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The book is intended for students studying medical and biological specialties. CHAPTER I. EPIGENETICS INTRODUCTION The science of epigenetics looks at the mechanisms of molecular modifications of histones and DNA that can regulate gene activity without affecting the nucleotide sequences in the DNA molecule. Recognized epigenetic regulators are DNA methylation, post-translational modifications of histones, and non-coding RNAs (nkRNAs). One of the most important differences between eukaryotic cells and prokaryotes is the presence of a complex nucleo-protein chromatin complex in eukaryotes. It is in this form that the DNA molecule is stored in our cells. On the one hand, the complex structural organization of chromatin provides a compact arrangement of DNA in the cell nucleus. On the other hand, chromatin is directly involved in the process of regulating gene expression. At the same time, the nucleosome depicted in Fig. 1 (a structural and functional unit of chromatin) is considered as a key component in the processes of regulating gene expression. The nucleus of the nucleosome is 8 histone proteins (octamers). The nucleus of the nucleosome consists of two copies of each of the histone proteins H2A, H2B, H3 and H4. The DNA chain, which includes 147 nucleotides, folds 1.65 times around the octamer of histones. The nucleosomes are arranged as a linear array along the DNA molecule in the form of "beads on a string". The linker section of DNA connecting adjacent nucleosomes (transcriptionally inactive) is sealed with H1-histone protein. The length of the linker section is 30 nm. Moreover, the site of the beginning of transcription is usually located inside the nucleosome. Consequently, the nucleosome serves as a gene repressor, preventing the initiation of transcription. That is, chromatin provides a total repression of genes. In contrast, transcription becomes possible as a result of chromatin remodeling factors that enable the "dismantling" of nucleosomes or otherwise alter their structure and organization. Thus, the repression (inactivation) of genes begins with wrapping the DNA molecule around the histones in the nucleosome, and the liberation of genes from repression (activation) involves freeing DNA from binding to histone proteins and unfolding DNA by chromatin remodeling factors (Lorch Y., Kornberg R. D., 2017). Thanks to this mechanism, selective expression of only those genes that are needed at a given time by the cell or tissue is possible. It should be emphasized that nucleosome repression extends not only to transcription, but also to most other biological processes associated with the DNA molecule, such as replication, mitotic division, repair of double-strand breaks, and maintenance of telomeres. Thus, epigenetic mechanisms control various physiological and pathological processes by regulating the expression of the corresponding genes by changing the availability of epigenetic control systems to chromatin. The scope of application of epigenetic research methods is rapidly expanding. Currently, we are witnessing the active introduction of epigenetic approaches in the field of practical medicine aimed at diagnosing and treating dangerous human diseases. CHAPTER II. TRANSCRIPTION FACTORS INTRODUCTION For the first time, the existence of transcription factors was revealed on the basis of a discovery that made it possible to establish in vitro purified RNA polymerase-II can initiate transcription on the DNA template in the presence of a cell extract (Weil P. A. et al., 1979). Further research aimed at the fractionation and identification of the general transcription factors (GTF) required to initiate transcription in vitro has identified similar factors in rats, Drosophila, and yeast and substantiated the assumption that GTFs are indeed "common" factors necessary for the expression of genes transcribed by RNA polymerase II. is highly conserved in a number of eukaryotic organisms (Matsui T. et al., 1980). We only mention RNA polymerase II because only this type of enzyme has the ability to synthesize mRNA. Whereas RNA polymerase I is responsible for the synthesis of pro-rRNA, and RNA polymerase III is responsible for the synthesis of tRNA and other non-coding cell RNAs. Meanwhile, the regulation of transcription in eukaryotes is quite complex, since it depends on chromatin remodeling complexes (Burns L. G., Peterson C. L., 1997) and covalent modification of histone proteins (Natsume-Kitatani Y., Mamitsuka H., 2016). In transcription initiation, the immediate target of GTF is a well-defined promo zone of a structural gene. In the structure of the promotra of eukaryotes, the main elements and regulatory elements can be distinguished. The main elements of the promotra (bark promoter, see Fig. 2.1) can be attributed to the site for assembling the transcription initiation complex (PIC), including the TATA sequence located above from the transcription start site (TSS ), and an initiating sequence (Inr) covering the start site. Promoters may include a TATA unit, an initiator sequence (Inr), or both (Hampsey M., 1998). A third major element, the downstream promoter element (DPE), was originally described in Drosophila and is located about 30 p.p. below TSS. The DPE promoter element appears to function in conjunction with the Inr element as a binding site for the transcription factor TFIID on non-TATA promoters. According to current research, the cellular (main) promoters of multicellular organisms that control the initiation of transcription by RNA polymerase II may contain short sequences of nucleotides called cow promoter elements (motifs) (e.g., the TATA block, the initiator (Inr), and the lower element of the cow promoter (DPE)) that recruit RNA polymerase II through a common transcription initiation mechanism (Dreos R. et al., 2021). The authors report that the classes of Promoters of Inr+DPE are not only present in the genome of Drosophila and humans and are structurally similar to each other, but may also be common to different species of multicellular organisms. The most studied element of the cow promoter is the TATA box, but the TATA box is found only in about 10-20% of multicellular cortical promoters. Therefore, along with the TATA sequence, it is necessary to name other possible key DNA sequences known as cortical promoter elements, which include: BRE, MTE, TST and DPE sequences. The two BRE (TFIIB recognition element) motifs are located either above (BREu) or below (BREd) elements of the TATA box. It should be emphasized that TBP, TATA box, and BRE demonstrate high levels of conservatism in the range from archaebacteria to humans (Kadonaga J. T., 2012). In doing so, BREu as well as BREd have both positive and negative effects on transcription activity. The downstream core promoter element (DPE) was detected in the analysis of non-TATA gene promoters in Drosophila. The MTE element (motif ten element), which is located directly in front of the DPE, was identified as an overrepresented sequence of a cow promoter called "motif 10" and then discovered, that it is a functional element of a cow promoter. The MTE and DPE motifs exhibit high conservatism in the range from Drosophila to humans, and both motifs appear to be directly recognized by the subunits of the main transcription factor TFIID, TAF proteins that resemble histone proteins in structure. In turn, the TCT sequence regulates the transcription of ribosomal protein genes in Drosophila and humans. Although there are no universal cortical promoter elements that are present in all promoters, the concept of a cow promoter of nuclear RNA polymerase II can be defined as a minimum stretch of DNA that is sufficient to accurately initiate transcription by RNA polymerase II (Kadonaga J. T., 2012; Haberle V., Stark A., 2018). It should be noted that the results of modern research will constantly supplement the list of all new components of the cow promoter, for example, DNA-replicatedrelated element (DRE), Ohler 1,6 and 7 motifs (Danino Y. M. et al., 2015; Haberle V., Stark A., 2018). According to the authors, the bark promoter may be transformed in the course of evolution. Due to this, gene expression levels can be modulated by the composition of cow promoter elements. Such modulation is directly achieved through the emergence of combinations of new elements of the cow promoter, as a result of which an additional level of transcription regulation is realized. To summarize the above facts, transcription is usually initiated at a specific position, the Transcription Initiation Site (TSS), at the 5' end of the gene. The TSS site is embedded in a bark promoter, which is a short sequence spanning 50 base pairs above and 50 below TSS. The cortical promoter serves as a binding platform for the components required to initiate transcription, including RNA polymerase II and related common transcription factors (GTFs). Regulatory elements. The cortical promoter is sufficient to initiate transcription, but such transcription has low basal activity, which can be further activated, generally by more distally arranged regulatory elements called enhancers (discussed below). Enhancers bind regulatory proteins known as transcription factors, recruit transcription cofactors, and can further enhance transcription. CHAPTER III. CELL SIGNALING PATHWAYS INTRODUCTION In a multicellular organism, the work of each cell is regulated by a large number of signals. These signals can be formed both in the organism itself, reflecting the specific needs of a living organism (metabolic state, stages of development, differentiation, reproduction), and in the form of a reaction to the effects of the external environment. The implementation of each of these signals encompasses all the biological and biochemical processes that lead from the cell's perception of the signal to the cell's response. A signal to a cell is something that is recogni

Immune cells and immune molecules in the intestinal mucosa participate in innate and adaptive immunity to maintain local and systematic homeostasis. With aging, intestinal mucosal immune dysfunction will promote the emergence of age-associated diseases. Although there have been a number of studies on the impact of aging on systemic immunity, relatively fewer studies have been conducted on the impact of aging on the intestinal mucosal immune system. In this review, we will briefly introduce the impact of aging on the intestinal mucosal barrier, the impact of aging on intestinal immune cells as well as immune molecules, and the process of interaction between intestinal mucosal immunity and gut microbiota during aging. After that we will discuss potential strategies to slow down intestinal aging in the elderly.

Colorectal cancer (CRC) is a severe threat to human health. Ginsenosides such as ginsenoside Rh4 have been widely studied in the antitumor field. Here, we investigated the antiproliferative activity and mechanism of Rh4 against CRC in vivo and in vitro. The CRC xenograft model showed that Rh4 inhibited xenograft tumor growth with few side effects ( <a:math xmlns:a="http://www.w3.org/1998/Math/MathML" id="M1"> <a:mi>p</a:mi> <a:mo>&lt;</a:mo> <a:mn>0.05</a:mn> </a:math> ). As determined by MTT colorimetric assays, Western blotting, and immunohistochemical analysis, Rh4 effectively inhibited CRC cell proliferation through autophagy and ferroptosis ( <c:math xmlns:c="http://www.w3.org/1998/Math/MathML" id="M2"> <c:mi>p</c:mi> <c:mo>&lt;</c:mo> <c:mn>0.05</c:mn> </c:math> ). Rh4 significantly upregulated autophagy and ferroptosis marker expression in CRC cells and xenograft tumor tissues in the present study ( <e:math xmlns:e="http://www.w3.org/1998/Math/MathML" id="M3"> <e:mi>p</e:mi> <e:mo>&lt;</e:mo> <e:mn>0.05</e:mn> </e:math> ). Interestingly, the ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed Rh4-induced ferroptosis ( <g:math xmlns:g="http://www.w3.org/1998/Math/MathML" id="M4"> <g:mi>p</g:mi> <g:mo>&lt;</g:mo> <g:mn>0.05</g:mn> </g:math> ). Moreover, the autophagy inhibitor 3-methyladenine (3-MA) also reversed Rh4-induced ferroptosis ( <i:math xmlns:i="http://www.w3.org/1998/Math/MathML" id="M5"> <i:mi>p</i:mi> <i:mo>&lt;</i:mo> <i:mn>0.05</i:mn> </i:math> ). These results indicate that Rh4-induced ferroptosis is regulated via the autophagy pathway. In addition, Rh4 increased reactive oxygen species (ROS) accumulation, leading to the activation of the ROS/p53 signaling pathway ( <k:math xmlns:k="http://www.w3.org/1998/Math/MathML" id="M6"> <k:mi>p</k:mi> <k:mo>&lt;</k:mo> <k:mn>0.05</k:mn> </k:math> ). Transcriptome sequencing also confirmed this ( <m:math xmlns:m="http://www.w3.org/1998/Math/MathML" id="M7"> <m:mi>p</m:mi> <m:mo>&lt;</m:mo> <m:mn>0.05</m:mn> </m:math> ). Moreover, the ROS scavenger N-acetyl-cysteine (NAC) reversed the inhibitory effect of Rh4 on CRC cells ( <o:math xmlns:o="http://www.w3.org/1998/Math/MathML" id="M8"> <o:mi>p</o:mi> <o:mo>&lt;</o:mo> <o:mn>0.05</o:mn> </o:math> ). Therefore, this study proves that Rh4 inhibits cancer cell proliferation by activating the ROS/p53 signaling pathway and activating autophagy to induce ferroptosis, which provides necessary scientific evidence of the great anticancer potential of Rh4.

HomeCirculationVol. 135, No. 3A Surgeon's View on the Pathogenesis of Atherosclerosis Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBA Surgeon's View on the Pathogenesis of Atherosclerosis Axel Haverich, MD Axel HaverichAxel Haverich From Department of Cardiothoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany. Originally published17 Jan 2017https://doi.org/10.1161/CIRCULATIONAHA.116.025407Circulation. 2017;135:205–207August 19, 2016, my coronary artery bypass grafting procedure #3431. A 67-year-old woman presents with calcified triple-vessel coronary artery disease, hypercholesterolemia, 42 pack-years of smoking, and arterial hypertension. Her left carotid artery is totally occluded, there is stenosis of the right subclavian artery, and she has had previous femoral artery reconstruction. Hours after completion of triple-bypass surgery, I am reflecting about the fact that atherosclerosis does not uniformly involve all large- and medium-sized human arteries, an observation I have made hundreds of times before. We had started the procedure by harvesting the left radial artery, which showed no evidence of atherosclerosis, but increased wall thickness with no visible vasa vasorum (VV) on its adventitial surface. After sternotomy, the left internal mammary artery was dissected, with no atherosclerosis, a thin wall, and again, no visible VV. Both grafts appeared unscathed from atherosclerosis despite the risk factors mentioned. Against the background of her coronary disease and the status of her supra-aortic and femoral vessels, it is remarkable that certain segments of the arterial tree remained free from disease.Later, her ascending aorta appeared heavily calcified, as did the proximal segments of all epicardial coronary arteries. Distally, the left anterior descending and right coronary arteries exhibited localized calcified plaques, and highly vascularized areas with an inflamed adventitial layer, as well. Suitable sites for bypass insertion could be identified. The only branch of the circumflex artery large enough for a bypass anastomosis, however, displayed maximum sclerosis in its peripheral segments. One short stretch was diving into the myocardium of the lateral wall of the left ventricle. After dissecting the flat myocardial bridge, a thin-walled, plaque-free artery was visualized without any adventitial VV.This picture has been described repeatedly, with many surgeons taking advantage of these well-known disease-free sites in coronary artery bypass grafting procedures. My second assistant, however, a sixth-year medical student, started asking questions. Rightfully so! How can an artery showing severe proximal and distal sclerosis have, at its midpoint, a segment entirely free from disease with an infant-like wall structure? Why do the patient's risk factors not affect the intramyocardial segment of her circumflex artery? How should the external muscle bridge prevent damage of the intima, the location thought to be where disease is initiated? As a long-term skeptic of intimal damage being the primary initiator of atherosclerosis, I brought to his attention the fact that areas predictably spared from atherosclerosis often lack VV. Alas, I could not impart to the student the underlying pathogenesis of the disease.With our observations and my sparse comments to the student still on my mind, I tried to develop a unifying theory. If a single mechanism like muscular coverage can protect a blood vessel wall against a plethora of atherosclerosis risk factors, perhaps there is an additional unrecognized pathophysiological mechanism that could account for the initiation of the disease process. This factor would need to involve the adventitia rather than the intima, because growing evidence supports an outside-in progression of disease development whereby vascular inflammation is initiated in the adventitia and is propagated inward toward the intima. The mechanism should also be able to precipitate the 2 major phenotypes of atherosclerosis, namely obstruction by plaques and aneurysmal dilatation.As with the phenomenon of healthy arteries in multifocal disease, cardiac surgeons know the reverse pattern: vascular structures in terminal stages of degeneration in individuals free from multifocal atherosclerosis. Such focal processes may occur under conditions of accelerated disease development, examples of which include:Obstructed, autologous venous bypass grafts that often require reoperation within a few years after coronary artery bypass grafting. During graft harvesting, we have learned to preserve adventitial integrity because vessel wall ischemia from disrupted VV is the single most important factor in vein graft degeneration, a process resembling accelerated atherosclerosis in arteries.Calcified allografts that frequently require valve re-replacement. Current preservation techniques of such grafts do not allow for the functional integrity of VV to be maintained. We and others have developed decellularized homografts, where vessel wall ischemia is ameliorated by reducing oxygen demand attributable to the absence of cells. Here, in our experience, no degeneration has been observed in >200 patients in the past 14 years.1Syphilitic aortitis is the result in focal necrosis of the aorta. Interestingly, spirochaetes have been repeatedly found inside the aortic wall, located within the lumen of VV, resulting in their inflammatory obstruction. In this case, local vessel wall ischemia results in focal calcification and aneurysm formation.The ductus arteriosus in premature babies consists of a thin-layered arterial wall that can be surgically clipped easily. If we have to occlude it in older babies, its wall is severely thickened and, if still open in adults, it is usually calcified. Normally, it occludes spontaneously in the first few days of life by obstruction of the VV,2 thus representing the most accelerated form of atherosclerosis.These examples would suggest that blood vessel wall ischemia participates in the early stages of the process of atherosclerosis. Indeed, in experimental animals, physical constriction of VV precipitates fatty streak development in the underlying arterial segment,3 and obstruction of VV in the abdominal aorta results in aneurysm formation.4VV are responsible for vessel wall nutrition via the adventitial layer in large- and medium-sized arteries. When operating on arteries in infants, no VV are detectable, not even in the ascending aorta. With growth, wall thickness in our arterial system, especially in the intimal layer,5 increases because of a rise in wall tension, and VV are needed because nutrition via diffusion is limited. Because they are functional end arteries, VV obstruction results in ischemic necrosis of cells in subintimal layers, corresponding to their individual supply area. In all the examples listed above, vessel wall ischemia from disrupted or occluded VV would represent a uniform pathophysiological mechanism early in the process of atherosclerosis. Accordingly, we propose that atherosclerosis represents a microvascular disease rather than a large-vessel disease. Larger arteries are involved secondarily after microvascular disease of their vessel wall. Areas predictably spared from atherosclerosis (eg, intramyocardial bridges, mammary arteries) carry few if any VV and thus cannot suffer from vessel wall ischemia from disturbed microcirculation.Two major theories on the initiating factors of atherosclerosis have been proposed by others: response to injury and response to inflammation. In both, the endothelium would be the prime target. Endothelium dysfunction, however, would cause much more damage from thrombotic events in microvessels than in larger arteries. Obstruction of VV then translates into functional impairment followed by structural damage in the mother vessel.When one considers atherosclerosis as an adventitial microvessel disease, many risk factors like hypertension, stress, smoking, and perivascular adipose tissue (increased in obesity), start to make sense. Therefore, much of what pediatric and adult cardiologists recommend today for prevention and treatment of atherosclerosis is already directed toward protection of the microvascular system. Future research focusing on microvessel disease could build on many proven concepts already being investigated. As surgeons, we cannot protect all larger arteries in the human body from VV dysfunction. Blood vessel walls of our species require external blood supply, with more VV probably being better than less. Their augmentation could be a field of future research in regenerative medicine, if my assisting medical student's generation keeps on asking questions.AcknowledgmentsThe author thanks Erin Boyle for editorial assistance.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Circulation is available at http://circ.ahajournals.org.Correspondence to: Axel Haverich, MD, Department of Cardiothoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Carl-Neuberg Str 1, 30625, Hannover, Germany. E-mail [email protected]References1. Sarikouch S, Horke A, Tudorache I, Beerbaum P, Westhoff-Bleck M, Boethig D, Repin O, Maniuc L, Ciubotaru A, Haverich A, Cebotari S. Decellularized fresh homografts for pulmonary valve replacement: a decade of clinical experience.Eur J Cardiothorac Surg. 2016; 50:281–290. doi: 10.1093/ejcts/ezw050.CrossrefMedlineGoogle Scholar2. Kajino H, Goldbarg S, Roman C, Liu BM, Mauray F, Chen YQ, Takahashi Y, Koch CJ, Clyman RI. Vasa vasorum hypoperfusion is responsible for medial hypoxia and anatomic remodeling in the newborn lamb ductus arteriosus.Pediatr Res. 2002; 51:228–235. doi: 10.1203/00006450-200202000-00017.CrossrefMedlineGoogle Scholar3. Heistad DD, Marcus ML. Role of vasa vasorum in nourishment of the aorta.Blood Vessels. 1979; 16:225–238.MedlineGoogle Scholar4. Tanaka H, Zaima N, Sasaki T, Sano M, Yamamoto N, Saito T, Inuzuka K, Hayasaka T, Goto-Inoue N, Sugiura Y, Sato K, Kugo H, Moriyama T, Konno H, Setou M, Unno N. Hypoperfusion of the adventitial vasa vasorum develops an abdominal aortic aneurysm.PLoS One. 2015; 10:e0134386. doi: 10.1371/journal.pone.0134386.CrossrefMedlineGoogle Scholar5. Nakashima Y, Wight TN, Sueishi K. Early atherosclerosis in humans: role of diffuse intimal thickening and extracellular matrix proteoglycans.Cardiovasc Res. 2008; 79:14–23. doi: 10.1093/cvr/cvn099.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Goldberg D, Khatib S and Yu Q (2022) Atherogenesis, Transcytosis, and the Transmural Cholesterol Flux: A Critical Review, Oxidative Medicine and Cellular Longevity, 10.1155/2022/2253478, 2022, (1-14), Online publication date: 14-Apr-2022. Fleig S, Kapanadze T, Bernier-Latmani J, Lill J, Wyss T, Gamrekelashvili J, Kijas D, Liu B, Hüsing A, Bovay E, Jirmo A, Halle S, Ricke-Hoch M, Adams R, Engel D, von Vietinghoff S, Förster R, Hilfiker-Kleiner D, Haller H, Petrova T and Limbourg F (2022) Loss of vascular endothelial notch signaling promotes spontaneous formation of tertiary lymphoid structures, Nature Communications, 10.1038/s41467-022-29701-x, 13:1, Online publication date: 1-Dec-2022. Zinserling V (2021) Vsevolod Dmitrievich Zinserling. (On the occasion of the 130th anniversary of his birth), Arkhiv patologii, 10.17116/patol20218306171, 83:6, (71), . Soleimani M, Haverich A and Wriggers P (2021) Mathematical Modeling and Numerical Simulation of Atherosclerosis Based on a Novel Surgeon's View, Archives of Computational Methods in Engineering, 10.1007/s11831-021-09623-5, 28:6, (4263-4282), Online publication date: 1-Oct-2021. Dula K and Remonda L (2021) Digitale Volumentomographie zur Diagnostik von opaken Strukturen in Weichgewebsregionen Digitale Volumentomographie, 10.1007/978-3-662-57405-8_15, (353-391), . DeAnda A and Shokrzadeh C (2020) Aortic Intramural Hematoma and Penetrating Aortic Ulcer Cardiac Surgery, 10.1007/978-3-030-24174-2_55, (507-514), . Xia N, Morteza A, Yang F, Cao H and Wang A (2018) Review of the role of cigarette smoking in diabetic foot, Journal of Diabetes Investigation, 10.1111/jdi.12952, 10:2, (202-215), Online publication date: 1-Mar-2019. Bauersachs J and Berliner D (2018) Poor oral health and coronary artery disease: Association or causality?, European Journal of Preventive Cardiology, 10.1177/2047487318761053, 25:6, (596-597), Online publication date: 1-Apr-2018. Boyle E, Sedding D and Haverich A (2017) Targeting vasa vasorum dysfunction to prevent atherosclerosis, Vascular Pharmacology, 10.1016/j.vph.2017.08.003, 96-98, (5-10), Online publication date: 1-Sep-2017. Ricklefs M, Korossis S, Haverich A and Schilling T (2017) Polymeric Scaffolds for Bioartificial Cardiovascular Prostheses Scaffolds in Tissue Engineering - Materials, Technologies and Clinical Applications, 10.5772/intechopen.71846 Sedding D, Boyle E, Demandt J, Sluimer J, Dutzmann J, Haverich A and Bauersachs J (2018) Vasa Vasorum Angiogenesis: Key Player in the Initiation and Progression of Atherosclerosis and Potential Target for the Treatment of Cardiovascular Disease, Frontiers in Immunology, 10.3389/fimmu.2018.00706, 9 Alberts A, Klingberg A, Hoffmeister L, Wessig A, Brand K, Pich A and Neumann K (2020) Binding of Macrophage Receptor MARCO, LDL, and LDLR to Disease-Associated Crystalline Structures, Frontiers in Immunology, 10.3389/fimmu.2020.596103, 11 Altabas V and Biloš L (2022) The Role of Endothelial Progenitor Cells in Atherosclerosis and Impact of Anti-Lipemic Treatments on Endothelial Repair, International Journal of Molecular Sciences, 10.3390/ijms23052663, 23:5, (2663) January 17, 2017Vol 135, Issue 3 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.116.025407PMID: 28093492 Originally publishedJanuary 17, 2017 Keywordshypoxiaatherosclerosisvasa vasorumPDF download Advertisement SubjectsAtherosclerosisVascular Disease

BACKGROUND: In epidemics of highly infectious diseases, such as Ebola, severe acute respiratory syndrome (SARS), or coronavirus (COVID-19), healthcare workers (HCW) are at much greater risk of infection than the general population, due to their contact with patients' contaminated body fluids. Personal protective equipment (PPE) can reduce the risk by covering exposed body parts. It is unclear which type of PPE protects best, what is the best way to put PPE on (i.e. donning) or to remove PPE (i.e. doffing), and how to train HCWs to use PPE as instructed. OBJECTIVES: To evaluate which type of full-body PPE and which method of donning or doffing PPE have the least risk of contamination or infection for HCW, and which training methods increase compliance with PPE protocols. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and CINAHL to 20 March 2020. SELECTION CRITERIA: We included all controlled studies that evaluated the effect of full-body PPE used by HCW exposed to highly infectious diseases, on the risk of infection, contamination, or noncompliance with protocols. We also included studies that compared the effect of various ways of donning or doffing PPE, and the effects of training on the same outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted data and assessed the risk of bias in included trials. We conducted random-effects meta-analyses were appropriate. MAIN RESULTS: Earlier versions of this review were published in 2016 and 2019. In this update, we included 24 studies with 2278 participants, of which 14 were randomised controlled trials (RCT), one was a quasi-RCT and nine had a non-randomised design. Eight studies compared types of PPE. Six studies evaluated adapted PPE. Eight studies compared donning and doffing processes and three studies evaluated types of training. Eighteen studies used simulated exposure with fluorescent markers or harmless microbes. In simulation studies, median contamination rates were 25% for the intervention and 67% for the control groups. Evidence for all outcomes is of very low certainty unless otherwise stated because it is based on one or two studies, the indirectness of the evidence in simulation studies and because of risk of bias. Types of PPE The use of a powered, air-purifying respirator with coverall may protect against the risk of contamination better than a N95 mask and gown (risk ratio (RR) 0.27, 95% confidence interval (CI) 0.17 to 0.43) but was more difficult to don (non-compliance: RR 7.5, 95% CI 1.81 to 31.1). In one RCT (59 participants) coveralls were more difficult to doff than isolation gowns (very low-certainty evidence). Gowns may protect better against contamination than aprons (small patches: mean difference (MD) -10.28, 95% CI -14.77 to -5.79). PPE made of more breathable material may lead to a similar number of spots on the trunk (MD 1.60, 95% CI -0.15 to 3.35) compared to more water-repellent material but may have greater user satisfaction (MD -0.46, 95% CI -0.84 to -0.08, scale of 1 to 5). According to three studies that tested more recently introduced full-body PPE ensembles, there may be no difference in contamination. Modified PPE versus standard PPE The following modifications to PPE design may lead to less contamination compared to standard PPE: sealed gown and glove combination (RR 0.27, 95% CI 0.09 to 0.78), a better fitting gown around the neck, wrists and hands (RR 0.08, 95% CI 0.01 to 0.55), a better cover of the gown-wrist interface (RR 0.45, 95% CI 0.26 to 0.78, low-certainty evidence), added tabs to grab to facilitate doffing of masks (RR 0.33, 95% CI 0.14 to 0.80) or gloves (RR 0.22, 95% CI 0.15 to 0.31). Donning and doffing Using Centers for Disease Control and Prevention (CDC) recommendations for doffing may lead to less contamination compared to no guidance (small patches: MD -5.44, 95% CI -7.43 to -3.45). One-step removal of gloves and gown may lead to less bacterial contamination (RR 0.20, 95% CI 0.05 to 0.77) but not to less fluorescent contamination (RR 0.98, 95% CI 0.75 to 1.28) than separate removal. Double-gloving may lead to less viral or bacterial contamination compared to single gloving (RR 0.34, 95% CI 0.17 to 0.66) but not to less fluorescent contamination (RR 0.98, 95% CI 0.75 to 1.28). Additional spoken instruction may lead to fewer errors in doffing (MD -0.9, 95% CI -1.4 to -0.4) and to fewer contamination spots (MD -5, 95% CI -8.08 to -1.92). Extra sanitation of gloves before doffing with quaternary ammonium or bleach may decrease contamination, but not alcohol-based hand rub. Training The use of additional computer simulation may lead to fewer errors in doffing (MD -1.2, 95% CI -1.6 to -0.7). A video lecture on donning PPE may lead to better skills scores (MD 30.70, 95% CI 20.14 to 41.26) than a traditional lecture. Face-to-face instruction may reduce noncompliance with doffing guidance more (odds ratio 0.45, 95% CI 0.21 to 0.98) than providing folders or videos only. AUTHORS' CONCLUSIONS: We found low- to very low-certainty evidence that covering more parts of the body leads to better protection but usually comes at the cost of more difficult donning or doffing and less user comfort. More breathable types of PPE may lead to similar contamination but may have greater user satisfaction. Modifications to PPE design, such as tabs to grab, may decrease the risk of contamination. For donning and doffing procedures, following CDC doffing guidance, a one-step glove and gown removal, double-gloving, spoken instructions during doffing, and using glove disinfection may reduce contamination and increase compliance. Face-to-face training in PPE use may reduce errors more than folder-based training. We still need RCTs of training with long-term follow-up. We need simulation studies with more participants to find out which combinations of PPE and which doffing procedure protects best. Consensus on simulation of exposure and assessment of outcome is urgently needed. We also need more real-life evidence. Therefore, the use of PPE of HCW exposed to highly infectious diseases should be registered and the HCW should be prospectively followed for their risk of infection.

// Anna V. Kudryavtseva 1,2 , George S. Krasnov 1 , Alexey A. Dmitriev 1 , Boris Y. Alekseev 2 , Olga L. Kardymon 1 , Asiya F. Sadritdinova 1,2 , Maria S. Fedorova 1 , Anatoly V. Pokrovsky 3 , Nataliya V. Melnikova 1 , Andrey D. Kaprin 2 , Alexey A. Moskalev 1,4 and Anastasiya V. Snezhkina 1 1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia 2 National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia 3 A.V. Vishnevsky Institute of Surgery, Moscow, Russia 4 Moscow Institute of Physics and Technology, Dolgoprudny, Russia Correspondence to: Anna V. Kudryavtseva, email: // Keywords : oxidative stress, mitochondrial dysfunction, ROS, aging, cancer, Gerotarget Received : November 23, 2015 Accepted : May 28, 2016 Published : June 05, 2016 Abstract Aging and cancer are the most important issues to research. The population in the world is growing older, and the incidence of cancer increases with age. There is no doubt about the linkage between aging and cancer. However, the molecular mechanisms underlying this association are still unknown. Several lines of evidence suggest that the oxidative stress as a cause and/or consequence of the mitochondrial dysfunction is one of the main drivers of these processes. Increasing ROS levels and products of the oxidative stress, which occur in aging and age-related disorders, were also found in cancer. This review focuses on the similarities between ageing-associated and cancer-associated oxidative stress and mitochondrial dysfunction as their common phenotype.

Intraoperative fluorescence diagnostics of high-grade gliomas is widely used in neurosurgical practice. This work analyzes the possibilities of fluorescence diagnostics for low-grade gliomas (LGG) using chlorin e6 photosensitizer. The study included patients with newly diagnosed LGG, for whom chlorin e6 was used for intraoperative fluorescence control at a dose of 1 mg/kg. During the operation, the fluorescence intensity of various areas of the putative tumor tissue was analyzed using the RSS Cam – Endo 1.4.313 software. Tissue samples with various degrees of fluorescence intensity were compared with the results of their histopathological analysis (WHO tumor diagnosis, Ki-67 index, P53, VEGF). Fluorescence was detected in more than half of the cases, but in most cases had a focal character and low fluorescence intensity. The fluorescence intensity directly correlated with the data of histopathological examination of tumor tissues (Ki-67 index (p=0.002), expression of P53 (p=0.0015) and VEGF (p=0.001)). The sensitivity of the method for LGG surgery was 72%, the specificity was 56,7%. Intraoperative fluorescence diagnostics with chlorin e6 can be used in LGG surgery, especially to visualize intratumoral areas with a higher degree of anaplasia.

Endocrine-paracrine cells of the prostate (also known as APUD or neuroendocrine cells) constitute, in addition to the basal and exocrine secretory cells, a third population of highly specialized epithelial cells in the prostate gland. These endocrine-paracrine cells contain, and most likely secrete, serotonin and calcitonin, as well as variety of other peptides. Little is known of the functional role of these cells, but they probably subserve a paracrine or local regulatory role. They may also regulate via endocrine, lumencrine, or neurocrine mechanisms. These endocrine-paracrine cells probably play a significant role during prostatic growth and differentiation as well as regulating the secretory process of the mature gland. Neuroendocrine differentiation in prostatic carcinoma occurs in the form of the relatively rare small cell carcinoma and carcinoid or carcinoid-like tumor, but most commonly as focal neuroendocrine differentiation in a conventional prostatic adenocarcinoma that is a very frequent, if not ubiquitous phenomenon, and reflects tumor cell heterogeneity mimicking the normal differentiation process. The world's literature on neuroendocrine differentiation in prostatic carcinoma is reviewed. Neuroendocrine differentiation in all types of prostatic carcinoma appears to correlate with a poor prognosis. This correlation is probably multifactorial and may relate to a positive correlation with grade, a direct resistance to hormonal manipulation, and/or autocrine/paracrine growth factor activity due to the secretion of neuroendocrine products. Neuron-specific enolase and chromogranin, as well as other neuroendocrine products, may be useful as serum markers in patients with prostatic carcinoma with neuroendocrine differentiation. New therapeutic strategies need to be developed to treat these tumors. This includes the use of specialized protocols that have been effective against neuroendocrine carcinomas arising in other organ systems.