Репозиторий Университета

Nonalcoholic fatty liver disease, induced by a Western diet (WD), evokes central and peripheral inflammation that is accompanied by altered emotionality. These changes can be associated with abnormalities in social behaviour, hippocampus-dependent cognitive functions, and metabolism. Female C57BL/6J mice were fed with a regular chow or with a WD containing 0.2% of cholesterol and 21% of saturated fat for three weeks. WD-treated mice exhibited increased social avoidance, crawl-over and digging behaviours, decreased body-body contacts, and hyperlocomotion. The WD-fed group also displayed deficits in hippocampal-dependent performance such as contextual memory in a fear conditioning and pellet displacement paradigms. A reduction in glucose tolerance and elevated levels of serum cholesterol and leptin were also associated with the WD. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1a) mRNA, a marker of mitochondrial activity, was decreased in the prefrontal cortex, hippocampus, hypothalamus, and dorsal raphe, suggesting suppressed brain mitochondrial functions, but not in the liver. This is the first report to show that a WD can profoundly suppress social interactions and induce dominant-like behaviours in naïve adult mice. The spectrum of behaviours that were found to be induced are reminiscent of symptoms associated with autism, and, if paralleled in humans, suggest that a WD might exacerbate autism spectrum disorder.

(PDF) Autism-Like Behaviours and Memory Deficits Result from a Western Diet in Mice. Available from: https://www.researchgate.net/publication/317417307_Autism-Like_Behaviours_and_Memory_Deficits_Result_from_a_Western_Diet_in_Mice [accessed Dec 24 2018].

Background: The vascular endothelial growth factor (VEGF) is a neuroprotective cytokine that promotes neurogenesis and angiogenesis in the brain. In animal models, it has been shown that environmental enrichment and exercise, two non-pharmacological interventions that are beneficial decreasing the progression of Alzheimer disease (AD) and depressive-like behavior, enhance hippocampal VEGF expression and neurogenesis. Furthermore, the stimulation of VEGF expression promotes neurotransmission and synaptic plasticity processes such as neurogenesis. It is thought that these VEGF actions in the brain, may underly its beneficial therapeutic effects against psychiatric and other neurological conditions.

Conclusion: In this review, evidence linking VEGF deficit with the development of AD as well as the potential role of VEGF signaling as a therapeutic target for cotinine and other interventions in neurodegenerative conditions are discussed.

Glucose homeostasis is crucial for neuronal survival, synaptic plasticity, and is indispensable for learning and memory. Reduced sensitivity of cells to insulin and impaired insulin signaling in brain neurons participate in the pathogenesis of Alzheimer disease (AD). The tumor suppressor protein p53 coordinates with multiple cellular pathways in response to DNA damage and cellular stresses. However, prolonged stress conditions unveil deleterious effects of p53-evoked insulin resistance in neurons; enhancement of transcription of pro-oxidant factors, accumulation of toxic metabolites (e.g.: ceramide, products of advanced glycation) and ROS-modified cellular components, together with activation of proapoptotic genes, could finally induce a suicide death program of autophagy/apoptosis in neurons. Recent studies reveal the impact of p53 on expression and processing of several microRNAs (miRs) under DNA damage-inducing conditions. Additionally, the role of miRs in promotion of insulin resistance and type 2 diabetes mellitus has been well documented. Detailed recognition of the role of p53/miRs crosstalk in driving insulin resistance in AD brains could improve the disease diagnostics and aid future therapy.

Gliomas are central nervous system tumors originated from glial cells, whose incidence and mortality is expected to rise in coming years, especially in developing countries. Diagnosis and classification of gliomas have largely relied on tumor histopathologic features that provide limited information regarding response to therapy or prognosis. Current treatment of gliomas is surgery combined with chemotherapy and/or radiotherapy. However, many tumors show a high resistance to these interventions, and recurrences are frequent since conventional therapies do not take into account the unique molecular features of different subtypes of glioma. Molecular genetics provide new insights in classifying gliomas and predicting response to therapy that can range from conventional treatments to new revolutionary therapeutic approaches. This article offers a review of the intracellular signaling pathways involved in carcinogenesis of gliomas, as well as a description of new tools for their diagnosis, prognosis, and treatment with a target-oriented approach.

Recent evidence indicates that the vascular endothelial growth factor (VEGF) may be involved in the neuronal mechanisms underlying both the depression aetiology and the response to pharmacological and non pharmacological antidepressant treatments. To investigate whether VEGF peripheral levels are altered in depression and are modulated by antidepressant therapies, we analyzed the serum VEGF concentrations in 25 subjects affected by major depression (MD) before (T0) and after 8 (T8) and 12 (T12) weeks of escitalopram treatment. No significant alterations in VEGF serum levels were found at T0, even considering possible effects of confounders such as gender and smoking habit (r2=0.227 p=0.74). No changes appeared during the treatment (F(1.83, 43.86)=0.962; p=0.383) and there was no correlation between percentage VEGF variations at T12 and symptoms improvements (p=0.823). The present work represents the first report on the evaluation of serum VEGF levels in MD patients. However, before discarding serum VEGF as a biochemical marker in the diagnosis and treatment of depression, our negative results need to be confirmed in larger patient samples stratified for clinical characteristics, co-morbidities, cardiovascular diseases and confounding factors.

Previous studies have indicated that paracrine factors (conditioned medium) increase wound closure and reduce reactive oxygen species in a traumatic brain injury in vitro model. Although the beneficial effects of conditioned medium from human adipose tissue-derived mesenchymal stem cells (hMSCA-CM) have been previously suggested for various neurological diseases, their actions on astrocytic cells are not well understood. In this study, we have explored the effect of hMSCA-CM on human astrocyte model (T98G cells) subjected to scratch assay. Our results indicated that hMSCA-CM improved cell viability, reduced nuclear fragmentation, attenuated the production of reactive oxygen species, and preserved mitochondrial membrane potential and ultrastructural parameters. In addition, hMSCA-CM upregulated neuroglobin in T98G cells and the genetic silencing of this protein prevented the protective action of hMSCA-CM on damaged cells, suggesting that neuroglobin is mediating, at least in part, the protective effect of hMSCA-CM. Overall, this evidence suggests that the use of hMSCA-CM is a promising therapeutic strategy for the protection of astrocytic cells in central nervous system (CNS) pathologies.

Background: Alzheimer disease (AD) typically affects behavior, memory and thinking. The change in brain have been reported to begin approx. 10-20 years before the appearance of actual symptoms and diagnosis of AD. An early stage diagnosis and treatment of this lethal disease is the prime challenge, which is mainly halted by the lack of validated biomarkers. Method: Recent nanotechnological advancements have the potential to offer large scale effective diagnostic and therapeutic options. Targeted drug (e.g. Rivastigmine) delivery with the help of nanoparticles (NPs) in the range of 1-100 nm diameters can effectively cross the blood brain barrier with minimized side effects. Moreover, biocompatible nanomaterials with increased magnetic and optical properties can act as excellent alternative agents for an early diagnosis. With the high volume of research coming in support of the effective usage of NP based drug delivery in critical environment of CNS, it is quite likely that this approach can end up providing remarkable breakthroughs in early stage diagnosis and therapy of AD.

A ruthenium photocatalyst mediates a synthesis of 3-fluoroindoles from N-arylamines substituted with the CF₂I group in the presence of a substoichiometric amount of triphenylphosphine upon irradiation with blue light. The starting N-arylamines are readily obtained by nucleophilic iododifluoromethylation of iminium ions.

The [4+2] cycloaddition of chromone-fused dienes with enamines is an efficient method of synthesis of 4,4a- and 3,4-dihydroxanthone derivatives. Either product type can be obtained by choosing the proper conditions (reaction time and addition of La(NO3)3 as Lewis acid). Calculations using density functional theory and Møller-Plesset perturbation theory show that the isomerization of 4,4a-dihydroxanthones to 3,4-dihydroxanthones occurs as a base-assisted sigmatropic rearrangement. The described reaction provides a convenient route to a natural product inspired group of 4,4a-dihydroxanthones with cytotoxic activity.

Malaria was eliminated in Tajikistan by the beginning of the 1960s. However, sporadic introduced cases of malaria occurred subsequently probably as a result of transmission from infected mosquito Anopheles flying over river the Punj from the border areas of Afghanistan. During the 1970s and 1980s local outbreaks of malaria were reported in the southern districts bordering Afghanistan. The malaria situation dramatically changed during the 1990s following armed conflict and civil unrest in the newly independent Tajikistan, which paralyzed health services including the malaria control activities and a large-scale malaria epidemic occurred with more than 400,000 malaria cases. The malaria epidemic was contained by 1999 as a result of considerable financial input from the Government and the international community. Although Plasmodium falciparum constituted only about 5% of total malaria cases, reduction of its incidence was slower than that of Plasmodium vivax. To prevent increase in P. falciparum malaria both in terms of incidence and territory, a P. falciparum elimination programme in the Republic was launched in 200, jointly supported by the Government and the Global Fund for control of AIDS, tuberculosis and malaria. The main activities included the use of pyrethroids for the IRS with determined periodicity, deployment of mosquito nets, impregnated with insecticides, use of larvivorous fishes as a biological larvicide, implementation of small-scale environmental management, and use of personal protection methods by population under malaria risk. The malaria surveillance system was strengthened by the use of ACD, PCD, RCD and selective use of mass blood surveys. All detected cases were timely epidemiologically investigated and treated based on the results of laboratory diagnosis. As a result, by 2009, P. falciparum malaria was eliminated from all of Tajikistan, one year ahead of the originally targeted date. Elimination of P. falciparum also contributed towards speedy reduction of P. vivax incidence in Tajikistan. Electronic supplementary material The online version of this article (doi:10.1186/s12936-017-1861-5) contains supplementary material, which is available to authorized users.

(PDF) Elimination of Plasmodium falciparum malaria in Tajikistan. Available from: https://www.researchgate.net/publication/317319424_Elimination_of_Plasmodium_falciparum_malaria_in_Tajikistan [accessed Dec 24 2018].

Over the last decade, biologic agents have become an important component of therapy for systemic vasculitides, e.g., rituximab for granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis, or tocilizumab for giant cell arteritis. However, a risk/benefit ratio of biologic therapy for eosinophilic granulomatosis with polyangiitis (Churg‐Strauss) (EGPA) has not been well studied. Jachiet et al have reported results of a retrospective study of treatment with omalizumab (an anti‐IgE monoclonal antibody) in 17 patients with refractory and/or relapsing EGPA and severe steroid‐dependent asthma and/or sinonasal involvement 1. Treatment response was defined as improvement of asthma and/or ear/nose/throat (ENT) exacerbations. Therefore, this was an “asthma” study rather than a “vasculitis” study, and efficacy of omalizumab in vasculitis remains unclear. Notably, 7 patients described in Jachiet and colleagues' report had other signs and symptoms (skin disease, myalgia, arthralgia, pulmonary infiltrates) in addition to asthma and/or ENT involvement. Following treatment, these relatively mild manifestations of active vasculitis had improved significantly in only 3 patients. Thus, omalizumab does not appear to be a promising agent for management of vasculitis. Moreover, treatment with omalizumab may result in manifestation of other disease features due to steroid tapering: 2 of the patients in Jachiet et al's study developed retrobulbar optic neuritis related to disease relapse. Unlike GPA, severe eye disease is a rare finding in EGPA; therefore, this high incidence (∼12%) of retrobulbar optic neuritis in patients treated with omalizumab would not have been expected.

It has previously been suggested that clinical vasculitis manifestations, such as peripheral neuropathy or renal involvement, occur more frequently in patients with antineutrophil cytoplasmic antibody (ANCA)–positive EGPA than those with ANCA‐negative disease 2. It can be speculated that the risk/benefit ratio of omalizumab may be more favorable in patients with ANCA‐negative EGPA. Jachiet et al did not report the ANCA status of patients with vasculitis relapse, though they stated in the Discussion that response to omalizumab seemed to be independent of ANCA positivity.

Omalizumab induced a complete or partial response (i.e., absence of asthma and/or ENT exacerbations) in 65% of patients. However, the moderate reduction in prednisone dosage following biologic therapy raises a question as to whether the same effect could have been achieved by intensification of treatment with inhaled corticosteroids and/or long‐acting bronchodilators. Jachiet et al did not present data on concomitant use of antiasthmatic medications (this information was likely not available given the retrospective design of the study). Recently, Detoraki et al reported on 5 patients with EGPA and moderate‐to‐severe asthma who were treated with omalizumab as add‐on therapy to prednisone, inhaled corticosteroids, and bronchodilators 3. Over a treatment period of 36 months, omalizumab was found to be safe and enabled corticosteroid tapering while reducing eosinophilia and improving asthma symptoms. Although the steroid‐sparing effect of omalizumab is apparently beneficial, it should not be overestimated. In a Cochrane systematic review, a significant benefit of subcutaneous omalizumab versus placebo was noted with regard to reduction in the frequency of hospitalization or discontinuation of inhaled corticosteroids in patients with bronchial asthma 4. However, there was no significant difference between omalizumab and placebo groups in the proportion of participants who were able to discontinue oral corticosteroid therapy.

Unlike omalizumab, rituximab (an anti‐CD20 monoclonal antibodу) has no antiasthmatic activity and is being used to treat relapsing and/or refractory vasculitis. Mohammad et al have reported on 41 patients with EGPA treated with rituximab in 4 centers 5. At 6 months and 12 months, respectively, remission or partial response was achieved in 83% and 87% of patients. In our own series, complete or partial remission was achieved following rituximab administration in all 6 patients with moderately severe or severe relapsing EGPA that was refractory to conventional immunosuppression 6. Notably, in 2 patients, attempts to reduce the dosage of or discontinue corticosteroids led to a minor relapse that required intensification of treatment (increase in corticosteroid dosage or addition of mycophenolate mofetil), while 1 patient developed severe bronchospasm following rituximab infusion. Therefore, along with infections, the risk of aggravating asthma during rituximab infusion should be taken into account.

Mepolizumab (an anti–interleukin‐5 monoclonal antibody) is another promising biologic treatment for EGPA. Its efficacy in patients with refractory, relapsing, or steroid‐dependent EGPA manifestations was preliminarily shown in small open‐label studies 7, 8 and is currently under investigation in a randomized clinical trial (MIRRA; ClinicalTrials.gov: NCT00527566). Mepolizumab may have advantages over omalizumab and rituximab, as it seems to be effective in both vasculitis and eosinophilic asthma.

In conclusion, Jachiet et al have provided important data for rheumatologists caring for patients with EGPA. Regretfully, the future of omalizumab in EGPA does not look bright. Therefore, we should focus on other biologic agents that would ideally have activity against both vasculitis and asthmatic/sinonasal manifestations of EGPA.

Over the last decades, introduction of high-dose corticosteroids and immunosuppressive agents and later rituximab into the current algorithms for remission induction and maintenance treatment resulted in a tremendous improvement in the survival of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). However, in the recent meta-analysis of observational studies, Tan et al showed a 2.7-fold increased risk of death in patients with AAV when compared with the general population.1 Notably, there was a trend towards lower mortality in the most recent compared with the earlier cohorts. In our own study in 242 patients with granulomatosis with polyangiitis, we also found a significant decrease in mortality in the recent years (2004–2012 vs 1970–2003; p=0.04) and a shift towards a higher percentage of cardiovascular events and complications of immunosuppression as the causes of death.2

Two approaches to the synthesis of dinitrosyl iron complexes (DNIC) with glutathione and l-cysteine in aqueous solutions based on the use of gaseous NO and appropriate S-nitrosothiols, viz., S-nitrosoglutathione (GS-NO) or S-nitrosocysteine (Cys-NO), respectively, are considered. A schematic representation of a vacuum unit for generation and accumulation of gaseous NO purified from the NO2 admixture and its application for obtaining aqueous solutions of DNIC in a Thunberg apparatus is given. To achieve this, a solution of bivalent iron in distilled water is loaded into the upper chamber of the Thunberg apparatus, while the thiol solution in an appropriate buffer (рН 7.4) is loaded into its lower chamber. Further steps, which include degassing, addition of gaseous NO, shaking of both solutions and formation of the Fe²⁺-thiol mixture, culminate in the synthesis of DNIC. The second approach consists in a stepwise addition of Fe²⁺ salts and nitrite to aqueous solutions of glutathione or cysteine. In the presence of Fe²⁺ and after the increase in рН to the physiological level, GS-NO or Cys-NO generated at acid media (pH < 4) are converted into DNIC with glutathione or cysteine. Noteworthy, irrespective of the procedure used for their synthesis DNIC with glutathione manifest much higher stability than DNIC with cysteine. The pattern of spin density distribution in iron-dinitrosyl fragments of DNIC characterized by the d⁷ electronic configuration of the iron atom and described by the formula Fe⁺(NO⁺)2 is unique in that it provides a plausible explanation for the ability of DNIC to generate NO and nitrosonium ions (NO⁺) and the peculiar characteristics of the EPR signal of their mononuclear form (M-DNIC).

This study describes the development and cell culture application of nanometer thick photocrosslinkable thermoresponsive polymer films prepared by physical adsorption. Two thermoresponsive polymers, poly(N-isopropylacrylamide (NIPAm)-co-acrylamidebenzophenone (AcBzPh)) and poly(NIPAm-co-AcBzPh-co-N-tertbutylacrylamide) are investigated. Films are prepared both above and below the polymers' lower critical solution temperatures (LCSTs) and cross-linked, to determine the effect, adsorption preparation temperature has on the resultant film. The films prepared at temperatures below the LCST are smoother, thinner, and more hydrophilic than those prepared above. Human pulmonary microvascular endothelial cell (HPMEC) adhesion and proliferation are superior on the films produced below the polymers LCST compared to those produced above. Cells sheets are detached by simply lowering the ambient temperature to below the LCST. Transmission electron, scanning electron, and light microscopies indicate that the detached HPMEC sheets maintain their integrity.

Background Urethral reconstruction is one of the great surgical challenges for urologists. A cell-based tissue-engineered urethra may be an alternative for patients who have complicated long strictures and need urethral reconstruction. Here, we demonstrated the feasibility of using autologous urine-derived stem cells (USCs) seeded on small intestinal submucosa (SIS) to repair a urethral defect in a rabbit model. Methods Autologous USCs were obtained and characterized, and their capacity to differentiate into urothelial cells (UCs) and smooth muscle cells (SMCs) was tested. Then, USCs were labeled with PKH67, seeded on SIS, and transplanted to repair a urethral defect. The urethral defect model was surgically established in New Zealand white male rabbits. A ventral urethral gap was created, and the urethral mucosa was completely removed, with a mean rabbit penile urethra length of 2 cm. The urethral mucosal defect was repaired with a SIS scaffold (control group: SIS with no USCs; experimental group: autologous USC-seeded SIS; n = 12 for each group). A series of tests, including a retrograde urethrogram, histological analysis, and immunofluorescence, was undertaken 2, 3, 4, and 12 weeks after the operation to evaluate the effect of the autologous USCs on urethral reconstruction. ResultsAutologous USCs could be easily collected and induced to differentiate into UCs and SMCs. In addition, the urethral caliber, speed of urothelial regeneration, content of smooth muscle, and vessel density were significantly improved in the group with autologous USC-seeded SIS. Moreover, inflammatory cell infiltration and fibrosis were found in the control group with only SIS, but not in the experimental autologous USC-seeded SIS group. Furthermore, immunofluorescence staining demonstrated that the transplanted USCs differentiated into UCs and SMCs in vivo. Conclusions Autologous USCs can be used as an alternative cell source for cell-based tissue engineering for urethral reconstruction.

Context: Stress urinary incontinence (SUI) significantly diminishes the quality of patients' lives. Currently available surgical and nonsurgical therapies remain far from ideal. At present advancements in cellular technologies have stirred growing interest in the use of autologous cell treatments aimed to regain urinary control. Objective: To conduct a review of the literature and analyze preclinical and clinical studies dedicated to various cell therapies for SUI, assessing their effectiveness, safety, and future prospects. Evidence acquisition: A systematic literature search in PubMed was conducted using the following key terms: "stem," "cell," "stress," "urinary," and "incontinence." A total of 32 preclinical studies and 15 clinical studies published between 1946 and December 2014 were included in the review. Evidence synthesis: Most preclinical trials have used muscle-derived stem cells (MDSCs) and adipose-derived stem cells (ADSCs). Yet, at present, the application of other types of cells, such as human amniotic fluid stem muscle-derived progenitor cells (hAFSCs), and bone marrow mesenchymal stromal cells (BMSCs), is becoming more extensive. While the evidence shows that these therapies are effective and safe, further work is required to standardize surgical techniques, as well as to identify indications for their use, doses and number of doses. Conclusion: Future research will have to focus on clinical applications of cell therapies; namely, it will have to determine indications for their use, doses of cells, optimal surgical techniques and methods, attractive cell sources, as well as to develop clinically relevant animal models and make inroads into understanding the mechanisms of SUI improvement by cell therapies.

Urethral strictures and anomalies remain among the difficult problems in urology, with urethroplasty procedures being the most effective treatment options. The two major types of urethroplasty are anastomotic urethroplasty and widening the urethral lumen using flaps or grafts (i.e. substitution urethroplasty). However, no ideal material for the latter has been found so far. Designing and selecting such a material is a necessary and challenging endeavour, driving the need for further bioengineered urethral tissue research. This article reviews currently available studies on the potentialities of tissue engineering in urethral reconstruction, in particular those describing the use of both acellular and recellularized tissue-engineered constructs in animal and human models. Possible future developments in this field are also discussed. Copyright © 2015 John Wiley & Sons, Ltd.

In the presented study, we have developed a synthetic strategy allowing a gradual variation of a polylactide arms' length, which later influences the micromorphology of the scaffold surface, formed by a two-photon polymerization technique. It has been demonstrated that the highest number of cells is present on the scaffolds with the roughest surface made of the polylactide with longer arms (PLA760), and osteogenic differentiation of mesenchymal stem cells is most pronounced on such scaffolds. According to the results of biological testing, the PLA760 scaffolds were implanted into a created cranial defect in a mouse for an in vivo assessment of the bone tissue formation. The in vivo experiments have shown that, by week 10, deposition of calcium phosphate particles occurs in the scaffold at the defect site, as well as, the formation of a new bone and ingrowth of blood vessels from the surrounding tissues. These results demonstrate that the cross-linked microstructured tetrafunctional polylactide scaffolds are promising microstructures for bone regeneration in tissue engineering.

Cartilaginous structures are at the core of embryo growth and shaping before the bone forms. Here we report a novel principle of vertebrate cartilage growth that is based on introducing transversally-oriented clones into pre-existing cartilage. This mechanism of growth uncouples the lateral expansion of curved cartilaginous sheets from the control of cartilage thickness, a process which might be the evolutionary mechanism underlying adaptations of facial shape. In rod-shaped cartilage structures (Meckel, ribs and skeletal elements in developing limbs), the transverse integration of clonal columns determines the well-defined diameter and resulting rod-like morphology. We were able to alter cartilage shape by experimentally manipulating clonal geometries. Using in silico modeling, we discovered that anisotropic proliferation might explain cartilage bending and groove formation at the macro-scale.

Pores are vital for functioning of avascular tissues. Laser-induced pores play an important role in the process of cartilage regeneration. The aim of any treatment for osteoarthritis is to repair hyaline-type cartilage. The aims of this study are to answer two questions: (1) How do laser-assisted pores affect the cartilaginous cells to synthesize hyaline cartilage (HC)? and (2) How can the size distribution of pores arising in the course of laser radiation be controlled? We have shown that in cartilage, the pores arise predominately near chondrocytes, which promote nutrition of cells and signal molecular transfer that activates regeneration of cartilage. In vivo laser treatment of damaged cartilage of miniature pig joints provides cellular transformation and formation of HC. We propose a simple model of pore formation in biopolymers that paves the way for going beyond the trial-anderror approach when choosing an optimal laser treatment regime. Our findings support the approach toward laser healing of osteoarthritis.