Репозиторий Университета

Пептид, связанный с геном кальцитонина, играет важную роль в патофизиологии мигрени. Эренумаб, человеческое моноклональное антитело, которое ингибирует пептидный рецептор, связанный с геном кальцитонина, оценивается для предотвращения мигрени.

Articular hyaline cartilage is extensively hydrated, but it is neither innervated nor vascularized, and its low cell density allows only extremely limited self-renewal. Most clinical and research efforts currently focus on the restoration of cartilage damaged in connection with osteoarthritis or trauma. Here, we discuss current clinical approaches for repairing cartilage, as well as research approaches which are currently developing, and those under translation into clinical practice. We also describe potential future directions in this area, including tissue engineering based on scaffolding and/or stem cells as well as a combination of gene and cell therapy. Particular focus is placed on cell-based approaches and the potential of recently characterized chondro-progenitors; progress with induced pluripotent stem cells is also discussed. In this context, we also consider the ability of different types of stem cell to restore hyaline cartilage and the importance of mimicking the environment in vivo during cell expansion and differentiation into mature chondrocytes.

The heme in the active center of peroxidases reacts with hydrogen peroxide to form highly reactive intermediates, which then oxidize simple substances called peroxidase substrates. Human peroxidases can be divided into two groups: (1) True peroxidases are enzymes whose main function is to generate free radicals in the peroxidase cycle and (pseudo)hypohalous acids in the halogenation cycle. The major true peroxidases are myeloperoxidase, eosinophil peroxidase and lactoperoxidase. (2) Pseudo-peroxidases perform various important functions in the body, but under the influence of external conditions they can display peroxidase-like activity. As oxidative intermediates, these peroxidases produce not only active heme compounds, but also protein-based tyrosyl radicals. Hemoglobin, myoglobin, cytochrome c/cardiolipin complexes and cytoglobin are considered as pseudo-peroxidases. Рeroxidases play an important role in innate immunity and in a number of physiologically important processes like apoptosis and cell signaling. Unfavorable excessive peroxidase activity is implicated in oxidative damage of cells and tissues, thereby initiating the variety of human diseases. Hence, regulation of peroxidase activity is of considerable importance. Since peroxidases differ in structure, properties and location, the mechanisms controlling peroxidase activity and the biological effects of peroxidase products are specific for each hemoprotein. This review summarizes the knowledge about the properties, activities, regulations and biological effects of true and pseudo-peroxidases in order to better understand the mechanisms underlying beneficial and adverse effects of this class of enzymes. View Full-Text

ARC Centre of Excellence for Nanoscale Biophotonics, Faculty of Science and Engineering, Macquarie University, North Ryde, 2109, New South Wales, Australia. Liposomes have been well established as an effective drug delivery system, due to simplicity of their preparation and unique characteristics. However conventional liposomes are unsuitable for the on-demand content release, which limits their therapeutic utility. Here we report X-ray-triggerable liposomes incorporating gold nanoparticles and photosensitizer verteporfin. The 6 MeV X-ray radiation induces verteporfin to produce singlet oxygen, which destabilises the liposomal membrane and causes the release of cargos from the liposomal cavity. This triggering strategy is demonstrated by the efficiency of gene silencing in vitro and increased effectiveness of chemotherapy in vivo. Our work indicates the feasibility of a combinatorial treatment and possible synergistic effects in the course of standard radiotherapy combined with chemotherapy delivered via X-ray-triggered liposomes. Importantly, our X-ray-mediated liposome release strategy offers prospects for deep tissue photodynamic therapy, by removing its depth limitation.

Upconversion nanoparticles (UCNPs) coated with polyethylenimine (PEI) are popular background-free optical contrast probes and efficient drug and gene delivery agents attracting attention in science, industry and medicine. Their unique optical properties are especially useful for subsurface nanotheranostics applications, in particular, in skin. However, high cytotoxicity of PEI limits safe use of UCNP@PEI and this represents a major barrier for clinical translation of UCNP@PEI-based technologies. Our study aims to overcome this problem by exploring additional surface modifications to UCNP@PEI to create biocompatible and functional nanotheranostic materials. We designed and synthesized six types of layered polymer coatings that envelop the original UCNP@PEI surface, five of which reduced the cytotoxicity to human skin keratinocytes under acute (24h) and subacute (120h) exposure. In parallel, we examined the photoluminescence spectra and lifetime of the surface modified UCNP@PEI. To quantify their brightness, we developed original methodology to precisely measure the colloidal concentration to normalize the photoluminescence signal using a non-digesting mass spectrometry protocol. Our results, specified for the individual coatings, show that despite beneficial effect on biocompatibility, the external polymer coatings of UCNP@PEI quench the upconversion photoluminescence in biologically relevant aqueous environments. This trade-off between cytotoxicity and brightness for surface-coated UCNPs emphasizes the need for the combined assessment of biocompatibility and photophysical properties of post-modification UCNPs. We present an optimised methodology for rational surface design of UCNP@PEI in biologically relevant conditions, which is essential to facilitate the translation of such nanoparticles to the clinical applications.

Микробициды являются антисептическими топическими лекарственными средствами, способствующими напрямую или опосредованно сдерживать проникновение инфекционного агента в организм
человека, тем самым предотвращая половую передачу вируса иммунодефицита человека (ВИЧ) и
других заболеваний, передающихся половым путем. Они обладают не только прямым местным противовирусным механизмом действия при половой передаче ВИЧ, но и влияют на компоненты мукозального иммунитета во влагалище.
В данной статье авторами рассмотрены фармацевтические и биомедицинские аспекты применения
кандидатных микробицидов, представлены разнообразные классификации ýтих препаратов, описаны наиболее значимые представители каждой химической группы, указаны механизмы их действия.
Помимо ýтого даны представления о структуре и функции мукозального иммунитета и показана
значимость мукозального иммунного ответа на вирус при половой передаче ВИЧ-инфекции. Отдельно рассматриваются ýкспериментальные модели, которые применяются для тестирования кандидатных микробицидов. Для каждого описанного в статье химического соединения представлен
краткий обзор доклинических и клинических исследований по разработке на его основе микробицида. Даны общие представления о таком новом разнообразном классе медицинских иммунобиологических препаратов, как микробициды, которые должны в ближайшем будущем уменьшить
риск половой передачи ВИЧ и сдержать ýпидемию ВИЧ-инфекции и синдрома приобретенного
иммунодефицита (СПИД).

The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%–21% at 5 years in thrombotic APS and 20–28% in obstetrical APS [2, 3]. Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4–16]. Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency. Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial. This trial consists in two parts: a retrospective and a prospective study. The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.

The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%–21% at 5 years in thrombotic APS and 20–28% in obstetrical APS [2, 3]. Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4–16]. Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency. Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial. This trial consists in two parts: a retrospective and a prospective study. The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.

In this paper, we propose a computational approach for description of radiation transfer in a quasi-ordered medium and study the impact of scattering on electromagnetic wave propagation and image formation. It combines finite-difference time-domain method, Monte Carlo simulations, and radiative transfer theory. Using as an example terahertz imaging, we analyze modulation transfer function (MTF) of imaging system operated at 0.25 THz for scattering material layers placed between the object and the imaging plane. We experimentally study imaging of bar-pattern test-objects through a quasi-ordered scattering medium. Both numerical and experimental results are in good agreement and demonstrate an impact of quasi-ordered scatterers on quality of THz images, i.e. particular combination of the electromagnetic wavelength and parameters of scattering materials could enhance MTF compared with ones with random particle structures.

Terahertz (THz) frequency range opens significant opportunities in various fundamental and applied fields including condensed matter physics and chemistry, biology and medicine, public security and nondestructive testing. Despite significant advances in THz instrumentation, the problem of THz sensing in harsh environments, particularly at high temperatures and pressures, remains acute due to the lack of THz materials and optical components capable for operation under the extreme conditions. To address this problem, the THz hollow‐core photonic crystal sapphire waveguides that are fabricated using shaped crystal growth technique are developed. Numerical analysis and experimental study show that the proposed waveguides operate in a few‐mode regime and allow for the broadband transmission of THz pulses with small dispersions and low propagation losses. Thanks to the unique physical properties of sapphire, the proposed waveguides are capable of operating in a variety of aggressive environments. As an example, the developed waveguides are used to conduct the intra‐waveguide interferometric sensing of phase transitions in sodium nitrite films at high temperatures. It is believed that the proposed sapphire‐based material's platform has strong potential for developing THz guided optics for applications in intra‐waveguide spectroscopy, interferometry, and remote sensing in aggressive environments. In order to address the problem of terahertz (THz) sensing in harsh environments, the hollow‐core photonic crystal sapphire waveguides are developed and fabricated using shaped crystal growth technique. Thanks to the unique physical properties of sapphire, the developed THz waveguides can be used in intra‐waveguide spectroscopy, interferometry, and remote sensing in aggressive environments, at high temperatures and pressures.

We have developed a method of terahertz (THz) solid immersion (SI) microscopy for continuous-wave reflection-mode imaging of soft biological tissues with a sub-wavelength spatial resolution. In order to achieve strong reduction in the dimensions of the THz beam caustic, an electromagnetic wave is focused into the evanescent field volume behind a medium with a high refractive index. We have experimentally demonstrated a 0.15λ-resolution of the proposed imaging modality at λ = 500 μm, which is beyond the Abbe diffraction limit and represents a considerable improvement over the previously-reported arrangements of SI imaging setups. The proposed technique does not involve any sub-wavelength near-field probes and diaphragms, thus, avoiding the THz beam attenuation due to such elements. We have applied the developed method for THz imaging of various soft tissues: a plant leaf blade, cell spheroids, and tissues of the breast ex vivo. Our THz images clearly reveal sub-wavelength features in tissues, therefore, promising applications of THz SI microscopy in biology and medicine.

In this review, we describe dielectric properties of biological tissues and liquids in the context of terahertz (THz) biophotonics. We discuss a model of the THz dielectric permittivity of water and water-containing media, which yields analysis of the relaxation and damped resonant molecules modes. We briefly describe modern techniques of THz spectroscopy and imaging employed in biophotonics with a strong emphasize on a THz time-domain spectroscopy. Furthermore, we consider the methods of sub-wavelength resolution THz imaging and the problem of THz wave delivery to hard to access tissues and internal organs. We consider the THz dielectric properties of biological solutions and liquids. Although strong absorption by water molecules prevents THz-waves from penetration of hydrated tissues and probing biological molecules in aqueous solutions, we discuss approaches for overcoming these drawbacks – novel techniques of freezing and temporal dehydration by application of hyperosmotic agents which have a potential for cancer detection. We review recent applications of THz technology in diagnosis of malignancies and aiding histology paying particular attention to the origin of contrast observed between healthy and pathological tissues. We consider recent applications of THz reflectometry in sensing the thinning dynamics of human pre-corneal tear film. Modern modalities of THz imaging, which relies on the concepts of multi-spectral and multi-temporal domains and employing the principles of color vision, phase analysis and tomography are discussed. Novel methods of THz spectra analysis based on machine learning, pattern recognition, chemical imaging and the revealing of the spatial distribution of various substances in a tissue, are analyzed. Advanced thermal model describing biological object irradiated by THz waves and phantoms mimicking the optical properties of tissues at THz frequencies are presented. Finally, application of the high-resolution THz spectroscopy in analytic chemistry, biology and medicine are described.

For efficient manufacturing of fibrous collagen‐based materials by electrospinning, the search on optimal rheological parameters is of the great importance. Rheological characteristics and denaturation of collagen in aqueous dispersions were studied as a function of shear rate and acetic acid concentration in the range of 3‐9% w/w at temperature from 20 to 40°C. It was shown that an increase in temperature, acetic acid concentration of the collagen dispersion leads to a significant decrease in its viscosity. It was found that helical conformation of the collagen macromolecules is preserved up to 31°C. An increase in acetic acid concentration leads to a reduction of denaturation temperature. The complex viscosity of collagen dispersions exhibits a sharp drop, followed by a rapid growth of damping factor in the temperature range from 22 to 35°C. Both storage (G') and loss (G”) moduli increase with frequency and collagen concentration. It was revealed that optimal parameters for electrospinning of highly concentrated collagen dispersions can be achieved by adjusting of the concentration of acetic acid, temperature and stirring speed. As a result, collagen nonwoven materials with diameter from 100 to 700 nm were obtained. This article is protected by copyright. All rights reserved.

Facial shape is the basis for facial recognition and categorization. Facial features reflect the underlying geometry of the skeletal structures. Here, we reveal that cartilaginous nasal capsule (corresponding to upper jaw and face) is shaped by signals generated by neural structures: brain and olfactory epithelium. Brain-derived Sonic Hedgehog (SHH) enables the induction of nasal septum and posterior nasal capsule, whereas the formation of a capsule roof is controlled by signals from the olfactory epithelium. Unexpectedly, the cartilage of the nasal capsule turned out to be important for shaping membranous facial bones during development. This suggests that conserved neurosensory structures could benefit from protection and have evolved signals inducing cranial cartilages encasing them. Experiments with mutant mice revealed that the genomic regulatory regions controlling production of SHH in the nervous system contribute to facial cartilage morphogenesis, which might be a mechanism responsible for the adaptive evolution of animal faces and snouts.

Osteoarthritis (OA), the most common form of arthritis, is characterized by inflammation of joints and cartilage degradation leading to disability, discomfort, severe pain, inflammation, and stiffness of the joint. It has been shown that adenosine, a purine nucleoside composed of adenine attached to ribofuranose, is enzymatically produced by the human synovium. However, the functional significance of adenosine signaling in homeostasis and pathology of synovial joints remains unclear. Adenosine acts through four cell surface receptors, i.e., A1, A2A, A2B, and A3, and here, we have systematically analyzed mice with a deficiency for A3 receptor as well as pharmacological modulations of this receptor with specific analogs. The data show that adenosine receptor signaling plays an essential role in downregulating catabolic mechanisms resulting in prevention of cartilage degeneration. Ablation of A3 resulted in development of OA in aged mice. Mechanistically, A3 signaling inhibited cellular catabolic processes in chondrocytes including downregulation of Ca2+/calmodulin-dependent protein kinase (CaMKII), an enzyme that promotes matrix degradation and inflammation, as well as Runt-related transcription factor 2 (RUNX2). Additionally, selective A3 agonists protected chondrocytes from cell apoptosis caused by pro-inflammatory cytokines or hypo-osmotic stress. These novel data illuminate the protective role of A3, which is mediated via inhibition of intracellular CaMKII kinase and RUNX2 transcription factor, the two major pro-catabolic regulators in articular cartilage.

Department of Medical Biochemistry and Biophysics, Section for Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden.

Background: Collagen XI (CXI) is a heterotrimeric molecule with triple helical structure in which the α3(XI) chain is identical to the α1(II) chain of collagen II (CII), but with extensive posttranslational modifications. CXI molecules are intermingled in the cartilage collagen fibers, which are mainly composed of CII. One of the alpha chains in CXI is shared with CII and contains the immunodominant T cell epitope, but it is unclear whether there are shared B cell epitopes as the antibodies tend to recognize the triple helical structures.

Methods: Mice expressing the susceptible immune response gene were immunized with CII or CXI. Serum antibody responses were measured, monoclonal antibodies were isolated and analyzed for specificity to CII, CXI, and triple helical collagen peptides using bead-based multiplex immunoassays, enzyme-linked immunosorbent assays, and Western blots. Arthritogenicity of the antibodies was investigated by passive transfer experiments.

Results: Immunization with CII or CXI leads to a strong T and B cell response, including a cross-reactive response to both collagen types. Immunization with CII leads to severe arthritis in mice, with a response toward CXI at the chronic stage, whereas CXI immunization induces very mild arthritis only. A series of monoclonal antibodies to CXI were isolated and of these, the L10D9 antibody bound to both CXI and CII equally strong, with a specific binding for the D3 epitope region of α3(XI) or α1(II) chain. The L10D9 antibody binds cartilage and induced severe arthritis. In contrast, the L5F3 antibody only showed weak binding and L7D8 antibody has no binding to cartilage and did not induce arthritis. The arthritogenic L10D9 antibody bound to an epitope shared with CII, the triple helical D3 epitope. Antibody levels to the shared D3 epitope were elevated in the sera from mice with arthritis as well as in rheumatoid arthritis.

The first example of an unusual addition of chromone‐substituted acrylic acid to enamines is described. The process shows high versatility concerning both enamines and chromones. The reaction is catalyzed by tertiary amines and is highly likely of Morita–Baylis–Hillman‐type. The described compounds show combined moderate inhibitory action on BChE and antagonism towards NMDA receptors which makes them a perspective group for the development of anti‐Alzheimer drugs. An unusual addition of enamines to chromone‐substituted acrylic acid is an efficient and versatile method of synthesis of allylamine derivatives. The reaction is catalyzed by amines and is highly likely of Morita–Baylis–Hillman‐type. The described compounds show combined moderate inhibitory action on BChE and antagonism towards NMDA receptors

Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs may prevent or postpone acquired resistance, thus increasing treatment efficiency. We cultured human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cancer cell lines in the presence of Tyrosine Kinase Inhibitors (Pazopanib, Sorafenib, and Sunitinib) and Rapalogues (Temsirolimus and Everolimus) for four months and obtained cell lines demonstrating increased drug resistance. We investigated gene expression profiles of intact and resistant cells by microarrays and analyzed alterations in 378 cancer-related signaling pathways using the bioinformatical platform Oncobox. This revealed numerous pathways linked with development of drug resistant phenotypes. Our approach is based on targeting proteins involved in as many as possible signaling pathways upregulated in resistant cells. We tested 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs. View Full-Text