Publications by authors named "Ivan Kodvanj"

6 Publications

  • Page 1 of 1

Cytokines and Chemokines Involved in Osteoarthritis Pathogenesis.

Int J Mol Sci 2021 Aug 26;22(17). Epub 2021 Aug 26.

St. Catherine Specialty Hospital, 49210 Zabok, Croatia.

Osteoarthritis is a common cause of disability worldwide. Although commonly referred to as a disease of the joint cartilage, osteoarthritis affects all joint tissues equally. The pathogenesis of this degenerative process is not completely understood; however, a low-grade inflammation leading to an imbalance between anabolic and katabolic processes is a well-established factor. The complex network of cytokines regulating these processes and cell communication has a central role in the development and progression of osteoarthritis. Concentrations of both proinflammatory and anti-inflammatory cytokines were found to be altered depending on the osteoarthritis stage and activity. In this review, we analyzed individual cytokines involved in the immune processes with an emphasis on their function in osteoarthritis.
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http://dx.doi.org/10.3390/ijms22179208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431625PMC
August 2021

Is Galactose a Hormetic Sugar? An Exploratory Study of the Rat Hippocampal Redox Regulatory Network.

Mol Nutr Food Res 2021 Nov 9;65(21):e2100400. Epub 2021 Sep 9.

Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia.

Scope: Galactose, a ubiquitous monosaccharide with incompletely understood physiology is often exploited for inducing oxidative-stress mediated aging in animals. Recent research demonstrates that galactose can conserve cellular function during periods of starvation and prevent/alleviate cognitive deficits in a rat model of sporadic Alzheimer's disease. The present aim is to examine the acute effects of oral galactose on the redox regulatory network (RRN).

Methods And Results: Rat plasma and hippocampal RRNs are analyzed upon acute orogastric gavage of galactose (200 mg kg ). No systemic RRN disbalance is observed; however, a mild pro-oxidative shift accompanied by a paradoxical increment in tissue reductive capacity suggesting overcompensation of endogenous antioxidant systems is observed in the hippocampus. Galactose-induced increment of reductive capacity is accompanied by inflation of the hippocampal pool of nicotinamide adenine dinucleotide phosphates indicating ROS detoxification through disinhibition of the oxidative pentose phosphate pathway flux, reduced neuronal activity, and upregulation of Leloir pathway gatekeeper enzyme galactokinase-1.

Conclusion: Based on the observed findings, and in the context of previous work on galactose, a hormetic hypothesis of galactose is proposed suggesting that the protective effects may be inseparable from its pro-oxidative action at the biochemical level.
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http://dx.doi.org/10.1002/mnfr.202100400DOI Listing
November 2021

An Additional Perspective on Proton Pump Inhibitors as Risk Factors for COVID-19.

Clin Drug Investig 2021 03 19;41(3):287-289. Epub 2021 Feb 19.

Department of Pharmacology, University of Zagreb School of Medicine, 10 000, Zagreb, Croatia.

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http://dx.doi.org/10.1007/s40261-021-01007-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892720PMC
March 2021

5-aminoimidazole-4-carboxamide ribonucleoside induces differentiation in a subset of primary acute myeloid leukemia blasts.

BMC Cancer 2020 Nov 11;20(1):1090. Epub 2020 Nov 11.

Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10 000, Zagreb, Croatia.

Background: All-trans retinoic acid (ATRA)-based treatment of acute promyelocytic leukemia (APL) is the most successful pharmacological treatment of acute myeloid leukemia (AML). Recent development of inhibitors of mutated isocitrate dehydrogenase and dihydroorotate dehydrogenase (DHODH) has revived interest in differentiation therapy of non-APL AML. Our previous studies demonstrated that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induced differentiation of monocytic cell lines by activating the ATR/Chk1 via pyrimidine depletion. In the present study, the effects of AICAr on the viability and differentiation of primary AML blasts isolated from bone marrow of patients with non-APL AML were tested and compared with the effects of DHODH inhibitor brequinar and ATRA.

Methods: Bone marrow samples were obtained from 35 patients and leukemia blasts were cultured ex vivo. The cell viability was assessed by MTT assay and AML cell differentiation was determined by flow cytometry and morphological analyses. RNA sequencing and partial data analysis were conducted using ClusterProfiler package. Statistical analysis was performed using GraphPad Prism 6.0.

Results: AICAr is capable of triggering differentiation in samples of bone marrow blasts cultured ex vivo that were resistant to ATRA. AICAr-induced differentiation correlates with proliferation and sensitivity to DHODH inhibition. RNA-seq data obtained in primary AML blasts confirmed that AICAr treatment induced downregulation of pyrimidine metabolism pathways together with an upregulation of gene set involved in hematopoietic cell lineage.

Conclusion: AICAr induces differentiation in a subset of primary non-APL AML blasts, and these effects correlate with sensitivity to a well-known, potent DHODH inhibitor.
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http://dx.doi.org/10.1186/s12885-020-07533-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657321PMC
November 2020

The ribonucleoside AICAr induces differentiation of myeloid leukemia by activating the ATR/Chk1 via pyrimidine depletion.

J Biol Chem 2019 10 20;294(42):15257-15270. Epub 2019 Aug 20.

Department of Physiology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia

Metabolic pathways play important roles in proliferation and differentiation of malignant cells. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr), a precursor in purine biosynthesis and a well-established activator of AMP-activated protein kinase (AMPK), induces widespread metabolic alterations and is commonly used for dissecting the role of metabolism in cancer. We have previously reported that AICAr promotes differentiation and inhibits proliferation of myeloid leukemia cells. Here, using metabolic assays, immunoblotting, flow cytometry analyses, and siRNA-mediated gene silencing in leukemia cell lines, we show that AICAr-mediated differentiation was independent of the known metabolic effects of AMPK, including glucose consumption, but instead depends on the activation of the DNA damage-associated enzyme checkpoint kinase 1 (Chk1) induced by pyrimidine depletion. LC/MS/MS metabolomics analysis revealed that AICAr increases orotate levels and decreases uridine monophosphate (UMP) levels, consistent with inhibition of UMP synthesis at a step downstream of dihydroorotate dehydrogenase (DHODH). AICAr and the DHODH inhibitor brequinar had similar effects on differentiation markers and S-phase arrest, and genetic or pharmacological Chk1 inactivation abrogated both of these effects. Our results delineate an AMPK-independent effect of AICAr on myeloid leukemia differentiation that involves perturbation of pyrimidine biosynthesis and activation of the DNA damage response network.
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http://dx.doi.org/10.1074/jbc.RA119.009396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802504PMC
October 2019
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