Publications by authors named "Zornitza Mladenova"

196 Publications

A survey of the knowledge, perceptions of and attitudes to digital health of healthcare professionals in 14 Bulgarian hospitals: First large-scale study on digital health in Bulgarian inpatient facilities.

Authors:
Damyan Petrov Mila Petrova Irena Mladenova Nedko Dimitrov Galina Mratskova

Digit Health 2023 1;9:20552076231185276. Epub 2023 Aug 1.

Department of Physical and Rehabilitation Medicine, Medical Faculty, Trakia University, Stara Zagora, Bulgaria.

Objective: To explore the knowledge, perceptions of and attitudes to digital health of Bulgarian hospital professionals in the first study of digital health in this professional group.

Methods: A paper-based questionnaire was administered to doctors, trainee doctors, nurses, midwives, and laboratory assistants working in multiprofile or specialized hospitals. Topics included the following: state, objectives, benefits, and future of digital health; data storage, access, security, and sharing; main software used; patient-held Personal Information System (PIS); and telemedicine. A total of 1187 participants from 14 hospitals completed the survey in two phases: September 2013-April 2014 and May 2015-April 2017. Data were analyzed through descriptive statistics and multilevel logistic regression.

Results: Three-quarters of participants evaluated the state of development of digital health in Bulgaria as subpar (36.0% negative; 38.9% passable; 24.5% positive). 27.2% (323) endorsed patients having unconditional access to their data. In contrast, 89.5% (1062) of participants considered it appropriate to have full access to patient data recorded by colleagues. Doctors were more likely to endorse patients having access to their data than healthcare specialists (OR = 1.79 at facility, OR = 1.77 at location).

Conclusion: The largely negative or lukewarm attitudes toward the state of development of digital health in Bulgaria are likely to result from the high number of failed projects, unmet expectations, misunderstood benefits, and unforeseen challenges. This study provides a much-needed stimulus and baseline for researching the ways in which the digital health landscape in Bulgaria has matured-or not.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10399259PMC
http://dx.doi.org/10.1177/20552076231185276DOI Listing
August 2023

Epidemiology of Resistance to Antibiotics (A Narrative Review).

Authors:
Irena Mladenova

Antibiotics (Basel) 2023 Jul 13;12(7). Epub 2023 Jul 13.

Department of Hygiene, Epidemiology, Microbiology, Parasitology and Infectious Diseases, Medical Faculty, Trakia University, 6000 Stara Zagora, Bulgaria.

() is the most common bacterial infection worldwide and one of the main etiological factors of chronic gastritis, peptic ulcer disease, and stomach neoplasms. The mass application of antibiotics without testing, especially during the last years of the pandemic of SARS-CoV-2, could lead to a dramatic increase in antibiotic resistance and reduced effectiveness of eradication regimens for infection. The epidemiology of resistance to antibiotics still has unclear mechanisms. Antibiotic policy should be intensified to optimize treatment, and regular monitoring of resistance of in different geographical regions should be conducted. Individualized treatment according to susceptibility testing is strongly advisable, and the best treatment regimens should be selected. The mutations in the genes encoding the antibiotic target protein are significant risk factors for resistance. Iatrogenic errors in diagnosis and prescribing treatment for the failure of eradication are other important risk factors. The low level of awareness and compliance with the correct treatment influence the rate of resistance. Epidemiological surveillance of antibiotic resistance and the adoption of new treatment strategies are needed. The discovery of an efficient vaccine against could reduce the pressure of the world's growing antibiotic resistance.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10376713PMC
http://dx.doi.org/10.3390/antibiotics12071184DOI Listing
July 2023

Green Synthesis and the Evaluation of a Functional Amphiphilic Block Copolymer as a Micellar Curcumin Delivery System.

Authors:
Radostina Kalinova Georgy Grancharov Jordan Doumanov Kirilka Mladenova Svetla Petrova Ivaylo Dimitrov

Int J Mol Sci 2023 Jun 24;24(13). Epub 2023 Jun 24.

Institute of Polymers, Bulgarian Academy of Sciences, Akad. G. Bonchev St., bl. 103-A, 1113 Sofia, Bulgaria.

Polymer micelles represent one of the most attractive drug delivery systems due to their design flexibility based on a variety of macromolecular synthetic methods. The environmentally safe chemistry in which the use or generation of hazardous materials is minimized has an increasing impact on polymer-based drug delivery nanosystems. In this work, a solvent-free green synthetic procedure was applied for the preparation of an amphiphilic diblock copolymer consisting of biodegradable hydrophobic poly(acetylene-functional carbonate) and biocompatible hydrophilic polyethylene glycol (PEG) blocks. The cyclic functional carbonate monomer 5-methyl-5-propargyloxycarbonyl-1,3-dioxane-2-one (MPC) was polymerized in bulk using methoxy PEG-5K as a macroinitiator by applying the metal-free organocatalyzed controlled ring-opening polymerization at a relatively low temperature of 60 °C. The functional amphiphilic block copolymer self-associated in aqueous media into stable micelles with an average diameter of 44 nm. The copolymer micelles were physico-chemically characterized and loaded with the plant-derived anticancer drug curcumin. Preliminary in vitro evaluations indicate that the functional copolymer micelles are non-toxic and promising candidates for further investigation as nanocarriers for biomedical applications.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10342159PMC
http://dx.doi.org/10.3390/ijms241310588DOI Listing
June 2023

Environmentally Benign pSOFC for Emissions-Free Energy: Assessment of Nickel Network Resistance in Anodic Ni/BCY15 Nanocatalyst.

Authors:
Margarita Gabrovska Dimitrinka Nikolova Hristo Kolev Daniela Karashanova Peter Tzvetkov Blagoy Burdin Emiliya Mladenova Daria Vladikova Tatyana Tabakova

Nanomaterials (Basel) 2023 May 31;13(11). Epub 2023 May 31.

Institute of Catalysis, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.

Yttrium-doped barium cerate (BCY15) was used as ceramic matrix to obtain Ni/BCY15 anode cermet for application in proton-conducting solid oxide fuel cells (pSOFC). Ni/BCY15 cermets were prepared in two different types of medium, namely deionized water (W) and anhydrous ethylene glycol (EG) using wet chemical synthesis by hydrazine. An in-depth analysis of anodic nickel catalyst was made aiming to elucidate the effect of anode tablets' preparation by high temperature treatment on the resistance of metallic Ni in Ni/BCY15-W and Ni/BCY15-EG anode catalysts. On purpose reoxidation upon high-temperature treatment (1100 °C for 1 h) in air ambience was accomplished. Detailed characterization of reoxidized Ni/BCY15-W-1100 and Ni/BCY15-EG-1100 anode catalysts by means of surface and bulk analysis was performed. XPS, HRTEM, TPR, and impedance spectroscopy measurements experimentally confirmed the presence of residual metallic Ni in the anode catalyst prepared in ethylene glycol medium. These findings were evidence of strong metal Ni network resistance to oxidation in anodic Ni/BCY15-EG. Enhanced resistance of the metal Ni phase contributed to a new microstructure of the Ni/BCY15-EG-1100 anode cermet getting more stable to changes that cause degradation during operation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10254282PMC
http://dx.doi.org/10.3390/nano13111781DOI Listing
May 2023

Three-Dimensional Nucleic Acid Nanostructures Based on Self-Assembled Polymer-Oligonucleotide Conjugates of Comblike and Coil-Comb Chain Architectures.

Authors:
Erik Dimitrov Natalia Toncheva-Moncheva Jordan A Doumanov Kirilka Mladenova Svetla Petrova Stergios Pispas Stanislav Rangelov

Biomacromolecules 2023 May 4;24(5):2213-2224. Epub 2023 Apr 4.

Institute of Polymers, Bulgarian Academy of Sciences, Akad. G. Bonchev St. 103A, 1113 Sofia, Bulgaria.

Spherical nucleic acids have emerged as a class of nanostructures, exhibiting a wide variety of properties, distinctly different from those of linear nucleic acids, and a plethora of applications in therapeutics and diagnostics. Herein, we report on preparation of 3D nucleic acid nanostructures, prepared by self-assembly of polymer-oligonucleotide conjugates. The latter are obtained by grafting multiple alkyne-functionalized oligonucleotide strands onto azide-modified homo-, block, and random (co)polymers of chloromethylstyrene via initiator-free click coupling chemistry to form conjugates of comblike and coil-comb chain architectures. The resulting conjugates are amphiphilic and form stable nanosized supramolecular structures in aqueous solution. The nanoconstructs are thoroughly investigated and a number of physical characteristics, in particular, molar mass, size, aggregation number, zeta potential, material density, number of oligonucleotide strands per particle, grafting density, and their relation to hallmark properties of spherical nucleic acids - biocompatibility, resistance against DNase I, cellular uptake without the need for transfection agents - are determined.
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http://dx.doi.org/10.1021/acs.biomac.3c00126DOI Listing
May 2023

Effect of Gamma Irradiation on Fat Content, Fatty Acids, Antioxidants and Oxidative Stability of Almonds, and Electron Paramagnetic Resonance (EPR) Study of Treated Nuts.

Authors:
Svetlana Momchilova Adriana Kazakova Sabina Taneva Katerina Aleksieva Ralitsa Mladenova Yordanka Karakirova Zhanina Petkova Mariana Kamenova-Nacheva Desislava Teneva Petko Denev

Molecules 2023 Feb 2;28(3). Epub 2023 Feb 2.

Laboratory of Biologically Active Substances, Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, 139 Ruski Blvd., 4000 Plovdiv, Bulgaria.

Gamma irradiation has been applied as an efficient and inexpensive method for the sterilization of nuts for years. However, along with the benefits of such treatment, negative effects are possible because of the formation of reactive oxygen species with a toxic effect on important biologically active substances. Because of the scarce and contradictory information in the literature about gamma-irradiated almonds, the aim of our work was the examination of the lipid changes, antioxidant activity, and oxidative stability of almonds treated by 10 and 25 kGy gamma rays, as well as changes in intensity of the EPR spectra as an indicator for the stability of radiation-induced free radicals. The results revealed no significant differences in the EPR spectra of almonds treated at 10 and 25 kGy doses, neither in their intensity nor in kinetic behaviour. The EPR signals decayed exponentially over 250 days, with a decreasing of central line by 90%, with satellite lines by about 73%. No significant changes in the fat content, fatty acids composition, and acid value of irradiated almonds were observed. However, the amount of (alpha)tocopherols decreased from 292 to 175 mg/kg, whereas the conjugated dienes and trienes increased, K from 1.3 to 3 and K from 0.04 to 0.15, respectively, with the increasing of irradiation dose. The same was observed for total polyphenols in defatted almonds (1374 to 1520 mg/100 g), where in vitro antioxidant activity determined by ORAC and HORAC methods increased from 100 to 156 µmol TE/g and from 61 to 86 µmol GAE/g, respectively. The oxidative stability of oil decreased from 6 to 4 h at 120 °C and from 24.6 to 18.6 h at 100 °C (measured by Rancimat equipment). The kinetic parameters characterizing the oxidative stability of oil from 10 kGy irradiated almonds were studied before and after addition of different concentrations of ascorbyl palmitate as a synergist of tocopherols. Its effectiveness was concentration-dependent, and 0.75 mM ensured the same induction period as that of non-irradiated nut oil. Further enrichment with alpha-tocopherol in equimolar ratio with palmitate did not improve the oil stability. In conclusion, gamma irradiation is an appropriate method for the treatment of almonds without significant changes in fat content and fatty acids composition. The decreasing of oxidative stability after higher irradiation could be prevented by the addition of ascorbyl palmitate.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9920200PMC
http://dx.doi.org/10.3390/molecules28031439DOI Listing
February 2023

Nanoarchitectonics of Spherical Nucleic Acids with Biodegradable Polymer Cores: Synthesis and Evaluation.

Authors:
Radostina Kalinova Kirilka Mladenova Svetla Petrova Jordan Doumanov Ivaylo Dimitrov

Materials (Basel) 2022 Dec 13;15(24). Epub 2022 Dec 13.

Institute of Polymers, Bulgarian Academy of Sciences, Akad. G. Bonchev St., bl. 103-A, 1113 Sofia, Bulgaria.

Spherical nucleic acids (SNAs) have gained significant attention due to their unique properties allowing them to overcome the challenges that face current nanocarriers used for gene therapies. The aim of this study is to synthesize and characterize polymer-oligonucleotide conjugates of different architecture and to evaluate the possibility of forming SNAs with biodegradable cores. Initially, two types of azide (multi)functional polyester-based (co)polymers were successfully synthesized and characterized. In the next step, short oligonucleotide strands were attached to the polymer chains applying the highly efficient and metal-free "click" reaction, thus forming conjugates with block or graft architecture. Both conjugates spontaneously self-assembled in aqueous media forming nanosized SNAs with a biodegradable polyester core and a surface of oligonucleotide chains as evidenced from dynamic and electrophoretic light scattering measurements. The nano-assemblies were in vitro evaluated for potential cytotoxicity. Furthermore, the interactions of the newly synthesized SNAs with membrane lipids were studied. The preliminary results indicate that both types of polymer-based SNAs are good candidates for potential application in gene therapy and that it is worth to be further evaluated.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9786340PMC
http://dx.doi.org/10.3390/ma15248917DOI Listing
December 2022

BMN673 Is a PARP Inhibitor with Unique Radiosensitizing Properties: Mechanisms and Potential in Radiation Therapy.

Authors:
Aashish Soni Xixi Lin Emil Mladenov Veronika Mladenova Martin Stuschke George Iliakis

Cancers (Basel) 2022 Nov 16;14(22). Epub 2022 Nov 16.

Division of Experimental Radiation Biology, Department of Radiation Therapy, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.

BMN673 is a relatively new PARP inhibitor (PARPi) that exhibits superior efficacy in vitro compared to olaparib and other clinically relevant PARPi. BMN673, similar to most clinical PARPi, inhibits the catalytic activities of PARP-1 and PARP-2 and shows impressive anticancer potential as monotherapy in several pre-clinical and clinical studies. Tumor resistance to PARPi poses a significant challenge in the clinic. Thus, combining PARPi with other treatment modalities, such as radiotherapy (RT), is being actively pursued to overcome such resistance. However, the modest to intermediate radiosensitization exerted by olaparib, rucaparib, and veliparib, limits the rationale and the scope of such combinations. The recently reported strong radiosensitizing potential of BMN673 forecasts a paradigm shift on this front. Evidence accumulates that BMN673 may radiosensitize via unique mechanisms causing profound shifts in the balance among DNA double-strand break (DSB) repair pathways. According to one of the emerging models, BMN673 strongly inhibits classical non-homologous end-joining (c-NHEJ) and increases reciprocally and profoundly DSB end-resection, enhancing error-prone DSB processing that robustly potentiates cell killing. In this review, we outline and summarize the work that helped to formulate this model of BMN673 action on DSB repair, analyze the causes of radiosensitization and discuss its potential as a radiosensitizer in the clinic. Finally, we highlight strategies for combining BMN673 with other inhibitors of DNA damage response for further improvements.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9688666PMC
http://dx.doi.org/10.3390/cancers14225619DOI Listing
November 2022

Original Synthesis of a Nucleolipid for Preparation of Vesicular Spherical Nucleic Acids.

Authors:
Erik Dimitrov Natalia Toncheva-Moncheva Pavel Bakardzhiev Aleksander Forys Jordan Doumanov Kirilka Mladenova Svetla Petrova Barbara Trzebicka Stanislav Rangelov

Nanomaterials (Basel) 2022 Oct 18;12(20). Epub 2022 Oct 18.

Institute of Polymers, Bulgarian Academy of Sciences, Akad. G. Bonchev St. 103A, 1113 Sofia, Bulgaria.

Spherical nucleic acids (SNAs)-nanostructures, consisting of a nanoparticle core densely functionalized with a shell of short oligonucleotide strands-are a rapidly emerging class of nanoparticle-based therapeutics with unique properties and specific applications as drug and nucleic acid delivery and gene regulation materials. In this contribution, we report on the preparation of hollow SNA nanoconstructs by co-assembly of an originally synthesized nucleolipid-a hybrid biomacromolecule, composed of a lipidic residue, covalently linked to a DNA oligonucleotide strand-with other lipids. The nucleolipid was synthesized via a chemistry approach employing initiator-free, UV light-induced thiol-ene coupling of appropriately functionalized intermediates, performed in mild conditions using a custom-made UV light-emitting device. The SNA nanoconstructs were of a vesicular structure consisting of a self-closed bilayer membrane in which the nucleolipid was intercalated via its lipid-mimetic residue. They were in the lower nanometer size range, moderately negatively charged, and were found to carry thousands of oligonucleotide strands per particle, corresponding to a grafting density comparable to that of other SNA structures. The surface density of the strands on the bilayer implied that they adopted an unextended conformation. We demonstrated that preformed vesicular structures could be successfully loaded with either hydrophilic or hydrophobic dyes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9609631PMC
http://dx.doi.org/10.3390/nano12203645DOI Listing
October 2022

The high toxicity of DSB-clusters modelling high-LET-DNA damage derives from inhibition of c-NHEJ and promotion of alt-EJ and SSA despite increases in HR.

Authors:
Veronika Mladenova Emil Mladenov Shipra Chaudhary Martin Stuschke George Iliakis

Front Cell Dev Biol 2022 3;10:1016951. Epub 2022 Oct 3.

Department of Radiation Therapy, Division of Experimental Radiation Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Heavy-ion radiotherapy utilizing high linear energy transfer (high-LET) ionizing radiation (IR) is a promising cancer treatment modality owing to advantageous physical properties of energy deposition and associated toxicity over X-rays. Therapies utilizing high-LET radiation will benefit from a better understanding of the molecular mechanisms underpinning their increased biological efficacy. Towards this goal, we investigate here the biological consequences of well-defined clusters of DNA double-strand breaks (DSBs), a form of DNA damage, which on theoretical counts, has often been considered central to the enhanced toxicity of high-LET IR. We test clonal cell lines harboring in their genomes constructs with appropriately engineered I-SceI recognition sites that convert upon I-I expression to individual DSBs, or DSB-clusters comprising known numbers of DSBs with defined DNA-ends. We find that, similarly to high-LET IR, DSB-clusters of increasing complexity, i.e. increasing numbers of DSBs, with compatible or incompatible ends, compromise classical non-homologous end-joining, favor DNA end-resection and promote resection-dependent DSB-processing. Analysis of RAD51 foci shows increased engagement of error-free homologous recombination on DSB-clusters. Multicolor fluorescence hybridization analysis shows that complex DSB-clusters markedly increase the incidence of structural chromosomal abnormalities (SCAs). Since RAD51-knockdown further increases SCAs-incidence, we conclude that homologous recombination suppresses SCAs-formation. Strikingly, CtIP-depletion inhibits SCAs-formation, suggesting that it relies on alternative end-joining or single-strand annealing. Indeed, ablation of RAD52 causes a marked reduction in SCAs, as does also inhibition of PARP1. We conclude that increased DSB-cluster formation that accompanies LET-increases, enhances IR-effectiveness by promoting DNA end-resection, which suppresses c-NHEJ and enhances utilization of alt-EJ or SSA. Although increased resection also favors HR, on balance, error-prone processing dominates, causing the generally observed increased toxicity of high-LET radiation. These findings offer new mechanistic insights into high-LET IR-toxicity and have translational potential in the clinical setting that may be harnessed by combining high-LET IR with inhibitors of PARP1 or RAD52.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9574094PMC
http://dx.doi.org/10.3389/fcell.2022.1016951DOI Listing
October 2022

Nucleic acid-based supramolecular structures: vesicular spherical nucleic acids from a non-phospholipid nucleolipid.

Authors:
Erik Dimitrov Natalia Toncheva-Moncheva Pavel Bakardzhiev Aleksander Forys Jordan Doumanov Kirilka Mladenova Svetla Petrova Barbara Trzebicka Stanislav Rangelov

Nanoscale Adv 2022 Sep 9;4(18):3793-3803. Epub 2022 Aug 9.

Institute of Polymers, Bulgarian Academy of Sciences Akad. G. Bonchev St. 103A 1113 Sofia Bulgaria

Vesicular spherical nucleic acids are dynamic nucleic acid-based supramolecular structures that are held together non-covalent bonds. They have promising applications as drug and nucleic acid delivery materials, diagnostic and imaging tools and platforms for development of various therapeutic schemes. In this contribution, we report on vesicular spherical nucleic acids, constructed from a non-phospholipid nucleolipid - an original hybrid biomacromolecule, composed of a hydrophobic residue, resembling that of the naturally occurring phospholipids, and a DNA oligonucleotide strand. The nucleolipid was synthesized by coupling of dibenzocyclooctyne-functionalized oligonucleotide and azidated 1,3-dihexadecyloxy-propane-2-ol an azide-alkyne reaction. In aqueous solution it spontaneously self-associated into nanosized supramolecular structures, identified as unilamellar vesicles composed of a self-closed bilayer. Vesicular structures were also formed upon intercalation of the nucleolipid its lipid-mimetic residue in the phospholipid bilayer membrane of liposomes prepared from readily available and FDA-approved lipids (1,2-dipalmitoyl--3-phosphocholine and cholesterol). The vesicular structures are thoroughly investigated by light scattering (dynamic, static, and electrophoretic) and cryogenic TEM and the physical characteristics, in particular, number of strands per particle, grafting density, and conformation of the strands, were compared to those of reference spherical nucleic acids. Finally, the vesicular structures were shown to exhibit cellular internalization with no need of transfection agents and enhanced colloidal and nuclease stability.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9470030PMC
http://dx.doi.org/10.1039/d2na00527aDOI Listing
September 2022

Increased Gene Targeting in Hyper-Recombinogenic LymphoBlastoid Cell Lines Leaves Unchanged DSB Processing by Homologous Recombination.

Authors:
Emil Mladenov Katja Paul-Konietzko Veronika Mladenova Martin Stuschke George Iliakis

Int J Mol Sci 2022 Aug 16;23(16). Epub 2022 Aug 16.

Division of Experimental Radiation Biology, Department of Radiation Therapy, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.

In the cells of higher eukaryotes, sophisticated mechanisms have evolved to repair DNA double-strand breaks (DSBs). Classical nonhomologous end joining (c-NHEJ), homologous recombination (HR), alternative end joining (alt-EJ) and single-strand annealing (SSA) exploit distinct principles to repair DSBs throughout the cell cycle, resulting in repair outcomes of different fidelity. In addition to their functions in DSB repair, the same repair pathways determine how cells integrate foreign DNA or rearrange their genetic information. As a consequence, random integration of DNA fragments is dominant in somatic cells of higher eukaryotes and suppresses integration events at homologous genomic locations, leading to very low gene-targeting efficiencies. However, this response is not universal, and embryonic stem cells display increased targeting efficiency. Additionally, lymphoblastic chicken and human cell lines DT40 and NALM6 show up to a 1000-fold increased gene-targeting efficiency that is successfully harnessed to generate knockouts for a large number of genes. We inquired whether the increased gene-targeting efficiency of DT40 and NALM6 cells is linked to increased rates of HR-mediated DSB repair after exposure to ionizing radiation (IR). We analyzed IR-induced γ-H2AX foci as a marker for the total number of DSBs induced in a cell and RAD51 foci as a marker for the fraction of those DSBs undergoing repair by HR. We also evaluated RPA accretion on chromatin as evidence for ongoing DNA end resection, an important initial step for all pathways of DSB repair except c-NHEJ. We finally employed the DR-GFP reporter assay to evaluate DSB repair by HR in DT40 cells. Collectively, the results obtained, unexpectedly show that DT40 and NALM6 cells utilized HR for DSB repair at levels very similar to those of other somatic cells. These observations uncouple gene-targeting efficiency from HR contribution to DSB repair and suggest the function of additional mechanisms increasing gene-targeting efficiency. Indeed, our results show that analysis of the contribution of HR to DSB repair may not be used as a proxy for gene-targeting efficiency.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409177PMC
http://dx.doi.org/10.3390/ijms23169180DOI Listing
August 2022

Helicobacter pylori eradication in elderly patients: can we assume that a bismuth-based therapy is effective as in young people?

Authors:
Irena Mladenova

Panminerva Med 2022 Jun;64(2):289

Medical Faculty, Department of Hygiene, Epidemiology and Infectious Diseases, Faculty of Medicine, Trakia University, Stara Zagora, Bulgaria -

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http://dx.doi.org/10.23736/S0031-0808.22.04664-XDOI Listing
June 2022

Antitumor and Immunomodulatory Properties of the Bulgarian Endemic Plant Degen et Neič. (Lamiaceae).

Authors:
Tsvetelina Mladenova Tsvetelina Batsalova Balik Dzhambazov Rumen Mladenov Ivanka Teneva Plamen Stoyanov Anelia Bivolarska

Plants (Basel) 2022 Jun 26;11(13). Epub 2022 Jun 26.

Department of Medical Biochemistry, Faculty of Pharmacy, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria.

Extracts obtained from different species have been shown to possess important biological properties. The present study aimed to investigate the cytotoxicity, antitumor and immunomodulatory potential of the endemic plant (Lamiaceae) and thus, reveal new aspects of its biological activity. Methanolic extract obtained from inflorescences was analyzed for cytotoxicity against mammalian cell lines. The antitumor potential of the sample was determined using human cervical and lung adenocarcinoma cells (HeLa and A549). Programmed cell death-inducing effects against HeLa cells and peripheral blood lymphocytes, as well as immunomodulatory properties of the extract were determined by flow cytometry analysis. The research results demonstrated that the extract has significant inhibitory potential against HeLa cells (mean IC value 119.2 μg/mL). The sample selectively induced apoptotic death in tumor cells. Cytotoxic effects towards mouse cell lines were detected following treatment with high concentrations of extract (200 and 250 μg/mL). Twenty-four-hour ex vivo incubation of peripheral blood leucocytes in growth medium containing plant extract induced prominent effects in distinct immune cell populations. They included elevated levels of CD25 and CD56 T cells' lymphocytes, particularly CD4CD25 and CD8CD56 cells. The present study demonstrates that inflorescence extract possesses potential beneficial antitumor and immunomodulatory activity and could serve as a source of bioactive compounds with biomedical application.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268963PMC
http://dx.doi.org/10.3390/plants11131689DOI Listing
June 2022

Cholesterol Alters the Phase Separation in Model Membranes Containing hBest1.

Authors:
Pavel Videv Kirilka Mladenova Tonya D Andreeva Jong Hun Park Veselina Moskova-Doumanova Svetla D Petrova Jordan A Doumanov

Molecules 2022 Jul 2;27(13). Epub 2022 Jul 2.

Faculty of Biology, Sofia University "St. Kliment Ohridski", 8 Dragan Tzankov Str., 1164 Sofia, Bulgaria.

Human retinal pigment epithelial (RPE) cells express the transmembrane Ca-dependent Cl channel bestrophin-1 (hBest1) of the plasma membrane. Mutations in the hBest1 protein are associated with the development of distinct pathological conditions known as bestrophinopathies. The interactions between hBest1 and plasma membrane lipids (cholesterol (Chol), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and sphingomyelin (SM)) determine its lateral organization and surface dynamics, i.e., their miscibility or phase separation. Using the surface pressure/mean molecular area (π/A) isotherms, hysteresis and compressibility moduli (C) of hBest1/POPC/Chol and hBest1/SM/Chol composite Langmuir monolayers, we established that the films are in an LE (liquid-expanded) or LE-LC (liquid-condensed) state, the components are well-mixed and the Ca ions have a condensing effect on the surface molecular organization. Cholesterol causes a decrease in the elasticity of both films and a decrease in the ΔG values (reduction of phase separation) of hBest1/POPC/Chol films. For the hBest1/SM/Chol monolayers, the negative values of ΔG are retained and equalized with the values of ΔG in the hBest1/POPC/Chol films. Shifts in phase separation/miscibility by cholesterol can lead to changes in the structure and localization of hBest1 in the lipid rafts and its channel functions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268032PMC
http://dx.doi.org/10.3390/molecules27134267DOI Listing
July 2022

Health-Related Quality of Life following Surgery for Native and Prosthetic Valve Infective Endocarditis.

Authors:
Shekhar Saha Ralitsa Mladenova Caroline Radner Konstanze Maria Horke Joscha Buech Philipp Schnackenburg Ahmad Ali Sven Peterss Gerd Juchem Maximilian Luehr Christian Hagl Dominik Joskowiak

J Clin Med 2022 Jun 22;11(13). Epub 2022 Jun 22.

Department of Cardiac Surgery, Ludwig Maximillian University of Munich, 81377 Munich, Germany.

Objectives: The objective of this study was to compare the long-term outcomes and health-related quality of life (HRQOL) of patients following surgery for infective native valve endocarditis (NVE) and prosthetic valve endocarditis (PVE).

Methods: We retrospectively identified 633 consecutive patients who had undergone surgery for infective endocarditis at our center between January 2005 and October 2018. The patients were interviewed, and the SF-36 survey was used to assess the HRQOL of survivors. Propensity score matching (2:1) was performed with data from a German reference population. Multivariable analysis incorporated binary logistic regression using a forward stepwise (conditional) model.

Results: The median age of the cohort was 67 (55-74) years, and 75.6% were male. Operative mortality was 13.7% in the NVE group and 21.6% in the PVE group ( = 0.010). The overall survival at 1 year was 88.0% and was comparable between the groups. The physical health summary scores were 49 (40-55) for the NVE patients and 45 (37-52) for the PVE patients ( = 0.043). The median mental health summary scores were 52 (35-57) and 49 (41-56), respectively ( = 0.961). On comparison of the HRQOL to the reference population, the physical health summary scores were comparable. However, significant differences were observed with regard to the mental health summary scores ( = 0.005).

Conclusions: Our study shows that there are significant differences in the various domains of HRQOL, not only between NVE and PVE patients, but also in comparison to healthy individuals. In addition to preoperative health status, it is important to consider the patient's expectations regarding surgery. Further prospective studies are required.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9267565PMC
http://dx.doi.org/10.3390/jcm11133599DOI Listing
June 2022

Increased Resection at DSBs in G-Phase Is a Unique Phenotype Associated with DNA-PKcs Defects That Is Not Shared by Other Factors of c-NHEJ.

Authors:
Huaping Xiao Fanghua Li Emil Mladenov Aashish Soni Veronika Mladenova Bing Pan Rositsa Dueva Martin Stuschke Beate Timmermann George Iliakis

Cells 2022 Jul 2;11(13). Epub 2022 Jul 2.

Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.

The load of DNA double-strand breaks (DSBs) induced in the genome of higher eukaryotes by different doses of ionizing radiation (IR) is a key determinant of DSB repair pathway choice, with homologous recombination (HR) and ATR substantially gaining ground at doses below 0.5 Gy. Increased resection and HR engagement with decreasing DSB-load generate a conundrum in a classical non-homologous end-joining (c-NHEJ)-dominated cell and suggest a mechanism adaptively facilitating resection. We report that ablation of DNA-PKcs causes hyper-resection, implicating DNA-PK in the underpinning mechanism. However, hyper-resection in -deficient cells can also be an indirect consequence of their c-NHEJ defect. Here, we report that all tested mutants show hyper-resection, while mutants with defects in all other factors of c-NHEJ fail to do so. This result rules out the model of c-NHEJ versus HR competition and the passive shift from c-NHEJ to HR as the causes of the increased resection and suggests the integration of DNA-PKcs into resection regulation. We develop a model, compatible with the results of others, which integrates DNA-PKcs into resection regulation and HR for a subset of DSBs. For these DSBs, we propose that the kinase remains at the break site, rather than the commonly assumed autophosphorylation-mediated removal from DNA ends.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9265841PMC
http://dx.doi.org/10.3390/cells11132099DOI Listing
July 2022

Anti-adipogenic activity of maackiain and ononin is mediated via inhibition of PPARγ in human adipocytes.

Authors:
Saveta G Mladenova Martina S Savova Andrey S Marchev Claudio Ferrante Giustino Orlando Martin Wabitsch Milen I Georgiev

Biomed Pharmacother 2022 May 1;149:112908. Epub 2022 Apr 1.

Department of Plant Cell Biotechnology, Center of Plant Systems Biology and Biotechnology, 4000, Plovdiv, Bulgaria; Laboratory of Metabolomics, Department of Biotechnology, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 139 Ruski Blvd, 4000 Plovdiv, Bulgaria. Electronic address:

Obesity is a global health burden for which we do not yet have effective treatments for prevention or therapy. Plants are an invaluable source of bioactive leads possessing anti-adipogenic potential. Ethnopharmacological use of Ononis spinosa L. roots (OSR) for treatment of obesity and metabolic disorders requires а scientific rationale. The current study examined the anti-adipogenic capacity of OSR and its secondary metabolites ononin (ONON) and maackiain (MACK) in human adipocytes as an in vitro model of obesity. Both ONON and MACK diminished lipid accumulation during adipocyte differentiation. Molecular docking analysis exposed the potential interactions between MACK or ONON and target regulatory adipogenic proteins. Furthermore, results from an RT-qPCR analysis disclosed significant upregulation of AMPK by MACK and ONON treatment. In addition, ONON increased SIRT1, PI3K and ACC mRNA expression, while MACK notably downregulated CEBPA, AKT, SREBP1, ACC and ADIPOQ. The protein level of PI3K, C/EBPα, PPARγ and adiponectin was reduced upon MACK treatment in a concentration-dependent manner. Similarly, ONON suppressed PI3K, PPARγ and adiponectin protein abundance. Finally, our study provides evidence that ONON exerts anti-adipogenic effect by upregulation of SIRT1 and inhibition of PI3K, PPARγ and adiponectin, while MACK induced strong inhibitory effect on adipogenesis via hampering PI3K, PPARγ/C/EBPα signaling and anti-lipogenic effect through downregulation of SREBP1 and ACC. Even though OSR does not hamper adipogenic differentiation, it could be exploited as a source of natural leads with anti-adipogenic potential. The multidirectional mechanism of action of MACK warrant further validation in the context of in vivo obesity models.
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http://dx.doi.org/10.1016/j.biopha.2022.112908DOI Listing
May 2022

Design of an Epitope-Based Peptide Vaccine Against the Major Allergen Amb a 11 Using Immunoinformatic Approaches.

Authors:
Dzhemal Moten Desislava Kolchakova Krasimir Todorov Tsvetelina Mladenova Balik Dzhambazov

Protein J 2022 Apr 1;41(2):315-326. Epub 2022 Apr 1.

Department of Developmental Biology, Faculty of Biology, University of Plovdiv "Paisii Hilendarski", 24 Tsar Assen Str., 4000, Plovdiv, Bulgaria.

Allergic diseases are a socially significant problem of global importance. The number of people suffering from pollen allergies has increased dramatically in recent decades. Pollen allergies affect up to 30% of the world population. Pollen of the common ragweed (Ambrosia artemisiifolia L.) is one of the most aggressive allergens in the world. We have used a series of immunoinformatics approaches to design an effective epitope-based vaccine, which might induce a competent immunity against a major allergen Amb a 11. CD8+ and CD4+ T-cell epitopes and their corresponding MHC restricted alleles were identified by prediction tools provided by immune epitope database (IEDB). Among T-cell epitopes, MHC class I peptide (GLMEPAFTYV) and MHC class II peptide (LVCFSFSLVLILGLV) were identified as most suitable. From all predicted B-cell epitopes, only one epitope (GKLVKFSEQQLVDC) containing sequence from the conserved region was chosen for next processing. Selected epitopes have been validated by molecular docking analysis. These epitopes showed a very strong binding affinity to MHC I molecule and MHC II molecule with binding energy scores - 729.3 and - 725.0 kcal/mole respectively. Performed experimental validation showed that only the MHC class II peptide (LVCFSFSLVLILGLV) can stimulate T cells from ragweed allergic patients and IgE antibodies specific to the ragweed pollen do not recognize this epitope. Therefore, this peptide could be potentially used as a vaccine against the major allergen Amb a 11. The B-cell epitope GKLVKFSEQQLVDC forms a stable complex with the IgE molecule (energy weighted score - 695,0 kcal/mole). Tested sera from patients with ragweed allergy showed that the ragweed specific IgE antibodies can bind to the identified B-cell epitope. Population coverage analysis was performed for CD8+ and CD4+ T-cell epitopes. It was predicted that CD4+ T-cell epitope (LVCFSFSLVLILGLV) covers 90.56% of the population of Europe and 99.36% of the world population. CD8+ T-cell epitope (GLMEPAFTYV) has a population coverage of 77.37% for Europe and 71.35% for all the world.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8972712PMC
http://dx.doi.org/10.1007/s10930-022-10050-zDOI Listing
April 2022

Self-organization and surface properties of hBest1 in models of biological membranes.

Authors:
Jordan A Doumanov Kirilka Mladenova Vesselina Moskova-Doumanova Tonya D Andreeva Svetla D Petrova

Adv Colloid Interface Sci 2022 Apr 22;302:102619. Epub 2022 Feb 22.

Sofia University "St. Kliment Ohridski", Faculty of Biology, 8 Dragan Tzankov str., 1164 Sofia, Bulgaria.

The transmembrane Ca - activated Cl channel - human bestrophin-1 (hBest1) is expressed in retinal pigment epithelium and mutations of BEST1 gene cause ocular degenerative diseases colectivelly referred to as "bestrophinopathies". A large number of genetical, biochemical, biophysical and molecular biological studies have been performed to understand the relationship between structure and function of the hBest1 protein and its pathophysiological significance. Here, we review the current understanding of hBest1 surface organization, interactions with membrane lipids in model membranes, and its association with microdomains of cellular membranes. These highlights are significant for modulation of channel activity in cells.
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http://dx.doi.org/10.1016/j.cis.2022.102619DOI Listing
April 2022

DNA Damage Clustering after Ionizing Radiation and Consequences in the Processing of Chromatin Breaks.

Authors:
Veronika Mladenova Emil Mladenov Martin Stuschke George Iliakis

Molecules 2022 Feb 24;27(5). Epub 2022 Feb 24.

Clinic and Polyclinic for Radiation Therapy, Medical School, University of Duisburg-Essen, 45122 Essen, Germany.

Charged-particle radiotherapy (CPRT) utilizing low and high linear energy transfer (low-/high-LET) ionizing radiation (IR) is a promising cancer treatment modality having unique physical energy deposition properties. CPRT enables focused delivery of a desired dose to the tumor, thus achieving a better tumor control and reduced normal tissue toxicity. It increases the overall radiation tolerance and the chances of survival for the patient. Further improvements in CPRT are expected from a better understanding of the mechanisms governing the biological effects of IR and their dependence on LET. There is increasing evidence that high-LET IR induces more complex and even clustered DNA double-strand breaks (DSBs) that are extremely consequential to cellular homeostasis, and which represent a considerable threat to genomic integrity. However, from the perspective of cancer management, the same DSB characteristics underpin the expected therapeutic benefit and are central to the rationale guiding current efforts for increased implementation of heavy ions (HI) in radiotherapy. Here, we review the specific cellular DNA damage responses (DDR) elicited by high-LET IR and compare them to those of low-LET IR. We emphasize differences in the forms of DSBs induced and their impact on DDR. Moreover, we analyze how the distinct initial forms of DSBs modulate the interplay between DSB repair pathways through the activation of DNA end resection. We postulate that at complex DSBs and DSB clusters, increased DNA end resection orchestrates an increased engagement of resection-dependent repair pathways. Furthermore, we summarize evidence that after exposure to high-LET IR, error-prone processes outcompete high fidelity homologous recombination (HR) through mechanisms that remain to be elucidated. Finally, we review the high-LET dependence of specific DDR-related post-translational modifications and the induction of apoptosis in cancer cells. We believe that in-depth characterization of the biological effects that are specific to high-LET IR will help to establish predictive and prognostic signatures for use in future individualized therapeutic strategies, and will enhance the prospects for the development of effective countermeasures for improved radiation protection during space travel.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8911773PMC
http://dx.doi.org/10.3390/molecules27051540DOI Listing
February 2022

New Insights on the Nickel State Deposited by Hydrazine Wet-Chemical Synthesis Route in the Ni/BCY15 Proton-Conducting SOFC Anode.

Authors:
Dimitrinka Nikolova Margarita Gabrovska Gergana Raikova Emiliya Mladenova Daria Vladikova Krassimir L Kostov Yordanka Karakirova

Nanomaterials (Basel) 2021 Nov 27;11(12). Epub 2021 Nov 27.

Institute of Catalysis, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.

Yttrium-doped barium cerate (BCY15) was used as an anode ceramic matrix for synthesis of the Ni-based cermet anode with application in proton-conducting solid oxide fuel cells (pSOFC). The hydrazine wet-chemical synthesis was developed as an alternative low-cost energy-efficient route that promotes 'in situ' introduction of metallic Ni particles in the BCY15 matrix. The focus of this study is a detailed comparative characterization of the nickel state in the Ni/BCY15 cermets obtained in two types of medium, aqueous and anhydrous ethylene glycol environment, performed by a combination of XRD, N physisorption, SEM, EPR, XPS, and electrochemical impedance spectroscopy. Obtained results on the effect of the working medium show that ethylene glycol ensures active Ni cermet preparation with well-dispersed nanoscale metal Ni particles and provides a strong interaction between hydrazine-originating metallic Ni and cerium from the BCY15 matrix. The metallic Ni phase in the pSOFC anode is more stable during reoxidation compared to the Ni cermet prepared by the commercial mechanical mixing procedure. These factors contribute toward improvement of the anode's electrochemical performance in pSOFC, enhanced stability, and a lower degradation rate during operation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708419PMC
http://dx.doi.org/10.3390/nano11123224DOI Listing
November 2021

A New Approach for Determination of the Botanical Origin of Monofloral Bee Honey, Combining Mineral Content, Physicochemical Parameters, and Self-Organizing Maps.

Authors:
Tsvetomil Voyslavov Elisaveta Mladenova Ralitsa Balkanska

Molecules 2021 Nov 28;26(23). Epub 2021 Nov 28.

Department of Special Branches, Institute of Animal Science, 2232 Kostinbrod, Bulgaria.

A new approach for the botanical origin determination of monofloral bee honey is developed. The methodology combines mineral content and physicochemical parameters determination with intelligent statistics such as self-organizing maps (SOMs). A total of 62 monofloral bee honey samples were analysed, including 31 linden, 14 rapeseed, 13 sunflower, and 4 acacia. All of them were harvested in 2018 and 2019 from trusted beekeepers, after confirming their botanical origin, using melissopalynological analysis. Nine physicochemical parameters were determined, including colour, water content, pH, electrical conductivity, hydroxymethylfurfural content, diastase activity, specific optical rotation, invertase activity, and proline. The content of thirty chemical elements (Ag, Al, As, B, Ba, Bi, Ca, Cd, Co, Cr, Cs, Cu, Fe, Ga, In, K, Li, Mg, Mn, Na, Ni, P, Pb, Rb, S, Se, Sr, Te, V, and Zn) was measured using ICP-OES, ICP-MS, and FAAS as instrumental techniques. The visualisation of the SOMs shows an excellent separation of honey samples in five well-defined clusters-linden, rapeseed, acacia, sunflower, and polyfloral honey-using the following set of 16 descriptors: diastase activity, hydroxymethylfurfural content, invertase activity, pH, specific optical rotation, water content, Al, B, Cr, Cs, K, Na, Ni, Rb, V, and Zn.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8659082PMC
http://dx.doi.org/10.3390/molecules26237219DOI Listing
November 2021

Linking Microstructural Integrity and Motor Cortex Excitability in Multiple Sclerosis.

Authors:
Angela Radetz Kalina Mladenova Dumitru Ciolac Gabriel Gonzalez-Escamilla Vinzenz Fleischer Erik Ellwardt Julia Krämer Stefan Bittner Sven G Meuth Muthuraman Muthuraman Sergiu Groppa

Front Immunol 2021 12;12:748357. Epub 2021 Oct 12.

Neuroimaging and Neurostimulation, Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Motor skills are frequently impaired in multiple sclerosis (MS) patients following grey and white matter damage with cortical excitability abnormalities. We applied advanced diffusion imaging with 3T magnetic resonance tomography for neurite orientation dispersion and density imaging (NODDI), as well as diffusion tensor imaging (DTI) in 50 MS patients and 49 age-matched healthy controls to quantify microstructural integrity of the motor system. To assess excitability, we determined resting motor thresholds using non-invasive transcranial magnetic stimulation. As measures of cognitive-motor performance, we conducted neuropsychological assessments including the Nine-Hole Peg Test, Trail Making Test part A and B (TMT-A and TMT-B) and the Symbol Digit Modalities Test (SDMT). Patients were evaluated clinically including assessments with the Expanded Disability Status Scale. A hierarchical regression model revealed that lower neurite density index (NDI) in primary motor cortex, suggestive for axonal loss in the grey matter, predicted higher motor thresholds, i.e. reduced excitability in MS patients ( = .009, adjusted r² = 0.117). Furthermore, lower NDI was indicative of decreased cognitive-motor performance ( = .007, adjusted r² = .142 for TMT-A; = .009, adjusted r² = .129 for TMT-B; = .006, adjusted r² = .142 for SDMT). Motor WM tracts of patients were characterized by overlapping clusters of lowered NDI ( <.05, Cohen's d = 0.367) and DTI-based fractional anisotropy (FA) ( <.05, Cohen's d = 0.300), with NDI exclusively detecting a higher amount of abnormally appearing voxels. Further, orientation dispersion index of motor tracts was increased in patients compared to controls, suggesting a decreased fiber coherence ( <.05, Cohen's d = 0.232). This study establishes a link between microstructural characteristics and excitability of neural tissue, as well as cognitive-motor performance in multiple sclerosis. We further demonstrate that the NODDI parameters neurite density index and orientation dispersion index detect a larger amount of abnormally appearing voxels in patients compared to healthy controls, as opposed to the classical DTI parameter FA. Our work outlines the potential for microstructure imaging using advanced biophysical models to forecast excitability alterations in neuroinflammation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546169PMC
http://dx.doi.org/10.3389/fimmu.2021.748357DOI Listing
December 2021

Microbiota treatment: the future target to prevent cardiovascular disease?

Authors:
Irena Mladenova

Panminerva Med 2022 Mar 19;64(1):133-134. Epub 2021 Oct 19.

Department of Epidemiology and Infectious Diseases, Faculty of Medicine, Trakia University, Stara Zagora, Bulgaria -

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http://dx.doi.org/10.23736/S0031-0808.21.04505-5DOI Listing
March 2022

Anti-Adipogenic Effect of is Mediated PI3K/AKT Signaling Inhibition in Human Adipocytes.

Authors:
Saveta G Mladenova Liliya V Vasileva Martina S Savova Andrey S Marchev Daniel Tews Martin Wabitsch Claudio Ferrante Giustino Orlando Milen I Georgiev

Front Pharmacol 2021 18;12:707507. Epub 2021 Aug 18.

Laboratory of Metabolomics, Department of Biotechnology, Institute of Microbiology, Bulgarian Academy of Sciences, Plovdiv, Bulgaria.

Obesity is a persistent and continuously expanding social health concern. Excessive fat mass accumulation is associated with increased risk of chronic diseases including diabetes, atherosclerosis, non-alcoholic steatohepatitis, reproductive dysfunctions and certain types of cancer. Opiz. is a perennial plant of the Rosaceae family traditionally used to treat inflammatory conditions and as a component of weight loss herbal mixtures. In the search for bioactive leads with potential anti-adipogenic effect from extract (ALM), we have employed nuclear magnetic resonance (NMR) based metabolomics to obtain data for the phytochemical profile of the extract. Further, molecular docking simulation was performed against key adipogenic targets for selected pure compounds, present in the ALM extract. Evaluation of the biological activity was done in human adipocytes exposed to ALM (5, 10 and 25 μg/ml), pure astragalin (AST) or quercitrin (QUE) both at the concentrations of 5, 10 and 25 μM. Investigation of the molecular pathways involved was performed through real-time quantitative PCR and Western blot analyses. According to the docking predictions strong putative affinity was revealed for both AST and QUE towards peroxisome proliferator-activated receptor gamma (PPARγ) and phosphoinositide 3-kinase (PI3K). Assessment of the intracellular lipid accumulation revealed anti-adipogenic activity of ALM. Correspondingly, the expression of the adipogenic genes CCAAT/enhancer-binding protein alpha () and was downregulated upon ALM and AST treatment. The Western blotting results exposed protein kinase B (AKT), PI3K and PPARγ as targets for the inhibitory effect of ALM and AST on adipogenesis. Collectively, we provide a broader insight of the phytochemical composition of . Additionally, we demonstrate the anti-adipogenic effect of ALM and its active compound AST in human adipocytes. Furthermore, PI3K/AKT signaling pathway is identified to mediate the ALM anti-adipogenic action. Hence, the ALM extract and its secondary metabolite AST are worth further exploration as potentially active agents in obesity management.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416315PMC
http://dx.doi.org/10.3389/fphar.2021.707507DOI Listing
August 2021

Novel Mutation in the Gene Causing Marshall-Stickler Syndrome in Three Generations of a Bulgarian Family.

Authors:
M Mladenova T Todorov L Grozdanova V Mitev A Todorova

Balkan J Med Genet 2021 Jun 27;24(1):95-98. Epub 2021 Jul 27.

Department of Medical Chemistry and Biochemistry, Medical University Sofia, Sofia, Bulgaria.

Here we report the first familial case spread through at least three generations, genetically verified cases of Marshall-Stickler syndrome in Bulgaria. The proband, a 2-year-old girl, has craniofacial dysplasia, ocular hypertelorism, small saddle nose with a flat bridge and midface hypoplasia. The pedigree of the proband's family showed that her father has the same clinical manifestations of the disease. In addition, her father presented with a tall, thin stature and mild hearing loss, manifested with aging. The same dysmorphological symptoms were presented by the paternal grandfather. Both patients, the 2-year-old girl and her father, have been diagnosed to carry Marshall-Stickler syndrome. The gene tested negative in the family. Based on the higher percentage of mutations in the gene, we analyzed this gene as the first target in the family. The gene tested negative, and we sequenced the gene further. A novel splice site mutation c.3474+1G>A was found in intron 44. This variant is related to the clinical presentation in the patient and her father. The c.3474+1G>A mutation results in altered splicing affects at the donor splice site of intron 44, which most probably gives a nonfunctional protein. The variant affects the major triple-helical domain that represents a mutation hot-spot for the gene.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366474PMC
http://dx.doi.org/10.2478/bjmg-2021-0001DOI Listing
June 2021

Clinical Relevance of Infection.

Authors:
Irena Mladenova

J Clin Med 2021 Aug 6;10(16). Epub 2021 Aug 6.

Medical Faculty, Department of Hygiene, Epidemiology, Microbiology, Parasitology and Infectious Diseases, Trakia University, 6000 Stara Zagora, Bulgaria.

is a Gram-negative helical, microaerophilic bacterium which colonizes the antrum and body of the stomach, surviving in its harsh environment through mechanisms of acid resistance and colonization factors. It infects approximately 50% of the world population. Although the prevalence of this infection varies from country to country, as well as between different ethnic, social or age groups, it is estimated that about 50% of the human population only carries this microorganism. While has been found to play a major etiological and pathogenic role in chronic gastritis, peptic ulcer disease and gastric cancer, its importance for many types of extra-gastric disease needs to be further investigated. The choice of tests to diagnose infection, defined as invasive or non-invasive, depends on the clinical indication as to whether to perform upper gastrointestinal endoscopy. Focusing on bacterial eradication, the treatment should be decided locally based on the use of antibiotics and documented antibiotic resistance. The author provides an overview of the current state of knowledge about the clinical aspects of infection, especially its diagnostic and therapeutic management.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396975PMC
http://dx.doi.org/10.3390/jcm10163473DOI Listing
August 2021

Ziziphus jujuba Mill. leaf extract restrains adipogenesis by targeting PI3K/AKT signaling pathway.

Authors:
Martina S Savova Liliya V Vasileva Saveta G Mladenova Kristiana M Amirova Claudio Ferrante Giustino Orlando Martin Wabitsch Milen I Georgiev

Biomed Pharmacother 2021 Sep 18;141:111934. Epub 2021 Jul 18.

Department of Plant Cell Biotechnology, Center of Plant Systems Biology and Biotechnology, 4000 Plovdiv, Bulgaria; Laboratory Metabolomics, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 139 Ruski Blvd., 4000 Plovdiv, Bulgaria. Electronic address:

The escalation in the global prevalence of obesity has focused attention on finding novel approaches for its management. Ziziphus jujuba Mill. (ZJL) leaf extract is reported as a traditional remedy for diverse pathological conditions, including obesity. The present study investigated whether ZJL affects adipogenic differentiation in human adipocytes. Additionally, following metabolite profiling of the extract, apigenin (APG), betulinic acid (BA) and maslinic acid (MA) were selected for biological activity evaluation. The possible interactions between APG, BA, MA and target proteins with a central role in adipogenesis were assessed through molecular docking. The potential mechanisms of ZJL, APG, BA and MA were identified using transcriptional analysis through real-time quantitative PCR and protein abundance evaluation by Western blotting. The obtained results revealed a concentration-dependent reduction of accumulated lipids after ZJL, BA and MA application. The key adipogenic transcription factors peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT-enhancer-binding protein alpha (C/EBPα) were strongly decreased at a protein level by all treatments. Moreover, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway was found to be involved in the anti-adipogenic effect of ZJL, APG and BA. Collectively, our findings indicate that ZJL and its pure compounds hampered adipocyte differentiation through PI3K/AKT inhibition. Among the selected compounds, BA exhibits the most promising anti-adipogenic activity. Furthermore, being a complex mixture of phytochemicals, the ZJL extract could be utilized as source of yet unknown bioactive leads with potential implementation in obesity management.
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http://dx.doi.org/10.1016/j.biopha.2021.111934DOI Listing
September 2021

A Galantamine-Curcumin Hybrid Decreases the Cytotoxicity of Amyloid-Beta Peptide on SH-SY5Y Cells.

Authors:
Kirilka Mladenova Georgi Stavrakov Irena Philipova Mariyana Atanasova Svetla Petrova Jordan Doumanov Irini Doytchinova

Int J Mol Sci 2021 Jul 15;22(14). Epub 2021 Jul 15.

Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria.

Misfolded amyloid beta (Aβ) peptides aggregate and form neurotoxic oligomers. Membrane and mitochondrial damages, calcium dysregulation, oxidative stress, and fibril deposits are among the possible mechanisms of Aβ cytotoxicity. Galantamine (GAL) prevents apoptosis induced by Aβ mainly through the ability to stimulate allosterically the α7 nAChRs and to regulate the calcium cytosolic concentration. Here, we examined the cytoprotective effects of two GAL derivatives, namely compounds and , against Aβ cytotoxicity on the human neuroblastoma cell line SH-SY5Y. The protective effects were tested at simultaneous administration, pre-incubation and post-incubation, with Aβ. GAL and curcumin (CU) were used in the study as reference compounds. It was found that protects cells in a similar mode as GAL, while compound and CU potentiate the toxic effects of Aβ. Allosteric stimulation of α7 nAChRs is suggested as a possible mechanism of the cytoprotectivity of . These and previous findings characterize as a prospective non-toxic multi-target agent against neurodegenerative disorders with inhibitory activity on acetylcholinesterase, antioxidant, and cytoprotective properties.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307467PMC
http://dx.doi.org/10.3390/ijms22147592DOI Listing
July 2021
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