How the AHR Became Important in Cancer: The Role of Chronically Active AHR in Cancer Aggression

For decades, the aryl hydrocarbon receptor (AHR) was studied for its role in environmental chemical toxicity i.e., as a quirk of nature and a mediator of unintended consequences of human pollution. During that period, it was not certain that the AHR had a “normal” physiological function. However, the ongoing accumulation of data from an ever-expanding variety of studies on cancer, cancer immunity, autoimmunity, organ development, and other areas bears witness to a staggering array of AHR-controlled normal and pathological activities. The objective of this review is to discuss how the AHR has gone from a likely contributor to genotoxic environmental carcinogen-induced cancer to a master regulator of malignant cell progression and cancer aggression. Particular focus is placed on the association between AHR activity and poor cancer outcomes, feedback loops that control chronic AHR activity in cancer, and the role of chronically active AHR in driving cancer cell invasion, migration, cancer stem cell characteristics, and survival.     

Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus

LL37 acts as T-cell/B-cell autoantigen in Systemic lupus erythematosus (SLE) and psoriatic disease. Moreover, when bound to “self” nucleic acids, LL37 acts as “danger signal,” leading to type I interferon (IFN-I)/pro-inflammatory factors production. T-cell epitopes derived from citrullinated-LL37 act as better antigens than unmodified LL37 epitopes in SLE, at least in selected HLA-backgrounds, included the SLE-associated HLA-DRB1*1501/HLA-DRB5*0101 backgrounds. Remarkably, while “fully-citrullinated” LL37 acts as better T-cell-stimulator, it loses DNA-binding ability and the associated “adjuvant-like” properties. Since LL37 undergoes a further irreversible post-translational modification, carbamylation and antibodies to carbamylated self-proteins other than LL37 are present in SLE, here we addressed the involvement of carbamylated-LL37 in autoimmunity and inflammation in SLE. We detected carbamylated-LL37 in SLE-affected tissues. Most importantly, carbamylated-LL37-specific antibodies and CD4 T-cells circulate in SLE and both correlate with disease activity. In contrast to “fully citrullinated-LL37,” “fully carbamylated-LL37” maintains both innate and adaptive immune-cells’ stimulatory abilities: in complex with DNA, carbamylated-LL37 stimulates plasmacytoid dendritic cell IFN-α production and B-cell maturation into plasma cells. Thus, we report a further example of how different post-translational modifications of a self-antigen exert complementary effects that sustain autoimmunity and inflammation, respectively. These data also show that T/B-cell responses to carbamylated-LL37 represent novel SLE disease biomarkers.     

“Dividing and Conquering” and “Caching” in Molecular Modeling

Molecular modeling is widely utilized in subjects including but not limited to physics, chemistry, biology, materials science and engineering. Impressive progress has been made in development of theories, algorithms and software packages. To divide and conquer, and to cache intermediate results have been long standing principles in development of algorithms. Not surprisingly, most important methodological advancements in more than half century of molecular modeling are various implementations of these two fundamental principles. In the mainstream classical computational molecular science, tremendous efforts have been invested on two lines of algorithm development. The first is coarse graining, which is to represent multiple basic particles in higher resolution modeling as a single larger and softer particle in lower resolution counterpart, with resulting force fields of partial transferability at the expense of some information loss. The second is enhanced sampling, which realizes “dividing and conquering” and/or “caching” in configurational space with focus either on reaction coordinates and collective variables as in metadynamics and related algorithms, or on the transition matrix and state discretization as in Markov state models. For this line of algorithms, spatial resolution is maintained but results are not transferable. Deep learning has been utilized to realize more efficient and accurate ways of “dividing and conquering” and “caching” along these two lines of algorithmic research. We proposed and demonstrated the local free energy landscape approach, a new framework for classical computational molecular science. This framework is based on a third class of algorithm that facilitates molecular modeling through partially transferable in resolution “caching” of distributions for local clusters of molecular degrees of freedom. Differences, connections and potential interactions among these three algorithmic directions are discussed, with the hope to stimulate development of more elegant, efficient and reliable formulations and algorithms for “dividing and conquering” and “caching” in complex molecular systems.     

Photophysical Properties of BADAN Revealed in the Study of GGBP Structural Transitions

The fluorescent dye BADAN (6-bromoacetyl-2-dimetylaminonaphtalene) is widely used in various fields of life sciences, however, the photophysical properties of BADAN are not fully understood. The study of the spectral properties of BADAN attached to a number of mutant forms of GGBP, as well as changes in its spectral characteristics during structural changes in proteins, allowed to shed light on the photophysical properties of BADAN. It was shown that spectral properties of BADAN are determined by at least one non-fluorescent and two fluorescent isomers with overlapping absorbing bands. It was found that BADAN fluorescence is determined by the unsolvated “PICT” (planar intramolecular charge transfer state) and solvated “TICT” (twisted intramolecular charge transfer state) excited states. While “TICT” state can be formed both as a result of the “PICT” state solvation and as a result of light absorption by the solvated ground state of the dye. BADAN fluorescence linked to GGBP/H152C apoform is quenched by Trp 183, but this effect is inhibited by glucose intercalation. New details of the changes in the spectral characteristics of BADAN during the unfolding of the protein apo and holoforms have been obtained.     

The Potential of OMICs Technologies for the Treatment of Immune-Mediated Inflammatory Diseases

Immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel diseases and inflammatory arthritis (e.g., rheumatoid arthritis, psoriatic arthritis), are marked by increasing worldwide incidence rates. Apart from irreversible damage of the affected tissue, the systemic nature of these diseases heightens the incidence of cardiovascular insults and colitis-associated neoplasia. Only 40–60% of patients respond to currently used standard-of-care immunotherapies. In addition to this limited long-term effectiveness, all current therapies have to be given on a lifelong basis as they are unable to specifically reprogram the inflammatory process and thus achieve a true cure of the disease. On the other hand, the development of various OMICs technologies is considered as “the great hope” for improving the treatment of IMIDs. This review sheds light on the progressive development and the numerous approaches from basic science that gradually lead to the transfer from “bench to bedside” and the implementation into general patient care procedures.     

G Protein-Coupled Receptors in Cancer

Despite the fact that G protein-coupled receptors (GPCRs) are the largest signal-conveying receptor family and mediate many physiological processes, their role in tumor biology is underappreciated. Numerous lines of evidence now associate GPCRs and their downstream signaling targets in cancer growth and development. Indeed, GPCRs control many features of tumorigenesis, including immune cell-mediated functions, proliferation, invasion and survival at the secondary site. Technological advances have further substantiated GPCR modifications in human tumors. Among these are point mutations, gene overexpression, GPCR silencing by promoter methylation and the number of gene copies. At this point, it is imperative to elucidate specific signaling pathways of “cancer driver” GPCRs. Emerging data on GPCR biology point to functional selectivity and “biased agonism”; hence, there is a diminishing enthusiasm for the concept of “one drug per GPCR target” and increasing interest in the identification of several drug options. Therefore, determining the appropriate context-dependent conformation of a functional GPCR as well as the contribution of GPCR alterations to cancer development remain significant challenges for the discovery of dominant cancer genes and the development of targeted therapeutics.     

Cytokine Pathways and Investigational Target Therapies in Hidradenitis Suppurativa

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting areas with a high density of apocrine glands and characterized by subcutaneous nodules that may evolve into fistulas with pus secretion. Methods: The aim of this review is to investigate all current knowledge on cytokine regulation in the pathogenesis of HS. A systematic literature research using the words “cytokine”, “interleukin”, “pathway”, and “hidradenitis suppurativa” was performed in PubMed/Medline and Scopus/Embase databases. A search of the clinicaltrials.gov website for interventional recruiting and completed trials including the term “hidradenitis suppurativa” was also performed up to August 2020. We will discuss the pathogenetic role of various cytokines in HS and potential therapeutic targets for this debilitating disease. Results: The pathophysiology underlying this complex condition has not been clearly defined. An upregulation of various cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, IL-17, IL-23, and other molecules seems to be related to this inflammatory condition. Various cells, such as lymphocytes T Helper 1 and 17 and keratinocytes seem to be involved in the genesis of this condition. Conclusions: Several future studies and clinical trials are necessary in order to have new knowledge about HS and to properly treat this complex condition.     

Endothelial Dysfunction: An Intermediate Clinical Feature between Urolithiasis and Cardiovascular Diseases

An epidemiological relationship between urolithiasis and cardiovascular diseases has extensively been reported. Endothelial dysfunction is an early pathogenic event in cardiovascular diseases and has been associated with oxidative stress and low chronic inflammation in hypertension, coronary heart disease, stroke or the vascular complications of diabetes and obesity. The aim of this study is to summarize the current knowledge about the pathogenic mechanisms of urolithiasis in relation to the development of endothelial dysfunction and cardiovascular morbidities. Methods: A non-systematic review has been performed mixing the terms “urolithiasis”, “kidney stone” or “nephrolithiasis” with “cardiovascular disease”, “myocardial infarction”, “stroke”, or “endothelial dysfunction”. Results: Patients with nephrolithiasis develop a higher incidence of cardiovascular disease with a relative risk estimated between 1.20 and 1.24 and also develop a higher vascular disease risk scores. Analyses of subgroups have rendered inconclusive results regarding gender or age. Endothelial dysfunction has also been strongly associated with urolithiasis in clinical studies, although no systemic serum markers of endothelial dysfunction, inflammation or oxidative stress could be clearly related. Analysis of urine composition of lithiasic patients also detected a higher expression of proteins related to cardiovascular disease. Experimental models of hyperoxaluria have also found elevation of serum endothelial dysfunction markers. Conclusions: Endothelial dysfunction has been strongly associated with urolithiasis and based on the experimental evidence, should be considered as an intermediate and changeable feature between urolithiasis and cardiovascular diseases. Oxidative stress, a key pathogenic factor in the development of endothelial dysfunction has been also pointed out as an important factor of lithogenesis. Special attention must be paid to cardiovascular morbidities associated with urolithiasis in order to take advantage of pleiotropic effects of statins, angiotensin receptor blockers and allopurinol.     

Mesenchymal Stem Cell Treatment Perspectives in Peripheral Nerve Regeneration: Systematic Review

Traumatic peripheral nerve lesions affect hundreds of thousands of patients every year; their consequences are life-altering and often devastating and cause alterations in movement and sensitivity. Spontaneous peripheral nerve recovery is often inadequate. In this context, nowadays, cell therapy represents one of the most innovative approaches in the field of nerve repair therapies. The purpose of this systematic review is to discuss the features of different types of mesenchymal stem cells (MSCs) relevant for peripheral nerve regeneration after nerve injury. The published literature was reviewed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A combination of the keywords “nerve regeneration”, “stem cells”, “peripheral nerve injury”, “rat”, and “human” were used. Additionally, a “MeSH” research was performed in PubMed using the terms “stem cells” and “nerve regeneration”. The characteristics of the most widely used MSCs, their paracrine potential, targeted stimulation, and differentiation potentials into Schwann-like and neuronal-like cells are described in this paper. Considering their ability to support and stimulate axonal growth, their remarkable paracrine activity, their presumed differentiation potential, their extremely low immunogenicity, and their high survival rate after transplantation, ADSCs appear to be the most suitable and promising MSCs for the recovery of peripheral nerve lesion. Clinical considerations are finally reported.     

DAMPs and RAGE Pathophysiology at the Acute Phase of Brain Injury: An Overview

Early or primary injury due to brain aggression, such as mechanical trauma, hemorrhage or is-chemia, triggers the release of damage-associated molecular patterns (DAMPs) in the extracellular space. Some DAMPs, such as S100B, participate in the regulation of cell growth and survival but may also trigger cellular damage as their concentration increases in the extracellular space. When DAMPs bind to pattern-recognition receptors, such as the receptor of advanced glycation end-products (RAGE), they lead to non-infectious inflammation that will contribute to necrotic cell clearance but may also worsen brain injury. In this narrative review, we describe the role and ki-netics of DAMPs and RAGE at the acute phase of brain injury. We searched the MEDLINE database for “DAMPs” or “RAGE” or “S100B” and “traumatic brain injury” or “subarachnoid hemorrhage” or “stroke”. We selected original articles reporting data on acute brain injury pathophysiology, from which we describe DAMPs release and clearance upon acute brain injury, and the implication of RAGE in the development of brain injury. We will also discuss the clinical strategies that emerge from this overview in terms of biomarkers and therapeutic perspectives     

The Potential Effect of Lidocaine,Ropivacaine, Levobupivacaine and Morphine on Breast Cancer Pre-Clinical Models: A Systematic Review

Breast cancer (BC) is one of the most common types of cancer and the second leading cause of death in women. Local anaesthetics (LAs) and opioids have been shown to influence cancer progression and metastasis formation in several pre-clinical studies. However, their effects do not seem to promote consensus. A systematic review was conducted using the databases Medline (via PubMed), Scopus, and Web of Science (2010 to December 2021). Search terms included “lidocaine”, “ropivacaine”, “levobupivacaine”, “morphine”, “methadone”, “breast cancer”, “breast carcinoma” and “breast neoplasms” in diverse combinations. The search yielded a total of 784 abstracts for initial review, 23 of which met the inclusion criteria. Here we summarise recent studies on the effect of analgesics and LAs on BC cell lines and animal models and in combination with other treatment regimens. The results suggest that local anaesthetics have anti-tumorigenic properties, hence their clinical application holds therapeutic potential. Regarding morphine, the findings are conflicting, but this opioid appears to be a tumour-promoting agent. Methadone-related results are scarce. Additional research is clearly required to further study the mechanisms underlying the controversial effects of each analgesic or LA to establish the implications upon the outcome and prognosis of BC patients’ treatment.     

The “Angiogenic Switch” and Functional Resources in Cyclic Sports Athletes

Regular physical activity in cyclic sports can influence the so-called “angiogenic switch”, which is considered as an imbalance between proangiogenic and anti-angiogenic molecules. Disruption of the synthesis of angiogenic molecules can be caused by local changes in tissues under the influence of excessive physical exertion and its consequences, such as chronic oxidative stress and associated hypoxia, metabolic acidosis, sports injuries, etc. A review of publications on signaling pathways that activate and inhibit angiogenesis in skeletal muscles, myocardium, lung, and nervous tissue under the influence of intense physical activity in cyclic sports. Materials: We searched PubMed, SCOPUS, Web of Science, Google Scholar, Clinical keys, and e-LIBRARY databases for full-text articles published from 2000 to 2020, using keywords and their combinations. Results: An important aspect of adaptation to training loads in cyclic sports is an increase in the number of capillaries in muscle fibers, which improves the metabolism of skeletal muscles and myocardium, as well as nervous and lung tissue. Recent studies have shown that myocardial endothelial cells not only respond to hemodynamic forces and paracrine signals from neighboring cells, but also take an active part in heart remodeling processes, stimulating the growth and contractility of cardiomyocytes or the production of extracellular matrix proteins in myofibroblasts. As myocardial vascularization plays a central role in the transition from adaptive heart hypertrophy to heart failure, further study of the signaling mechanisms involved in the regulation of angiogenesis in the myocardium is important in sports practice. The study of the “angiogenic switch” problem in the cerebrovascular and cardiovascular systems allows us to claim that the formation of new vessels is mediated by a complex interaction of all growth factors. Although the lungs are one of the limiting systems of the body in cyclic sports, their response to high-intensity loads and other environmental stresses is often overlooked. Airway epithelial cells are the predominant source of several growth factors throughout lung organogenesis and appear to be critical for normal alveolarization, rapid alveolar proliferation, and normal vascular development. There are many controversial questions about the role of growth factors in the physiology and pathology of the lungs. The presented review has demonstrated that when doing sports, it is necessary to give a careful consideration to the possible positive and negative effects of growth factors on muscles, myocardium, lung tissue, and brain. Primarily, the “angiogenic switch” is important in aerobic sports (long distance running). Conclusions: Angiogenesis is a physiological process of the formation of new blood capillaries, which play an important role in the functioning of skeletal muscles, myocardium, lung, and nervous tissue in athletes. Violation of the “angiogenic switch” as a balance between proangiogenic and anti-angiogenic molecules can lead to a decrease in the functional resources of the nervous, musculoskeletal, cardiovascular, and respiratory systems in athletes and, as a consequence, to a decrease in sports performance.     

Systematical Screening of Intracellular Protein Targets of Polyphemusin-I Using Escherichia coli Proteome Microarrays

With their wide repertoire of mechanisms, antimicrobial peptides (AMPs) are promising alternatives to fight against varied pathogenic microorganisms (bacteria, fungi, viruses, parasites, etc.). AMPs, novel components of the innate immune defense system, are secreted by all organisms. The aquatic environment represents a huge population and an enormous source of varied AMPs. Polyphemusin-I, a marine AMP isolated from hemocytes of an American horseshoe crab, possesses high antimicrobial activities. Studies on polyphemusin-I have verified the intracellular mechanisms of action, however, its intracellular targets are not yet explored. In this study, we employed Escherichia coli proteome microarrays to systematically screen the entire intracellular protein targets of polyphemusin-I. A total of 97 protein targets of polyphemusin-I were statistically analyzed from the quadruplicate Escherichia coli proteome microarrays assays. Among these identified protein targets, 56 proteins had cellular location inside the cell (i.e., cytoplasm), one in the plasma membrane, one in the periplasm and the rest 39 proteins had no specified cellular location. The bioinformatics analysis of these identified protein targets of polyphemusin-I in gene ontology (GO) enrichment category of molecular function revealed significant enrichment in nucleic acid related GO terms i.e., “RNA binding”, “nucleotide binding”, “nuclease activities”, “uracil DNA N-glycosylase activities” and others. Moreover, enrichment in GO category of biological process also depicted enrichment in nucleic acid related GO terms, such as “nucleic acid phosphodiester bond hydrolysis”, “deoxyribonucleotide metabolism”, and others. In accordance to GO enrichment analysis, protein families (PFAM) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis also showed significant enrichment in nucleic acid terms. These enrichment results suggest that polyphemusin-I targets nucleic acid-associated proteins. Furthermore, to provide a comprehensive study, we compared the identified protein targets of polyphemusin-I with previously identified protein targets of four AMPs (P-Der, Lfcin B, PR-39, and Bac 7) using Escherichia coli proteome microarrays. The comparison study of five AMPs (polyhemusin-I, P-Der, Lfcin B, PR-39, and Bac 7) showed only nine common protein targets in all the five AMPs, whereas a total of 39 and 43 common protein targets were identified among the two marine AMPs (polyphemusin-I and P-Der) and three terrestrial AMPs (Lfcin B, PR-39 and Bac7), respectively. To further reveal the target pattern of marine and terrestrial AMPs, the enrichment results obtained from common protein targets of marine AMPs with terrestrial AMPs were compared. The comparison result indicated that AMPs have unique mechanism of action among marine or terrestrial AMPs. Hence, in this study, we have not only identified the intracellular protein targets of polyphemusin-I, but also revealed the protein target differences between marine AMPs and terrestrial AMPs.     

Metagenomic Insights into Rhizospheric Microbiome Profiling in Lentil Cultivars Unveils Differential Microbial Nitrogen and Phosphorus Metabolism under Rice-Fallow Ecology

The plant rhizosphere interfaces an array of microbiomes related to plant growth and development. Cultivar-specific soil microbial communities with respect to their taxonomic structure and specific function have not been investigated explicitly in improving the adaptation of lentil cultivars under rice-fallow ecology. The present study was carried out to decipher the rhizosphere microbiome assembly of two lentil cultivars under rice-fallow ecology for discerning the diversity of microbial communities and for predicting the function of microbiome genes related to nitrogen (N) and phosphorus (P) cycling processes deploying high-throughput whole (meta) genome sequencing. The metagenome profile of two cultivars detected variable microbiome composition with discrete metabolic activity. Cyanobacteria, Bacteroidetes, Proteobacteria, Gemmatimonadetes, and Thaumarchaeota were abundant phyla in the “Farmer-2” rhizosphere, whereas Actinobacteria, Acidobacteria, Firmicutes, Planctomycetes, Chloroflexi, and some incompletely described procaryotes of the “Candidatus” category were found to be robustly enriched the rhizosphere of “Moitree”. Functional prediction profiles of the microbial metagenomes between two cultivars revealed mostly house keeping genes with general metabolism. Additionally, the rhizosphere of “Moitree” had a high abundance of genes related to denitrification processes. Significant difference was observed regarding P cycling genes between the cultivars. “Moitree” with a profuse root system exhibited better N fixation and translocation ability due to a good “foraging strategy” for improving acquisition of native P under the nutrient depleted rice-fallow ecology. However, “Farmer-2” revealed a better “mining strategy” for enhancing P solubilization and further transportation to sinks. This study warrants comprehensive research for explaining the role of microbiome diversity and cultivar–microbe interactions towards stimulating microbiome-derived soil reactions regarding nutrient availability under rice-fallow ecology.     

Complex Analysis of Antioxidant Activity,Abscisic Acid Level,and Accumulation of Osmotica in Apple and Cherry In Vitro Cultures under Osmotic Stress

Plant response to osmotic stress is a complex issue and includes a wide range of physiological and biochemical processes. Extensive studies of known cultivars and their reaction to drought or salinity stress are very important for future breeding of new and tolerant cultivars. Our study focused on the antioxidant activity, accumulations of osmotica, and the content of abscisic acid in apple (cv. “Malinové holovouské”, “Fragrance”, “Rubinstep”, “Idared”, “Car Alexander”) and cherry (cv. “Regina”, “Napoleonova”, “Kaštánka”, “Sunburst”, “P-HL-C”) cultivated in vitro on media containing different levels of polyethylene glycol PEG-6000. Our results indicated that the studied genotypes responded differently to osmotic stress manifested as reduction in the leaf relative water content (RWC) and increment in the activities of antioxidant enzymes, proline, sugars, and abscisic acid content. Overall, cherry cultivars showed a smaller decrease in percentage RWC and enzymatic activities, but enhanced proline content compared to the apple plants cultivars. Cultivars “Rubinstep”, “Napoleonova”, and “Kaštánka” exhibited higher antioxidant capacity and accumulation of osmoprotectants like proline and sorbitol that can be associated with the drought-tolerance system.     

Diagnostic Performance of Pancreatic Cytology with the Papanicolaou Society of Cytopathology System: A Systematic Review,before Shifting into the Upcoming WHO International System

The Papanicolaou Society of Cytopathology (PSC) reporting system classifies pancreatobiliary samples into six categories (I–VI), providing guidance for personalized management. As the World Health Organization (WHO) has been preparing an updated reporting system for pancreatobiliary cytopathology, this systematic review aimed to evaluate the risk of malignancy (ROM) of each PSC category, also the sensitivity and specificity of pancreatic FNA cytology using the current PSC system. Five databases were investigated with a predefined search algorithm. Inclusion and exclusion criteria were applied to select the eligible studies for subsequent data extraction. A study quality assessment was also performed. Eight studies were included in the qualitative analysis. The ROM of the PSC categories I, II, III, IV, V, VI were in the ranges of 8–50%, 0–40%, 28–100%, 0–31%, 82–100%, and 97–100%, respectively. Notably, the ROM IVB (“neoplastic—benign”) subcategory showed a 0% ROM. Four of the included studies reported separately the ROMs for the IVO subcategory (“neoplastic—other”; its overall ROM ranged from 0 to 34%) with low (LGA) and high-grade atypia (HGA). ROM for LGA ranged from 4.3 to 19%, whereas ROM for HGA from 64 to 95.2%. When the subcategory IVO with HGA was considered as cytologically positive, together with the categories V and VI, there was a higher sensitivity of pancreatic cytology, at minimal expense of the specificity. Evidence suggests the proposed WHO international system changes—shifting the IVB entities into the “benign/negative for malignancy” category and establishing two new categories, the “pancreatic neoplasm, low-risk/grade” and “pancreatic neoplasm, high-risk/grade”—could stratify pancreatic neoplasms more effectively than the current PSC system.     

Small GTPases and Their Regulators: A Leading Road toward Blood Vessel Development in Zebrafish

Members of the Ras superfamily have been found to perform several functions leading to the development of eukaryotes. These small GTPases are divided into five major subfamilies, and their regulators can “turn on” and “turn off” signals. Recent studies have shown that this superfamily of proteins has various roles in the process of vascular development, such as vasculogenesis and angiogenesis. Here, we discuss the role of these subfamilies in the development of the vascular system in zebrafish.