Effect of Silicon Dioxide Nanoparticles on Liver Morphology of Rats in Parenteral Administration

The issue of the potential safety of silicon dioxide nanoparticles (SDNPs) remains relevant. In this connection, in order to use the unique capabilities of silicon nanostructures for biomedical purposes, as well as to level their toxic effects, a detailed study of these nanoparticles interaction with cells and tissues in vivo is required.The aim of the research is to reveal morphofunctional changes in a rat's liver after a single parenteral administration of 12 nm silicon dioxide nanoparticles for the period of six months.Material and methods. Using general histological and immunohistochemical methods to study the rats' liver after a single parenteral administration of 1 ml of silicon dioxide nanoparticles at a dose of 7 mg/kg of body weight at a concentration of 2 mg/ml. The sections of the rats' liver were studied by general histological and immunohistochemical methods after injection of 1mL of a SDNPs saline suspension at a concentration of 2 mg/mL (7mg/kg of body weight). Control animals were injected with 1 ml of saline solution. The material was collected in 21 days, 2, 4 and 6 months months after the administration of the SDNPs and it was fixed in 10% neutral formaldehyde.Results. The formation of granulomas in the liver on the 21st day of the experiment and an increase in the number of Kupfer cells were revealed. However, by the 2nd month of the experiment, the number of granulomas significantly decreases compared to the 21st day of the experiment and continues to decrease in subsequent periods. The average size of granulomas decreases during the 2nd month of the experiment and does not change during the subsequent periods of the experiment. After 6 months of the experiment, the morphofunctional state of the liver is characterized by slightly pronounced aseptic inflammation.Conclusion. A single parenteral administration of silicon dioxide nanoparticles causes pronounced aseptic inflammation of the liver, decreasing by the 6th month of the experiment. Connective tissue remodeling in the liver is not observed at all periods of the experiment.

Perspectives of targeted therapy for nonspecific back pain: a review of recent publications

The high incidence of back pain in older people, its effect on quality and duration of life, and insufficient effectiveness of existing treatment methods determine the need to search for methods of back pain treatment that will reduce inflammatory and degenerative changes and the pain syndrome itself. The review analyzes the epidemiology, pathogenesis, current methods of pharmacotherapy for back pain, the role of genetic changes and biomarkers of chronic pain, discusses current prospects for the use of targeted therapy for the treatment of chronic nonspecific back pain based on pathogenetic mechanisms (genetic changes, aseptic inflammation, immune disorders, disorders of chondrogenesis, etc.).

Biological behavior of a new 68Ga-labelled glucose derivative as a potential agent for tumor imaging

Glucose analogs and derivatives labeled with positron emitter 68Ga are considered to be a promising alternative to widely used radiotracer 18F-FDG for tumor PET imaging. In this study a biodistribution of a new glucose derivative labeled with 68Ga (68Ga-NODA-thioglucose) was investigated. All biodistribution studies were carried out in Balb/c mice with experimental model of tumor or aseptic inflammation. The tumor uptake of 68Ga-NODA-TG decreased throughout the study from 3.00±0.08 % ID/g to 1.06±0.04 %ID/g. The peak amount of 68Ga-NODA-TG in muscle with inflammation reached 4.33±0.12 % ID/g, decreasing to 0.23±0.08 % ID/g. In other organs and tissues the biodistribution of 68Ga-NODA-TG was similar in tumor-bearing mice and mice with aseptic inflammation. In conclusion, the obtained results suggest that 68Ga-NODA-TG has the potential for clinical application as a PET tracer.

Blood clotting parameters in revision knee replacement patients with aseptic instability and periprosthetic infection

Введение. Представляет интерес оценка адаптационных возможностей системы гемостаза у пациентов, поступающих для ревизионного эндопротезирования коленного сустава, с использованием теста генерации тромбина (ТГТ). Цель исследования: оценить на основании ТГТ дооперационное состояние системы гемокоагуляции у больных, поступивших для ревизионного эндопротезирования коленного сустава по поводу асептической нестабильности протеза или перипротезной инфекции. Материалы и методы. Пациенты с воспалительными осложнениями, поступившие для ревизионного эндопротезирования коленного сустава, были разделены на 2 группы: 28 человек с асептическим воспалением и 24 с инфекционным. По результатам ТГТ в каждой группе были выделены подгруппы: пациенты с адекватной реакцией и пациенты с напряжённой реакцией системы гемостаза (всего 4 подгруппы). О состоянии плазменного гемостаза судили по тестам скрининговой коагулограммы. Активность воспаления оценивали по уровням С-реактивного белка (СРБ) и фибриногена. Результаты. Показано, что в каждой из 4 подгрупп больных адаптационные возможности системы гемокоагуляции различны. Выявлены наиболее угрожаемые по развитию тромбогеморрагических осложнений пациенты — это больные (подгруппы 3 и 4) с парадоксальной реакцией процесса тромбинообразования. Влияние воспалительного процесса на развитие гиперкоагуляционного синдрома у пациентов подгруппы 4 подтверждает наличие корреляционных связей между параметрами ТГТ и СРБ. Заключение. Анализ полученных данных показал различные адаптационные возможности системы гемостаза у пациентов с воспалительными осложнениями, развившимися после эндопротезирования коленного сустава. Background. The assessment of adaptive abilities of blood clotting system using thrombin generation assay (TGA) in revision knee replacement patients is a promising issue for researching. Objectives: to assess pre-surgical condition of blood clotting system using TGA in patients admitted for revision knee replacement due to prosthesis aseptic instability or periprosthetic infection. Patients/Methods. Patients with progressing inflammatory complications admitted for revision knee replacement were divided into two groups: 28 patients with aseptic inflammation and 24 patients with infectious inflammation. Based on TGA findings these groups were divided into subgroups: patients with adequate reaction and those with expressed hemostasis reactions (total of four groups). Plasma hemostasis was assessed by screening coagulogram tests. Inflammation severity was assessed by C-reactive protein (CRP) and fibrinogen levels. Results. It has been demonstrated that patients of these four groups had different adaptive abilities of their blood clotting systems. The most threatened patents for thrombohemorrhagic complications were found in groups 3 and 4 with their responses of thrombin generation process being paradoxical. The impact of inflammation on hypercoagulable syndrome in patients of group 4 proved correlations between TGA and CRP. Conclusions. Analysis of the data obtained revealed the diversity of adaptive abilities of hemostasis in patients with inflammation complications after total knee replacement.

Influence of cryoconserved placenta preparations on the course of non-specific gonarthrosis in the experiment

Background. Treatment of joint pathology, both degenerative and traumatic, is a long, multicomponent process that requires joint efforts of the doctor and the patient. The choice of the optimal therapy is complex and ambiguous. Biologically active compounds are one of the most powerful things for fighting with inflammatory process, which is a constant companion of dama-ge. Due to their antioxidant, immunomodulatory and regenerative properties, placental fragments were admitted as a perspective treatment for arthropathies of various etiologies. Purpose of the research: to determine the morphological characteristics of the constituent structures of the knee joints of rats in a comparative aspect under normal conditions, in experimental arthritis and after exposure to a cryopreserved placenta. Material and methods. An experimental study was carried out on 115 white rats. With the intact group (10 animals) we compared 3 control groups of 35 animals each, who underwent: 1) modeling of carrageenan-induced aseptic inflammation of the knee joint; 2) subcutaneous implantation of placental fragment; 3) subcutaneous implantation of placental fragment against the background of aseptic inflammation of the knee joint. Histological preparations were prepared according to the general methods with hematoxylin-eosin and Van Gieson staining. Results. During the creating an inflammatory focus, changes in the cartilaginous tissue were determined from day 3 in the form of lacunarity, karyopyknosis as a stage of necrobiosis of chondrocytes, especially pronounced on days 10–14. Morphological changes in the bone tissue of rats, which were injected λ-carrageenan, were noted on the 7th day of the research in the form of resorption and destruction of bone trabeculae. Later (day 10), the inflammatory process led to a picture of the fragmented architectonics of bone tissue, which was observed up to 21 days. From the side of the synovial membrane, villous hyperplasia, lymphoid infiltration, and the appearance of additional layers of synoviocytes were observed as a result of a proliferative reaction. The most pronounced changes were observed in the integumentary layer of the synovium. After a single injection of a cryopreserved placenta, the signs of inflammation significantly decreased: the area of destruction of cartilage and bone was limited, and signs of mucoid swel-ling in the synovium decreased. Processes of functional blood filling of the microvasculature prevailed over ischemic ones. Stimulation of regenerative processes provided structural recovery on day 21 of observation. Conclusions. Prepartions of cryopreserved placenta influence the course of the inflammatory process in experimental osteoarthritis. The most reliable therapeutic effect is determined from the side of the synovium.

On the prospects for the use of thiamine, pyridoxine, and cyanocobalamin in the complex therapy and rehabilitation of patients with COVID-19

The new coronavirus infection COVID-19 has highlighted the importance of ongoing support for innate antiviral immunity systems. The aim. Conduct a systematic review of publications on the research of the use of B vitamins to support immunity and rehabilitation of patients with COVID-19. Methods. Intelligent analysis of so-called Big Data and special computational methods for analyzing Big Data of biomedical publications, based on the topological theory of sentiment analysis of medical texts from PubMed/MEDLINE. Results. Low levels of B vitamins contribute to chronic comorbidities and aggravate the clinical course of COVID-19 significantly. Increasing the supply of B vitamins in COVID-19 patients is essential for the maintenance of energy and oxygen metabolism; the direct antiviral effects of vitamins (reduction of SARS-CoV-2 replication); compensation of chronic comorbidities (thromboembolism, impaired liver and kidney functions, diabetes mellitus, polyneuropathy), which aggravate the course of COVID-19; reducing hyperhomocysteinemia and chronic aseptic inflammation; inhibiting carbonic anhydrases to improve oxygen metabolism in the lungs, and increasing the clearance of lactate from the blood and preventing sepsis. Conclusion. By improving myelination of the olfactory sensory neurons, vitamin B 12 can help overcome anosmia, which occurs in 80% of COVID-19 patients. Short courses (up to 2 – 3 weeks) of high-dose parenteral therapy with thiamine, pyridoxine, and cyanocobalamin can be used as a part of a complex of therapeutic measures to improve clinical outcomes in patients with COVID-19, especially in elderly patients with polyhypovitaminosis, diabetes mellitus, hyperhomocysteinemia, thrombophilia, and high risk of sepsis. Oral therapy with thiamine, pyridoxine, and cyanocobalamin is justified as a part of rehabilitation measures after COVID-19 in patients who have faced its consequences in the form of clinical signs of vitamin B vitamin deficiency.

BTK Promotes Atherosclerosis by Regulating Oxidative Stress, Mitochondrial Injury, and ER Stress of Macrophages

Atherosclerosis (AS) is a chronic metabolic disease in arterial walls, characterized by lipid deposition and persistent aseptic inflammation. AS is regarded as the basis of a variety of cardiovascular and cerebrovascular diseases. It is widely acknowledged that macrophages would become foam cells after internalizing lipoprotein particles, which is an initial factor in atherogenesis. Here, we showed the influences of Bruton’s tyrosine kinase (BTK) in macrophage-mediated AS and how BTK regulates the inflammatory responses of macrophages in AS. Our bioinformatic results suggested that BTK was a potential hub gene, which is closely related to oxidative stress, ER stress, and inflammation in macrophage-induced AS. Moreover, we found that BTK knockdown could restrain ox-LDL-induced NK-κB signaling activation in macrophages and repressed M1 polarization. The mechanistic studies revealed that oxidative stress, mitochondrial injury, and ER stress in macrophages were also suppressed by BTK knockdown. Furthermore, we found that sh-BTK adenovirus injection could alleviate the severity of AS in ApoE-/- mice induced by a high-fat diet in vivo. Our study suggested that BTK promoted ox-LDL-induced ER stress, oxidative stress, and inflammatory responses in macrophages, and it may be a potential therapeutic target in AS.

Synthesis, Complexation Properties, and Evaluation of New Aminodiphosphonic Acids as Vector Molecules for 68Ga Radiopharmaceuticals

Two new aminodiphosphonic acids derived from salicylic acid and its phosphonic analogue were prepared through a simple and efficient synthesis. 2-[(2-Amino-2,2-diphosphono)ethyloxy]-benzoic acid 8 and 2-[(2-amino-2,2-diphosphono)ethyloxy]-5-ethyl-phenylphosphonic acid 9 were evaluated for their applicability as 68Ga binding bone-seeking agents. Protonation constants of 8 and 9 and stability constants of the Ga3+ complexes with 8 and 9 in water were determined. The stability constant of Ga3+ complex with fully phosphorylated acid 9 (logKGaL = 31.92 ± 0.32) significantly exceeds stability constant of Ga3+ complex with 8 (logKGaL = 26.63 ± 0.24). Ligands 8 and 9 are as effective for Ga3+ cation binding as ethylenediamine-N,N’-diacetic-N,N’-bis(methy1enephosphonic) acid and ethylenediamine-N,N,N’,N’-tetrakis(methylenephosphonic) acid, respectively. The labelling process and stability of [68Ga]Ga-8 and [68Ga]Ga-9 were studied. Both 8 and 9 readily form 68Ga-complexes stable to ten-fold dilution with saline. However, in fetal bovine serum, only [68Ga]Ga-9 was stable enough to be subject to biological evaluation. It was injected into rats with bone pathology and aseptic inflammation of soft tissues. For [68Ga]Ga-9 in animals with a bone pathology model in 60 and 120 min after injection, a slight accumulation in the pathology site, stable blood percentage level, and moderate accumulation in the liver were observed. For animals with an aseptic inflammation, the accumulation of [68Ga]Ga-9 in the pathology site was higher than that in animals with bone pathology. Moreover, the accumulation of [68Ga]Ga-9 in inflammation sites was more stable than that for [68Ga]Ga-citrate. The percentage of [68Ga]Ga-9 in the blood decreased from 3.1% ID/g (60 min) to 1.5% ID/g (120 min). Accumulation in the liver was comparable to that obtained for [68Ga]Ga-citrate.

Agnuside Alleviates Synovitis and Fibrosis in Knee Osteoarthritis through the Inhibition of HIF-1α and NLRP3 Inflammasome

Increasing evidence has shown that NLRP3 inflammasome activation participates in chronic aseptic inflammation and is related to tissue fibrosis. Our last study also revealed the vital role of NLRP3 inflammasome, highly associated with tissue hypoxia, in the onset and development of knee osteoarthritis (KOA). In this study, we tried to find a possible benign intervention for that pathological process. Agnuside (AGN), a nontoxic, natural small molecule isolated from the extract of Vitex negundo L. (Verbenaceae), has been demonstrated to have antioxidation, anti-inflammatory, analgesia, and many other properties as an iridoid glycoside, although its specific target is still unclear. Therefore, we established MIA-induced KOA model rats and investigated the effects of AGN oral gavage on oxygen-containing state, NLRP3 inflammasome, synovitis, and fibrosis in KOA. Pimonidazole staining and HIF-1α immunohistochemical assay both showed that AGN at the oral dose of 6.25 mg/kg can effectively relieve local hypoxia in synovial tissue. Besides, we observed a decrease of HIF-1α, caspase-1, ASC, and NLRP3 after AGN intervention, both in the mRNA and protein levels. In addition, rats treated with the AGN showed less inflammatory reaction and fibrosis, not only in the expression of NLRP3, inflammasome downstream factors IL-1β and IL-18, and fibrosis markers TGF-β, TIMP1, and VEGF but also in the observation of HE staining, anatomical characteristics, Sirius Red staining, and type I collagen immunohistochemistry. Subsequently, we established LPS-induced models of fibroblast-like synoviocytes (FLSs) mimicking the inflammatory environment of KOA and activating NLRP3 inflammasome. FLSs treated with AGN (3 μM) resulted in a downregulation of HIF-1α and the components required for NLRP3 inflammasome activation. Meanwhile, the content of proinflammatory factors IL-1β and IL-18 in FLS supernatant was also reduced by AGN. In addition, both mRNA and protein levels of the fibrotic markers were significantly decreased after AGN management. To conclude, this study demonstrates that AGN alleviates synovitis and fibrosis in experimental KOA through the inhibition of HIF-1α accumulation and NLRP3 inflammasome activation. Additionally, not only does it reveal some novel targets for anti-inflammatory and antioxidant effects of AGN but also announces its potential value in treating KOA in humans.

NETosis as a Pathogenic Factor for Heart Failure

Heart failure threatens the lives of patients and reduces their quality of life. Heart failure, especially heart failure with preserved ejection fraction, is closely related to systemic and local cardiac persistent chronic low-grade aseptic inflammation, microvascular damage characterized by endothelial dysfunction, oxidative stress, myocardial remodeling, and fibrosis. However, the initiation and development of persistent chronic low-grade aseptic inflammation is unexplored. Oxidative stress-mediated neutrophil extracellular traps (NETs) are the main immune defense mechanism against external bacterial infections. Furthermore, NETs play important roles in noninfectious diseases. After the onset of myocardial infarction, atrial fibrillation, or myocarditis, neutrophils infiltrate the damaged tissue and aggravate inflammation. In tissue injury, damage-related molecular patterns (DAMPs) may induce pattern recognition receptors (PRRs) to cause NETs, but whether NETs are directly involved in the pathogenesis and development of heart failure and the mechanism is still unclear. In this review, we analyzed the markers of heart failure and heart failure-related diseases and comorbidities, such as mitochondrial DNA, high mobility box group box 1, fibronectin extra domain A, and galectin-3, to explore their role in inducing NETs and to investigate the mechanism of PRRs, such as Toll-like receptors, receptor for advanced glycation end products, cGAS-STING, and C-X-C motif chemokine receptor 2, in activating NETosis. Furthermore, we discussed oxidative stress, especially the possibility that imbalance of thiol redox and MPO-derived HOCl promotes the production of 2-chlorofatty acid and induces NETosis, and analyzed the possibility of NETs triggering coronary microvascular thrombosis. In some heart diseases, the deletion or blocking of neutrophil-specific myeloperoxidase and peptidylarginine deiminase 4 has shown effectiveness. According to the results of current pharmacological studies, MPO and PAD4 inhibitors are effective at least for myocardial infarction, atherosclerosis, and certain autoimmune diseases, whose deterioration can lead to heart failure. This is essential for understanding NETosis as a therapeutic factor of heart failure and the related new pathophysiology and therapeutics of heart failure.