scholarly journals Dose-dependent effects of adiponectin on ADAMTS-9 gene expression in human chondrocytes

2017 ◽  
Vol 118 (07) ◽  
pp. 386-390 ◽  
Author(s):  
K. O. Yaykasli ◽  
O. F. Hatipoglu ◽  
E. Yaykasli ◽  
E. Kaya ◽  
M. Ozsahin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Chondrocytes ◽  
Dose Dependent

scholarly journals Cytotoxic Properties of HT-2 Toxin in Human Chondrocytes: Could T3 Inhibit Toxicity of HT-2?

Toxins ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 667 ◽  
Author(s):  
Feng’e Zhang ◽  
Mikko Juhani Lammi ◽  
Wanzhen Shao ◽  
Pan Zhang ◽  
Yanan Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Immunoblot Analysis ◽  
Human Chondrocytes ◽  
Hypertrophic Chondrocyte ◽  
Skeletal Malformations ◽  
Potential Factors ◽  
Differentiation Marker ◽  
Dose Dependent ◽  
Beck Disease

Thyroid hormone triiodothyronine (T3) plays an important role in coordinated endochondral ossification and hypertrophic differentiation of the growth plate, while aberrant thyroid hormone function appears to be related to skeletal malformations, osteoarthritis, and Kashin-Beck disease. The T-2 toxin, present extensively in cereal grains, and one of its main metabolites, HT-2 toxin, are hypothesized to be potential factors associated with hypertrophic chondrocyte-related osteochondropathy, known as the Kashin-Beck disease. In this study, we investigated the effects of T3 and HT-2 toxin on human chondrocytes. The immortalized human chondrocyte cell line, C-28/I2, was cultured in four different groups: controls, and cultures with T3, T3 plus HT-2 and HT-2 alone. Cytotoxicity was assessed using an MTT assay after 24-h-exposure. Quantitative RT-PCR was used to detect gene expression levels of collagen types II and X, aggrecan and runx2, and the differences in runx2 were confirmed with immunoblot analysis. T3 was only slightly cytotoxic, in contrast to the significant, dose-dependent cytotoxicity of HT-2 alone at concentrations ≥ 50 nM. T3, together with HT-2, significantly rescued the cytotoxic effect of HT-2. HT-2 induced significant increases in aggrecan and runx2 gene expression, while the hypertrophic differentiation marker, type X collagen, remained unchanged. Thus, T3 protected against HT-2 induced cytotoxicity, and HT-2 was an inducer of the pre-hypertrophic state of the chondrocytes.

389 Combining transcriptomic- and tissue-based immune biomarkers to evaluate GB1275, a CD11b modulator, as a single agent or with pembrolizumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A414-A414
Author(s):  
Wells Messersmith ◽  
Drew Rasco ◽  
Johann De Bono ◽  
Andrea Wang-Gillam ◽  
Wungki Park ◽  
...  
Keyword(s):  
Gene Expression ◽  
Solid Tumors ◽  
Peripheral Blood ◽  
Post Treatment ◽  
Transcriptomic Analysis ◽  
Gene Set Enrichment Analysis ◽  
Cancer Center ◽  
Advanced Solid Tumors ◽  
Core Tissue ◽  
Dose Dependent

BackgroundGB1275 is a first-in-class CD11b modulator in development as monotherapy and in combination with pembrolizumab or chemotherapy for the treatment of advanced solid tumors. Nonclinical data show that GB1275 reduced influx of tumor-associated myeloid-derived suppressor cells (MDSCs) and macrophages (TAMs), and repolarized M2 immuno-suppressive TAMs towards an M1 phenotype. We hypothesize that GB1275 administration can alleviate myeloid cell-mediated immunosuppressive effects and improve cancer treatment outcomes. A phase 1 trial evaluating GB1275 as monotherapy and in combination with pembrolizumab in specified advanced tumors in ongoing (NCT04060342).MethodsBlood gene expression variations as well as core tissue biopsies pre- and post-treatment were assessed following GB1275 monotherapy and combination with pembrolizumab. After obtaining informed consent, peripheral blood for MDSCs was collected from 21 patients pre- and two weeks post-treatment; core tissue biopsies were collected from 13 patients pre- and post-treatment. The frequency of MDSCs in whole blood was measured using the Serametrix MDSC FACS Assay. Gene expression transcriptome profiles were generated using NovaSeq platform. CD8 staining was performed at Neogenomics, and tumor infiltrating lymphocyte (TIL) quantification was performed by an independent pathologist.ResultsPreliminary statistical analysis of MDSC immunophenotyping pre- and post- treatment is consistent with the proposed mechanism of GB1275, showing modulation of peripheral blood MDSCs in some patients. Preliminary gene expression analysis in the blood showed dose-dependent clusters following treatment with GB1275 alone. Moreover, the transcriptomic analysis revealed two unique expression patterns for patients treated with GB1275 monotherapy or in combination with pembrolizumab. Gene Set Enrichment Analysis showed that the CD11b pathway is downregulated in patients treated with GB1275. Analyses of TIL count revealed an increase in lymphocyte trafficking into the tumor after treatment with GB1275 alone or in combination with pembrolizumab. CD8 expression and transcriptomic analysis are underway and will be presented.ConclusionsGB1275 alone or in combination with pembrolizumab demonstrates biological activity, which may be dose dependent. The observed increase in TILs after treatment is supportive of the mechanism of action of GB1275. Further biomarker analyses in blood and tissues are ongoing and will be correlated with clinical activity in a larger number of patients.Ethics ApprovalThis ongoing study is being conducted in accordance with the the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. The study was approved by the Ethics Boards of University of Colorado Hospital, Washington University School of Medicine - Siteman Cancer Center, Memorial Sloan Kettering Cancer Center, The Sarah Cannon Research Institute/Tennessee Oncology, South Texas Accelerated Research Therapeutics, and The Royal Marsden NHS Foundation Trust.

Phenotypic characteristics and gene expression profiles of human chondrocytes in tissuegene C

2021 ◽  
Vol 29 ◽  
pp. S211-S212
Author(s):  
I. Uzieliene ◽  
E. Bagdonas ◽  
J. Denkovskij ◽  
E. Bernotiene ◽  
H.-J. Yoon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Human Chondrocytes ◽  
Phenotypic Characteristics

P–543 Inhibition of cell proliferation and extracellular matrix formation in human uterine leiomyomas by 5-aza–2’-deoxycitidine via Wnt/ β-catenin pathway

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
M C Carbajo-García ◽  
A Corachán ◽  
M Segura ◽  
J Monleón ◽  
J Escrig ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Protein Expression ◽  
Hormonal Treatment ◽  
Dependent Manner ◽  
Dnmt Inhibitors ◽  
Qrt Pcr ◽  
Dose Dependent

Abstract Study question Is DNA methylation reversion through DNA methyltransferases (DNMT) inhibitors, such as 5-aza–2’-deoxycitidine, a potential therapeutic option for treatment of patients with uterine leiomyomas (UL)? Summary answer 5-aza–2’-deoxycitidine reduces proliferation and extracellular matrix (ECM) formation by inhibition of Wnt/ β-catenin pathway on UL cells, suggesting DNMT inhibitors as an option to treat UL. What is known already: UL is a multifactorial disease with an unclear pathogenesis and inaccurate treatment. Aberrant DNA methylation have been found in UL compared to myometrium (MM) tissue, showing hypermethylation of tumor suppressor genes, which contributes to the development of this tumor. The use of DNMT inhibitors, such as 5-aza–2’-deoxycytidine (5-aza-CdR), has been suggested to treat tumors in which altered methylation pattern is related to tumor progression, as occurs in UL. Based on this, we aimed to evaluate whether DNA methylation reversion through 5-aza-CdR reduces cell proliferation and ECM formation in UL cells, being a potential option for UL medical treatment. Study design, size, duration Prospective study comparing UL versus MM tissue and human uterine leiomyoma primary (HULP) cells treated with/without 5-aza-CdR at 0 µM (control), 2 µM, 5 µM and 10 µM for 72 hours. UL and MM tissue were collected from women without any hormonal treatment for the last 3 months (n = 16) undergoing myomectomy or hysterectomy due to symptomatic leiomyoma pathology. Participants were recruited between January 2019 and February 2020 at Hospital Universitario y Politecnico La Fe (Spain). Participants/materials, setting, methods Samples were collected from Caucasian premenopausal women aged 31–48 years, with a body mass index of < 30 and without hormonal treatment. DNMT1 gene expression was analysed in UL vs MM tissue by qRT-PCR and activity of DNMT was measured in UL and MM tissue and cells by ELISA. 5-aza-CdR effect on proliferation was assessed by CellTiter test and Western blot (WB), apoptosis and ECM analyzed by WB and Wnt/ β-catenin pathway by qRT-PCR and WB. Main results and the role of chance: DNMT1 gene expression was increased in UL compared to MM tissue (fold change [FC]=2.49, p-value [p]=0.0295). Similarly, DNMT activity was increased in both UL compared to MM tissue and HULP cells versus MM cells (6.50 vs 3.76 OD/h/mg, p = 0.026; 211.30 vs 63.67 OD/h/mg, p = 0.284, respectively). After 5-aza-CdR treatment, cell viability of HULP cells was reduced in a dose dependent manner, being statistically significant at 10 µM (85.25%, p = 0.0001). Accordantly, PCNA protein expression was significantly decreased at 10 µM in HULP cells (FC = 0.695, p = 0.034), demonstrating cell proliferation inhibition. Additionally, 5-aza-CdR inhibited ECM protein expression in HULP cells in a dose-dependent manner being statistically significant at 10 µM for COLLAGEN I (FC = 0.654, p = 0.023) and PAI–1 (FC = 0.654, p = 0.023), and at 2 µM and 10 µM for FIBRONECTIN (FC = 0.812, p = 0.020; FC = 0.733, p = 0.035; respectively). Final targets of Wnt/ β-catenin pathway were decreased after 5-aza-CdR treatment, protein expression of WISP1 was significantly inhibited at 10 µM (FC = 0.699, p = 0.026), while expression levels of Wnt/ β-catenin target genes C-MYC (FC = 0.745, p = 0.028 at 2 µM; FC = 0.728, p = 0.019 at 10 µM) and MMP7 (FC = 0.520, p = 0.003 at 5 µM, FC = 0.577, p = 0.007 at 10 µM) were also significantly downregulated in HULP-treated cells vs untreated cells. Limitations, reasons for caution: This study has strict inclusion criteria to diminish epigenetic variability, thereby we should be cautious extrapolating our results to general population. Besides, this is a proof of concept with the inherent cell culture limitations. Further studies are necessary to determine 5-aza-CdR dose and adverse effects on UL in vivo. Wider implications of the findings: 5-aza-CdR treatment reduces cell proliferation and ECM formation through Wnt/ β-catenin pathway inhibition, suggesting that inhibition of DNA methylation could be a promising new therapeutic approach to treat UL. Trial registration number Not applicable

ANALYSIS OF MT2A AND MT3 GENE EXPRESSION IN RAT'S LIVER AND KIDNEY IN RESPONSE TO CADMIUM CHLORIDE POISONING

2021 ◽  
pp. 38-42
Author(s):  
M. M. Ziatdinova ◽  
T. G. Yakupova ◽  
Ya. V. Valova ◽  
G. F. Mukhammadieva ◽  
D. O. Karimov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rat Liver ◽  
Cadmium Chloride ◽  
Transcriptional Activity ◽  
Female Rats ◽  
Expression Level ◽  
Cadmium Poisoning ◽  
Liver And Kidney ◽  
Dose Dependent ◽  
Higher Doses

The aim of this study was to investigate the expression of metallothionein genes in the liver and kidneys of rats with acute cadmium poisoning.Simulation of poisoning with cadmium chloride was carried out on white outbred female rats, divided into 4 groups depending on the dose of the injected toxicant. RNA samples isolated from rat liver and kidneys were used as research materials.The multiplicity of expression of the MT3 gene in the kidneys increased at the lowest dose of CdCl2 , which was used in this experiment (0.029 mg / kg); with increasing dosage, the expression level decreased, but not lower than the control values. Analysis of the expression of the same gene in the liver showed a tendency towards a decrease in the content of transcripts with increasing dose. The frequency of expression of the MT2A gene at higher doses of CdCl2 increased both in the liver and in the kidneys.In the present work, statistically significant dose-dependent changes in the expression multiplicity of metallothionein genes were detected 24 hours after CdCl2 administration. The revealed differences in the level of transcriptional activity of metallothionein genes require further investigation, since there are probably differences in the level of gene expression at earlier and later periods of toxicant action.

Role of soluble metals in oil fly ash-induced airway epithelial injury and cytokine gene expression

1999 ◽  
Vol 277 (3) ◽  
pp. L498-L510 ◽  
Author(s):  
Janice A. Dye ◽  
Kenneth B. Adler ◽  
Judy H. Richards ◽  
Kevin L. Dreher
Keyword(s):  
Gene Expression ◽  
Fly Ash ◽  
Dependent Manner ◽  
Airway Epithelial ◽  
Tracheal Epithelial Cells ◽  
Inflammatory Protein ◽  
Tracheal Epithelial ◽  
Oil Fly Ash ◽  
Dose Dependent ◽  
Macrophage Inflammatory Protein

Particulate matter (PM) metal content and bioavailability have been hypothesized to play a role in the health effects epidemiologically associated with PM exposure, in particular that associated with emission source PM. Using rat tracheal epithelial cells in primary culture, the present study compared and contrasted the acute airway epithelial effects of an emission source particle, residual oil fly ash (ROFA), with that of its principal constitutive transition metals, namely iron, nickel, and vanadium. Over a 24-h period, exposure to ROFA, vanadium, or nickel plus vanadium, but not to iron or nickel, resulted in increased epithelial permeability, decreased cellular glutathione, cell detachment, and lytic cell injury. Treatment of vanadium-exposed cells with buthionine sulfoximine further increased cytotoxicity. Conversely, treatment with the radical scavenger dimethylthiourea inhibited the effects in a dose-dependent manner. RT-PCR analysis of RNA isolated from ROFA-exposed rat tracheal epithelial cells demonstrated significant macrophage inflammatory protein-2 and interleukin-6 gene expression as early as 6 h after exposure, whereas gene expression of inducible nitric oxide synthase was maximally increased 24 h postexposure. Again, vanadium (not nickel) appeared to be mediating the effects of ROFA on gene expression. Treatment with dimethylthiourea inhibited both ROFA- and vanadium-induced gene expression in a dose-dependent manner. Corresponding effects were observed in interleukin-6 and macrophage inflammatory protein-2 synthesis. In summary, generation of an oxidative stress was critical to induction of the ROFA- or vanadium-induced effects on airway epithelial gene expression, cytokine production, and cytotoxicity.

scholarly journals Acute Iron Dextran Injection Increases Liver Weight and Reduces Glycerol Kinase Expression in Liver

2018 ◽  
Vol 7 (4) ◽  
pp. 236
Author(s):  
Ramdan Panigoro ◽  
Fadhal M. Ahmad ◽  
Uni Gamayani ◽  
Neni Anggraeni ◽  
Rini Widyastuti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Iron Overload ◽  
Liver Weight ◽  
Glycerol Kinase ◽  
Dependent Manner ◽  
Iron Dextran ◽  
Kinase Gene ◽  
Imagej Software ◽  
Kinase Expression ◽  
Dose Dependent

Iron is essential and needed in a very small amount. When iron exceeds normal need, metabolic alteration occurs, causing hepatosteatosis. The mechanism of iron inducing hepatosteatosis remains unclear. Glycerol kinase, the enzyme responsible in triglyceride synthesis initiation, is assumed to have a role in the pathomechanism of hepatosteatosis. This study aimed to investigate the gene expression of glycerol kinase in an acute iron overload condition. This study was conducted in Animal Laboratory Faculty of Medicine and Central Laboratory Universitas Padjadjaran from May to June 2017. Three groups of mice were divided by the dose of iron dextran injection (0, 0.1, 0.3 mg/day/mice). After 19 days, mice were terminated, liver weight was measured and glycerol kinase gene expression in the liver was determined by semi-qualitative PCR. Quantification of PCR result was calculated by ImageJ software. There was a significant change in liver weight of the mice in a dose-dependent manner of iron injection. The expression of glycerol kinase tended to decrease, but statistically insignificant. Acute iron dextran injection increases liver weight and tends to reduce glycerol kinase gene expression in mice liver.Keywords: Glycerol kinase, hepatosteatosis, iron overload Efek Zat Besi Dosis Tinggi Akut dalam Meningkatkan Berat Organ dan Menurunkan Ekspresi Gliserol Kinase HeparAbstrakZat besi merupakan nutrien esensial dan diperlukan dalam jumlah yang sangat kecil. Ketika kadar zat besi melebihi kadar normal dalam tubuh, terjadi perubahan metabolisme yang menyebabkan hepatosteatosis. Mekanisme zat besi dalam menyebabkan hepatosteatosis masih belum diketahui secara pasti. Gliserol kinase, enzim yang menginisiasi sintesis trigliserida, diduga berperan dalam patomekanisme hepatosteatosis. Penelitian ini bertujuan untuk meneliti ekspresi gen gliserol kinase pada hepar pada kondisi tinggi zat besi akut. Penelitian ini dilakukan di Laboratorium Hewan Fakultas Kedokteran dan Laboratorium Sentral Universitas Padjadjaran dari bulan Mei sampai dengan Juni 2017. Tiga kelompok mencit dibagi berdasarkan dosis injeksi iron dextran intraperitoneal (0, 0,1, 0,3 mg/hari/ekor). Setelah 19 hari, mencit diterminasi, berat hepar ditimbang dan ekspresi gen gliserol kinase diukur dengan metode semi-kualitatif PCR. Kuantifikasi hasil PCR dilakukan dengan menggunakan aplikasi ImageJ. Terdapat peningkatan berat hepar secara signifikan yang sejalan dengan dosis ijeksi zat besi. Ekspresi gen gliserol kinase cenderung menurun, meskipun secara statistik tidak signifikan. Keadaan tinggi kadar zat besi yang akut meningkatkan berat hepar dan cenderung menurunkan ekspresi gen gliserol kinase pada hepar mencit.Kata kunci: Gliserol kinase, hepatosteatosis, zat besi berlebih

scholarly journals Dectin-1-Mediated Production of Pro-Inflammatory Cytokines Induced by Yeast β-Glucans in Bovine Monocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Ana R. V. Pedro ◽  
Tânia Lima ◽  
Ricardo Fróis-Martins ◽  
Bárbara Leal ◽  
Isabel C. Ramos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Surface ◽  
Inflammatory Cytokines ◽  
Surface Expression ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
Feed Supplements ◽  
Surface Receptor ◽  
Dose Dependent ◽  
Pro Inflammatory Cytokines

Yeast-derived products containing β-glucans have long been used as feed supplements in domesticated animals in an attempt to increase immunity. β-glucans are mainly recognized by the cell surface receptor CLEC7A, also designated Dectin-1. Although the immune mechanisms elicited through Dectin-1 activation have been studied in detail in mice and humans, they are poorly understood in other species. Here, we evaluated the response of bovine monocytes to soluble and particulate purified β-glucans, and also to Zymosan. Our results show that particulate, but not soluble β-glucans, can upregulate the surface expression of costimulatory molecules CD80 and CD86 on bovine monocytes. In addition, stimulated cells increased production of IL-8 and of TNF, IL1B, and IL6 mRNA expression, in a dose-dependent manner, which correlated positively with CLEC7A gene expression. Production of IL-8 and TNF expression decreased significantly after CLEC7A knockdown using two different pairs of siRNAs. Overall, we demonstrated here that bovine monocytes respond to particulate β-glucans, through Dectin-1, by increasing the expression of pro-inflammatory cytokines. Our data support further studies in cattle on the induction of trained immunity using dietary β-glucans.

scholarly journals Novel analysis of drug-drug interactions reveals the appearance of non-linear dose dependence under the single drug treatment

2020 ◽  
Author(s):  
Yh. Taguchi ◽  
Turki Turki
Keyword(s):  
Gene Expression ◽  
Drug Interactions ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Tensor Decomposition ◽  
Dose Dependence ◽  
Linear Dose ◽  
Non Linear ◽  
New Interactions ◽  
Dose Dependent

ABSTRACTThe accurate prediction of new interactions between drugs is important for avoiding unknown (mild or severe) adverse reactions to drug combinations. The development of effective in silico methods for evaluating drug interactions based on gene expression data requires an under-standing of how various drugs alter gene expression. Current computational methods for the prediction of drug-drug interactions (DDIs) utilize data for known DDIs to predict unknown interactions. However, these methods are limited in the absence of known predictive DDIs. To improve DDIs’ interpretation, a recent study has demonstrated strong non-linear (i.e., dose-dependent) effects of DDIs. In this study, we present a new unsupervised learning approach involving tensor decomposition (TD)-based unsupervised feature extraction (FE) in 3D. We utilize our approach to reanalyze available gene expression profiles for Saccharomyces cerevisiae. We found that non-linearity is possible, even for single drugs. Thus, non-linear dose-dependence cannot always be attributed to DDIs. Our analysis provides a basis for the design of effective methods for evaluating DDIs.

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