Carbonic anhydrase 2 is a promising predictive factor in cholangiocarcinoma and potential mediator in Metformin treatment

2021 ◽  
Author(s):  
Chaofu Li ◽  
Li Qin ◽  
Jian Huang ◽  
Yu Zhan ◽  
Guanzhen Yu ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Dependent Manner ◽  
Rt Pcr ◽  
Continuous Administration ◽  
Tissue Samples ◽  
Advanced Stages ◽  
Relationship Of ◽  
The Relationship

Abstract Background Cholangiocarcinoma (CCA) is a rare tumor with an aggressive behavior, early diagnosis is impossible as symptoms emerge only in advanced stages. The discovery of a promising biomarker is urgently needed. Carbonic anhydrase 2 (CA2) was found to be dysregulated in diverse cancers, however limited knowledge of CA2 in CCA development was known. Materials and methods CA2 expression was detected both in human and rat thioacetamide (TAA)-induced CCA model by RT-PCR and IHC staining. The relationship of CA2 expression with clinical outcomes was evaluated by univariate and multivariate analyses. CA2 expression changes were also detected both in vivo and in vitro by a potential CA2 inhibitor, Metformin (Met), which was used to inhibit CCA development. Results The level of CA2 expression was increased in biliary lesions with continuous administration of TAA. CA2 was overexpressed in CCA compared with normal tissue samples in rat model and human samples, and correlated significantly with disease progression. Patients with high CA2 expression had a poorer outcome than those without CA2 expression. Met alleviated TAA-induced CCA lesions, and significantly decreased CA2 expression. Colony formation assay showed Met inhibition in CCA cell abilities to form colonies and CA2 expression. CA2 expression was downregulated by Met in a dose- and time-dependent manner in vitro. Conclusions These findings indicate that CA2 is a promising predictive and prognostic factor, and might serve as a potentially novel therapeutic target for human CCA.

The human proton-coupled folate transporter (hPCFT): modulation of intestinal expression and function by drugs

2010 ◽  
Vol 298 (2) ◽  
pp. G248-G254 ◽  
Author(s):  
Bradley L. Urquhart ◽  
Jamie C. Gregor ◽  
Nilesh Chande ◽  
Michael J. Knauer ◽  
Rommel G. Tirona ◽  
...  
Keyword(s):  
Folic Acid ◽  
Brush Border Membrane ◽  
Rt Pcr ◽  
Madin Darby Canine Kidney ◽  
And Function ◽  
Relationship Of ◽  
The Relationship ◽  
Darby Canine Kidney

Folic acid is a vitamin essential for thymidylate and purine synthesis. The human proton-coupled folate transporter (hPCFT) has recently been identified as a pH-dependent folic acid transporter, and mutations in this transporter have been linked to hereditary folic acid malabsorption. In this study, we assessed hPCFT-mediated transport activity in vitro, intersubject variability of intestinal expression in relation to blood folates, and the relationship of proton-pump inhibitor (PPI) therapy on hPCFT expression in vivo. We created a Madin-Darby canine kidney strain II (MDCKII) cell line stably expressing hPCFT to evaluate its drug substrates and inhibitors. Intestinal pinch biopsies (duodenum, ileum, colon) were collected from patients undergoing routine endoscopy procedures, and expressed levels of hPCFT were determined by RT-PCR. When assessed using MDCKII-hPCFT cells, folic acid and methotrexate were found to be high-affinity hPCFT substrates. Sulfasalazine and pyrimethamine were noted to inhibit hPCFT activity with Ki values of 42.3 and 161.7 μmol/l, respectively. hPCFT was localized to the brush-border membrane of enterocytes with highest expression in the duodenum and reduced levels in the ileum and colon. When we assessed hPCFT expression in a subset of patients who were receiving PPI therapy, a near 50% reduction in duodenal hPCFT mRNA expression was noted. These results suggest that hPCFT transporter activity can be modulated by many drugs in clinical use, and expression of this transporter in the gastrointestinal tract is higher in the duodenum than more distal sites (duodenum > ileum > colon). Importantly, we note that PPI drug use appears to be associated with reduced hPCFT expression in vivo.

scholarly journals Ferroptosis contributes to isoflurane-induced neurotoxicity and learning and memory impairment

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Pengfei Liu ◽  
Jing Yuan ◽  
Yetong Feng ◽  
Xin Chen ◽  
Guangsuo Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Learning And Memory ◽  
Memory Impairment ◽  
Close Association ◽  
Dimethyl Fumarate ◽  
Dependent Manner ◽  
Transport Chain ◽  
The Relationship

AbstractFerroptosis is a novel type of programmed cell death, which is different from apoptosis and autophagic cell death. Recently, ferroptosis has been indicated to contribute to the in vitro neurotoxicity induced by isoflurane, which is one of the most common anesthetics in clinic. However, the in vivo position of ferroptosis in isoflurane-induced neurotoxicity as well as learning and memory impairment remains unclear. In this study, we mainly explored the relationship between ferroptosis and isoflurane-induced learning and memory, as well as the therapeutic methods in mouse model. Our results indicated that isoflurane induced the ferroptosis in a dose-dependent and time-dependent manner in hippocampus, the organ related with learning and memory ability. In addition, the activity of cytochrome c oxidase/Complex IV in mitochondrial electron transport chain (ETC) was increased by isoflurane, which might further contributed to cysteine deprivation-induced ferroptosis caused by isoflurane exposure. More importantly, isoflurane-induced ferroptosis could be rescued by both ferroptosis inhibitor (ferrostatin-1) and mitochondria activator (dimethyl fumarate), which also showed effective therapeutic action against isoflurane-induced learning and memory impairment. Taken together, our data indicate the close association among ferroptosis, mitochondria and isoflurane, and provide a novel insight into the therapy mode against isoflurane-induced learning and memory impairment.

Adrenocortical function in aging exercise-trained rats

1977 ◽  
Vol 43 (5) ◽  
pp. 839-843 ◽  
Author(s):  
J. A. Severson ◽  
R. D. Fell ◽  
J. G. Tuig ◽  
D. R. Griffith
Keyword(s):  
Age Groups ◽  
Plasma Corticosterone ◽  
Treadmill Running ◽  
Adrenocortical Function ◽  
Elevated Plasma ◽  
Corticosterone Concentration ◽  
Relationship Of ◽  
The Relationship

Plasma corticosterone concentrations and in vitro adrenal secretion of corticosterone were determined in exercise-trained rats. Rats, 100, 200, and 300 days of age, were trained for a 10-wk period by treadmill running. Following the training program, rats were subjected to an acute bout of swimming. Acute swimming elevated plasma corticosterone concentrations in all age groups. At 170 days of age, the plasma corticosterone concentration following swimming was higher in exercise-trained rats than in controls. The opposite was true of acutely swum rats at 270 and 370 days of age. Acute swimming elevated the in vitro adrenal gland response to adrenocorticotropic hormone stimulation in control rats at all ages and in trained rats at 170 days of age. The in vivo relationship of epinephrine and the pituitary adrenal system is suggested as a mechanism which could have caused this response. The relationship of secretion rates to plasma corticosterone concentrations indicated that extra-adrenal mechanisms, such as decreased turnover, were also responsible for the elevated plasma corticosterone levels observed in response to acute swimming.

IN VITRO INHIBITION OF UDP GLUCURONOSYLTRANSFERASES BY ATAZANAVIR AND OTHER HIV PROTEASE INHIBITORS AND THE RELATIONSHIP OF THIS PROPERTY TO IN VIVO BILIRUBIN GLUCURONIDATION

2005 ◽  
Vol 33 (11) ◽  
pp. 1729-1739 ◽  
Author(s):  
Donglu Zhang ◽  
Theodore J. Chando ◽  
Donald W. Everett ◽  
Christopher J. Patten ◽  
Shangara S. Dehal ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
In Vitro Inhibition ◽  
Relationship Of ◽  
The Relationship

scholarly journals SIMILARITY OF THE KINETICS OF INVERTASE ACTION IN VIVO AND IN VITRO. III

1933 ◽  
Vol 16 (4) ◽  
pp. 571-577 ◽  
Author(s):  
J. M. Nelson ◽  
B. G. Wilkes
Keyword(s):  
Physiological Activity ◽  
Water Concentration ◽  
Invertase Activity ◽  
Yeast Cells ◽  
Identical Manner ◽  
A Cell ◽  
Relationship Of ◽  
The Relationship

1. The relationship of sucrose and water concentration to invertase activity in vivo and in vitro has been studied under the same environmental conditions. 2. The sucroclastic activity of S. cerevisiae cells and of invertase solutions prepared from them reacts to changes in sucrose and water concentration in an identical manner. 3. The invertase contained in living yeast cells is just as freely exposed to the conditions of sucrose and water concentrations of the suspending medium as it would be if it were contained in a cell-free solution. Weight is added to the previous suggestion (2) that yeast invertase exerts its physiological activity in a region quite close to the surface of the cell.

Hematopoietic-repopulating defects from STAT5-deficient bone marrow are not fully accounted for by loss of thrombopoietin responsiveness

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 2965-2972 ◽  
Author(s):  
Heath L. Bradley ◽  
Christine Couldrey ◽  
Kevin D. Bunting
Keyword(s):  
Bone Marrow ◽  
Hematopoietic Stem ◽  
Fold Reduction ◽  
Thrombopoietin Receptor ◽  
Direct Head ◽  
Relationship Of ◽  
The Relationship

Abstract Signal transducer and activator of transcription-5 (STAT5) plays an important role in repopulating activity of hematopoietic stem cells (HSCs). However, the relationship of STAT5 activation with early acting cytokine receptors is not well established. We have directly compared bone marrow (BM) from mice mutant for STAT5a and STAT5b (STAT5ab-/-) with that from mice lacking c-Mpl (c-Mpl-/-), the thrombopoietin receptor. Both STAT5 and c-Mpl deficiency only mildly affected committed myeloid progenitors assayed in vitro, but STAT5ab-/- BM showed lower Gr-1+ (4.4-fold), B220+ (23-fold), CD4+ (20-fold), and Ter119+ (17-fold) peripheral blood repopulating activity than c-Mpl-/- BM against wild-type competitor in long-term repopulating assays in vivo. Direct head-to-head competitions of STAT5ab-/- BM and c-Mpl-/- BM showed up to a 25-fold reduction in STAT5ab-/- contribution. Differences affecting reconstitution of primitive c-Kit+Lin-Sca-1+ multipotent progenitor (MPP)/HSC (1.8-fold) and c-Kit+Lin-Sca-1- oligopotent progenitor BM fractions (3.3-fold) were more modest. In serial transplantation experiments, STAT5ab-/- and c-Mpl-/- BM both failed to provide consistent engraftment in tertiary hosts and could not radioprotect lethally irradiated quaternary recipients. These results indicate substantial overlap in c-Mpl-STAT5 signaling defects at the MPP/HSC level but indicate that STAT5 is activated independent of c-Mpl to promote multilineage hematopoietic differentiation. (Blood. 2004;103:2965-2972)

scholarly journals Deoxyribonucleic acid synthesis in mammalian nuclei. Incorporation of deoxyribonucleotides and chain-terminating nucleotide analogues

1971 ◽  
Vol 121 (5) ◽  
pp. 803-809 ◽  
Author(s):  
M. A. Waqar ◽  
L. A. Burgoyne ◽  
M. R. Atkinson
Keyword(s):  
Dna Synthesis ◽  
Deoxyribonucleic Acid ◽  
Acid Synthesis ◽  
Deoxyribonucleic Acid Synthesis ◽  
Dna Chain ◽  
Relationship Of ◽  
The Relationship ◽  
Neighbour Analysis

The properties of a nuclear preparation from rat liver and thymus are described. (1) Nearest-neighbour analysis after incorporation of 32P-labelled nucleotide residues from dATP, dCTP, dGTP, dTTP and arabinofuranosyl analogues of CTP and ATP shows template-dependent DNA synthesis. (2) Where primer termini are limiting, incorporation of arabinofuranosyl analogues of AMP and CMP residues proceeds to a limit indicating that both of these analogues are DNA chain terminators. (3) No large differences have been found between the priming potentialities or the intrinsic DNA polymerase activities of nuclei from resting or regenerating liver and the relationship of this DNA synthesis in vitro to DNA replication or repair in vivo is briefly discussed.

scholarly journals JAK Inhibitors Suppress Colon Cancer Cachexia-Associated Anorexia and Adipose Wasting in Mice

2020 ◽  
Author(s):  
Gurpreet Arora ◽  
Arun Gupta ◽  
Tong Guo ◽  
Aakash Gandhi ◽  
Aaron Laine ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Colon Adenocarcinoma ◽  
Serum Levels ◽  
Immunoblot Analysis ◽  
Dependent Manner ◽  
Jak Inhibitors ◽  
Rt Pcr ◽  
Stat3 Phosphorylation

ABSTRACTBackgroundCachexia (CX), a syndrome of muscle atrophy, adipose loss, and anorexia, is associated with reduced survival in cancer patients. The colon adenocarcinoma C26c20 cell line secretes the cytokine leukemia inhibitor factor (LIF) which induces CX. We characterized how LIF promotes CX-associated weight loss and anorexia in mice through JAK-dependent changes in adipose and hypothalamic tissues.MethodsCX was induced in vivo with C26c20 colon adenocarcinoma cells or recombinant LIF administration in the absence or presence of JAK inhibitors. Blood, adipose, and hypothalamic tissues were collected and processed for cyto/adipokine ELISAs, immunoblot analysis, and quantitative RT-PCR. CX was induced in vitro by stimulating differentiated adipocytes with recombinant LIF or IL-6 in the absence or presence of lipase or JAK inhibitors. These activated adipocytes were processed for lipolysis, immunoblot analysis, and RT-PCR.ResultsTumor-secreted LIF induced changes in adipose tissue expression and serum levels of IL-6 and leptin in a JAK-dependent manner influencing CX-associated adipose wasting and anorexia. We identified two JAK inhibitors that block cytokine-mediated adipocyte lipolysis and IL-6 induction using an in vitro CX lipolysis assay. JAK inhibitors administered to in vivo colon cancer CX mouse models led to 1) a decrease in STAT3 phosphorylation in hypothalamic and adipose tissues, 2) a reverse in the CX serum cyto/adipokine signature, 3) a delay in colon cancer CX-associated anorexia and adipose loss, and 4) an improvement in overall survival.ConclusionsJAK inhibitors suppress cytokine-associated adipose loss and anorexia in multiple in vitro and in vivo models of cancer CX.

scholarly journals Oxytocin Controls Chondrogenesis and Correlates with Osteoarthritis

2020 ◽  
Vol 21 (11) ◽  
pp. 3966
Author(s):  
Christian H. Roux ◽  
Didier F. Pisani ◽  
Pierre Gillet ◽  
Eric Fontas ◽  
Hédi Ben Yahia ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Adipose Derived Stem Cells ◽  
Mrna Transcript ◽  
X Ray ◽  
Relationship Of ◽  
The Relationship ◽  
Immunohistochemical Analyses ◽  
Lesion Severity

This study investigated the relationship of oxytocin (OT) to chondrogenesis and osteoarthritis (OA). Human bone marrow and multipotent adipose-derived stem cells were cultured in vitro in the absence or presence of OT and assayed for mRNA transcript expression along with histological and immunohistochemical analyses. To study the effects of OT in OA in vivo, a rat model and a human cohort of 63 men and 19 women with hand OA and healthy controls, respectively, were used. The baseline circulating OT, interleukin-6, leptin, and oestradiol levels were measured, and hand X-ray examinations were performed for each subject. OT induced increased aggrecan, collagen (Col) X, and cartilage oligomeric matrix protein mRNA transcript levels in vitro, and the immunolabelling experiments revealed a normalization of Sox9 and Col II protein expression levels. No histological differences in lesion severity were observed between rat OA groups. In the clinical study, a multivariate analysis adjusted for age, body mass index, and leptin levels revealed a significant association between OA and lower levels of OT (odds ratio = 0.77; p = 0.012). Serum OT levels are reduced in patients with hand OA, and OT showed a stimulatory effect on chondrogenesis. Thus, OT may contribute to the pathophysiology of OA.

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