Filip Sedlić

University of Zagreb

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Zeljko J. Bosnjak

Medical College of Wisconsin

AŠ

Ana Šepac

University of Zagreb

Danijel Pravdić

University Clinical Hospital Mostar

Maria Muravyeva

Medical College of Wisconsin

Martin Bienengraeber

Medical College of Wisconsin

Ana Kulić

University Hospital Centre Zagreb

Tomo Svaguša

University Hospital Dubrava

Scott G. Canfield

Indiana University School of Medicine

Tetsuro Wakatsuki

Invivo Sciences (United States)

Xiaowen Bai

Medical College of Wisconsin

Cooperative Institutions

University of Zagreb

University Hospital Centre Zagreb

Medical College of Wisconsin

Northwestern University

Williams & Associates

University Hospital Dubrava

University of Rijeka

University of Split

University of Toronto

Klinički Bolnički Centar Rijeka

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SOD1 and MitoTEMPO partially prevent mitochondrial permeability transition pore opening, necrosis, and mitochondrial apoptosis after ATP depletion recovery

Free Radical Biology and Medicine (2010)

Huan Liang Filip Sedlić Zeljko J. Bosnjak Vani Nilakantan

Mitochondrial ROS

MPTP

Mitochondrial apoptosis-induced channel

10.1016/j.freeradbiomed.2010.08.018

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Citations (132)

Anesthetic preconditioning in human cardiomyocytes derived from non‐diabetic and diabetic‐induced pluripotent stem cells

The FASEB Journal (2011)

Scott G. Canfield Ana Šepac Filip Sedlić Maria Muravyeva Frank Park

Diabetes and hyperglycemia have shown to attenuate the cardioprotective effects of anesthetic pre-conditioning (APC) from an ischemic injury. We have developed an experimental in vitro model based on differentiation of human cardiomyocytes (CMs) from induced pluripotent stem cells (iPSCs) to further investigate the effects of genetic background and environmental factors on the attenuation of APC in diabetic individuals. CMs were generated by the differentiation of non-diabetic and type II diabetic-induced pluripotent stem cells; N-iPSC and DM-iPSC, respectively. The presence of 25 mM glucose alone inhibited mitoKATP opening and expedited the opening of mitochondrial permeability transition pore (mPTP), resulting in an attenuation of APC cardioprotection. In DM-CMs there was a reduction in mitoKATP opening in response to isoflurane compared to N-CMs. In N-CMs, APC delayed mPTP opening; however, in DM-CMs, APC was ineffective in delaying mPTP opening. Cardiomyocytes from N-iPSCs and DM-iPSCs enables comparative studies addressing genetic and environmental mechanisms. Preliminary results indicate that both a diabetic background and a high glucose environment have detrimental effects on mPTP opening and the actions of isoflurane to induce mitoKATP opening as a possible explanation for the inefficiency of APC. Supported by P01GM066730 and R01HL034708 (ZJB) from the NIH, Bethesda, MD.

10.1096/fasebj.25.1_supplement.1043.9

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Activator of G Protein Signaling 3 Promotes Epithelial Cell Proliferation in PKD

Journal of the American Society of Nephrology (2010)

Rama Nadella J Blumer Guangfu Jia Michelle Kwon Talha Akbulut

The activation of heterotrimeric G protein signaling is a key feature in the pathophysiology of polycystic kidney diseases (PKD). In this study, we report abnormal overexpression of activator of G protein signaling 3 (AGS3), a receptor-independent regulator of heterotrimeric G proteins, in rodents and humans with both autosomal recessive and autosomal dominant PKD. Increased AGS3 expression correlated with kidney size, which is an index of severity of cystic kidney disease. AGS3 expression localized exclusively to distal tubular segments in both normal and cystic kidneys. Short hairpin RNA-induced knockdown of endogenous AGS3 protein significantly reduced proliferation of cystic renal epithelial cells by 26 +/- 2% (P < 0.001) compared with vehicle-treated and control short hairpin RNA-expressing epithelial cells. In summary, this study suggests a relationship between aberrantly increased AGS3 expression in renal tubular epithelia affected by PKD and epithelial cell proliferation. AGS3 may play a receptor-independent role to regulate Galpha subunit function and control epithelial cell function in PKD.

10.1681/asn.2009121224

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Citations (48)

Non-linear actions of physiological agents: Finite disarrangements elicit fitness benefits

Redox Biology (2017)

Filip Sedlić Zdenko Kovač

Finite disarrangements of important (vital) physiological agents and nutrients can induce plethora of beneficial effects, exceeding mere attenuation of the specific stress. Such response to disrupted homeostasis appears to be universally conserved among species. The underlying mechanism of improved fitness and longevity, when physiological agents act outside their normal range is similar to hormesis, a phenomenon whereby toxins elicit beneficial effects at low doses. Due to similarity with such non-linear response to toxins described with J-shaped curve, we have coined a new term "mirror J-shaped curves" for non-linear response to finite disarrangement of physiological agents. Examples from the clinical trials and basic research are provided, along with the unifying mechanisms that tie classical non-linear response to toxins with the non-linear response to physiological agents (glucose, oxygen, osmolarity, thermal energy, calcium, body mass, calorie intake and exercise). Reactive oxygen species and cytosolic calcium seem to be common triggers of signaling pathways that result in these beneficial effects. Awareness of such phenomena and exploring underlying mechanisms can help physicians in their everyday practice. It can also benefit researchers when designing studies and interpreting growing number of scientific data showing non-linear responses to physiological agents.

10.1016/j.redox.2017.05.008

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Targeted Modification of Mitochondrial ROS Production Converts High Glucose-Induced Cytotoxicity to Cytoprotection: Effects on Anesthetic Preconditioning

Journal of Cellular Physiology (2016)

Filip Sedlić Maria Muravyeva Ana Šepac Marija Sedlić Anna Williams

Contradictory reports on the effects of diabetes and hyperglycemia on myocardial infarction range from cytotoxicity to cytoprotection. The study was designed to investigate acute effects of high glucose-driven changes in mitochondrial metabolism and osmolarity on adaptive mechanisms and resistance to oxidative stress of isolated rat cardiomyocytes. We examined the effects of high glucose on several parameters of mitochondrial bioenergetics, including changes in oxygen consumption, mitochondrial membrane potential, and NAD(P)H fluorometry. Effects of high glucose on the endogenous cytoprotective mechanisms elicited by anesthetic preconditioning (APC) and the mediators of cell injury were also tested. These experiments included real-time measurements of reactive oxygen species (ROS) production and mitochondrial permeability transition pore (mPTP) opening in single cells by laser scanning fluorescence confocal microscopy, and cell survival assay. High glucose rapidly enhanced mitochondrial energy metabolism, observed by increase in NAD(P)H fluorescence intensity, oxygen consumption, and mitochondrial membrane potential. This substantially elevated production of ROS, accelerated opening of the mPTP, and decreased survival of cells exposed to oxidative stress. Abrogation of high glucose-induced mitochondrial hyperpolarization with 2,4 dinitrophenol (DNP) significantly, but not completely, attenuated ROS production to a level similar to hyperosmotic mannitol control. DNP treatment reversed high glucose-induced cytotoxicity to cytoprotection. Hyperosmotic mannitol treatment also induced cytoprotection. High glucose abrogated APC-induced mitochondrial depolarization, delay in mPTP opening and cytoprotection. In conclusion, high glucose-induced mitochondrial hyperpolarization abolishes APC and augments cell injury. Attenuation of high glucose-induced ROS production by eliminating mitochondrial hyperpolarization protects cardiomyocytes. J. Cell. Physiol. 232: 216-224, 2017. © 2016 Wiley Periodicals, Inc.

Cytoprotection

Mitochondrial ROS

Hyperpolarization

10.1002/jcp.25413

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Citations (28)

Differences in Production of Reactive Oxygen Species and Mitochondrial Uncoupling as Events in the Preconditioning Signaling Cascade Between Desflurane and Sevoflurane

Anesthesia & Analgesia (2009)

Filip Sedlić Danijel Pravdić Marko Ljubković Jasna Marinović Anna Stadnicka

Signal transduction cascade of anesthetic-induced preconditioning has been extensively studied, yet many aspects of it remain unsolved. Here, we investigated the roles of reactive oxygen species (ROS) and mitochondrial uncoupling in cardiomyocyte preconditioning by two modern volatile anesthetics: desflurane and sevoflurane.Adult rat ventricular cardiomyocytes were isolated enzymatically. The preconditioning potency of desflurane and sevoflurane was assessed in cell survival experiments by evaluating myocyte protection from the oxidative stress-induced cell death. ROS production and flavoprotein fluorescence, an indicator of flavoprotein oxidation and mitochondrial uncoupling, were monitored in real time by confocal microscopy. The functional aspect of enhanced ROS generation by the anesthetics was assessed in cell survival and confocal experiments using the ROS scavenger Trolox.Preconditioning of cardiomyocytes with desflurane or sevoflurane significantly decreased oxidative stress-induced cell death. That effect coincided with increased ROS production and increased flavoprotein oxidation detected during acute myocyte exposure to the anesthetics. Desflurane induced significantly greater ROS production and flavoprotein oxidation than sevoflurane. ROS scavenging with Trolox abrogated preconditioning potency of anesthetics and attenuated flavoprotein oxidation.Preconditioning with desflurane or sevoflurane protects isolated rat cardiomyocytes from oxidative stress-induced cell death. Scavenging of ROS abolishes the preconditioning effect of both anesthetics and attenuates anesthetic-induced mitochondrial uncoupling, suggesting a crucial role for ROS in anesthetic-induced preconditioning and implying that ROS act upstream of mitochondrial uncoupling. Desflurane exhibits greater effect on stimulation of ROS production and mitochondrial uncoupling than sevoflurane.

Desflurane

Mitochondrial ROS

Trolox

10.1213/ane.0b013e3181a93ad9

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Citations (69)

Salivary Interleukin-13 and Transforming Growth Factor Beta as Potential Biomarkers of Cancer Cachexia

Cancers (2024)

Borislav Belev Ivan Vičić Filip Sedlić Matko Prtorić Majana Soče

Cancer cachexia is a syndrome characterized by weight and muscle loss and functional impairment, strongly influencing survival in cancer patients. In this study, we aimed to establish the role of saliva cytokine measurement in cancer cachexia investigation and define two potential independent salivary biomarkers of the condition.

10.3390/cancers16173035

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Citations (1)

Differentiating Between Malignant Mesothelioma and Other Pleural Lesions Using Fourier Transform Infrared Spectroscopy

Applied Spectroscopy (2020)

Fatlinda Sadiku-Zehri Ozren Gamulin Marko Škrabić Ardita Qerimi-Krasniqi Filip Sedlić

Histopathology, despite being the gold standard as a diagnostic tool, does not always provide a correct diagnosis for different pleural lesions. Although great progress was made in this field, the problem to differentiate between reactive and malignant pleural lesions still stimulates the search for additional diagnostic tools. Our research using vibrational spectroscopy and principal component analysis (PCA) statistical modeling represents a potentially useful tool to approach the problem. The objective method this paper explores is based on the correlation between different types of pleural lesions and their vibrational spectra. Obtained tissue spectra recorded by infrared spectroscopy allowed us to categorize spectra in different groups using a created PCA statistical model. The PCA model was built using tissues of known pathology as the model group. The validation samples were then used to confirm the functionality of our PCA model. Student’s t-test was also used for comparing samples in paired groups. The PCA model was able to clearly differentiate the spectra of mesothelioma, metastasis and reactive changes (inflammation), and place them in discrete groups. Thus, we showed that Fourier transform infrared spectroscopy combined with PCA can differentiate pleural lesions with high sensitivity and specificity. This new approach could contribute in objectively differentiating specific pleural lesions, thus helping pathologists to better diagnose difficult pleural samples but also could shed additional light into the biology of malignant pleural mesothelioma.

Histopathology

Gold standard (test)

10.1177/0003702820924726

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Prognostic value of circulating Bcl-2 and anti-p53 antibodies in patients with breast cancer: A long term follow-up (17.5 years)

Cancer Biomarkers (2020)

Maja Sirotković-Skerlev Natalija Dedić Plavetić Filip Sedlić Sanja Kusačić Kuna Damir Vrbanec

Apoptosis inhibition is a major tumorigenic factor. Bcl-2 dysregulation and TP53 mutation status, which may correlate with autoantibody generation, contribute to impaired apoptosis.This study aimed to investigate the prognostic value of circulating Bcl-2 and anti-p53 antibodies (p53Abs) in a 17.5-year follow-up of breast cancer patients. We also analyzed the correlations of Bcl-2 and p53Abs with various clinicopathological parameters in order to assess their impact on tumor aggressiveness.Serum Bcl-2 and p53Abs levels were analyzed by the enzyme-linked immunosorbent assay (ELISA) in 82 patients with invasive breast cancer and twenty individuals without malignancy.Serum Bcl-2 and p53Abs levels in breast cancer patients were significantly higher than those in controls. Patients with high levels of Bcl-2 (cut-off 200 U/ml) had a poorer prognosis (17.5-year survival) than those with lower Bcl-2 values. In combined analysis the subgroup of patients with elevated p53Abs (cut-off 15 U/ml) and elevated Bcl-2 (cut-offs 124 U/ml and 200 U/ml) had the worse prognosis in 17.5-year survival. In correlation analysis p53Abs and Bcl-2 were associated with unfavorable clinicopathological parameters.Our results suggest that breast cancer patients with high serum levels of p53Abs and Bcl-2 present an especially unfavorable group in a long follow-up.

10.3233/cbm-201497

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Citations (9)

Complex I and ATP synthase mediate membrane depolarization and matrix acidification by isoflurane in mitochondria

European Journal of Pharmacology (2012)

Danijel Pravdić Naoyuki Hirata Lauren E. Barber Filip Sedlić Zeljko J. Bosnjak

Oligomycin

Mitochondrial matrix

10.1016/j.ejphar.2012.07.003

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Citations (28)