup>1</sup>O<sub>2</sub> generation efficiency of 97.8%. <i>In vitro</i> and <i>in vivo</i> experiments confirmed that 4TPA-BQ exhibited potent photodynamic antibacterial performance against ampicillin-resistant <i>Escherichia coli</i> with good biocompatibility in a short time (15 min). When the incubation time persisted long enough (12 h), cancer cells were ablated efficiently, leaving normal cells essentially unaffected. This is the first reported time-dependent fluorescence-guided photodynamic therapy in one individual PS for ordered and multiple targeting by varying the external conditions. This can update the design principle of efficient PSs in potential clinical applications.

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