bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comprehensive Analysis into the Therapeutic Application of Natural Products as SIRT6 Modulators in Alzheimer’s Disease, Aging, Cancer, Inflammation, and Diabetes
Authors: Akter Raushanara , Afrose Afrina , Rahman Md. Rashidur , Chowdhury Rakhi , Nirzhor Saif Shahriar Rahman , Khan Rubayat Islam , Kabir Md. Tanvir
Published: April 2021

Natural products have long been used as drugs to treat a wide array of human diseases. The lead compounds discovered from natural sources are used as novel templates for developing more potent and safer drugs. Natural products produce biological activity by binding with biological macromolecules, since natural products complement the protein-binding sites and natural product–protein interactions are already optimized in nature. Sirtuin 6 (SIRT6) is an NAD+ dependent histone deacetylase enzyme and a unique Sirtuin family member. It plays a crucial role in different molecular pathways linked to DNA repair, tumorigenesis, glycolysis, gluconeogenesis, neurodegeneration, cardiac hypertrophic responses, etc. Thus, it has emerged as an exciting target of several diseases such as cancer, neurodegenerative diseases, aging, diabetes, metabolic disorder, and heart disease. Recent studies have shown that natural compounds can act as modulators of SIRT6. In the current review, a list of natural products, their sources, and their mechanisms of SIRT6 activity modulation has been compiled. The potential application of these naturally occurring SIRT6 modulators in the amelioration of major human diseases such as Alzheimer’s disease, aging, diabetes, inflammation, and cancer has also been delineated. Natural products such as isoquercetin, luteolin, and cyanidin act as SIRT6 activators, whereas vitexin, catechin, scutellarin, fucoidan, etc. work as SIRT6 inhibitors. It is noteworthy to mention that quercetin acts as both SIRT6 activator and inhibitor depending on its concentration used. Although none of them were found as highly selective and potent modulators of SIRT6, they could serve as the starting point for developing selective and highly potent scaffolds for SIRT6.
Effect of Glucocorticoid Receptor Antagonism on Alcohol Self-Administration in Genetically-Selected Marchigian Sardinian Alcohol-Preferring and Non-Preferring Wistar Rats
Authors: Benvenuti Federica , Cannella Nazzareno , Stopponi Serena , Soverchia Laura , Ubaldi Massimo , Lunerti Veronica , Vozella Valentina , Cruz Bryan , Roberto Marisa , Ciccocioppo Roberto
Published: April 2021

Alcoholism is a chronically relapsing disorder characterized by high alcohol intake and a negative emotional state during abstinence, which contributes to excessive drinking and susceptibility to relapse. Stress, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and alterations in glucocorticoid receptor (GR) function have been linked to transition from recreational consumption to alcohol use disorder (AUD). Here, we investigated the effect of pharmacological antagonisms of GR on alcohol self-administration (SA) using male and female Wistar and Marchigian Sardinian alcohol-preferring (msP) rats, a rodent line genetically selected for excessive alcohol drinking and highly sensitive to stress. Animals were trained to self-administer 10% (v/v) alcohol. Once a stable alcohol SA baseline was reached, we tested the effect of the GR antagonists mifepristone (0.0, 10, 30 and 60 mg/kg; i.p.) and CORT113176 (0.0, 10, 30 and 60 mg/kg) on alcohol SA. To evaluate whether the effects of the two compounds were specific for alcohol, the two drugs were tested on a similar saccharin SA regimen. Finally, basal blood corticosterone (CORT) levels before and after alcohol SA were determined. Systemic injection with mifepristone dose-dependently reduced alcohol SA in male and female Wistars but not in msPs. Administration of CORT113176 decreased alcohol SA in male and female Wistars as well as in female msPs but not in male msP rats. At the highest dose, mifepristone also reduced saccharin SA in male Wistars and female msPs, suggesting the occurrence of some nonspecific effects at 60 mg/kg of the drug. Similarly, the highest dose of CORT113176 (60 mg/kg) decreased saccharin intake in male Wistars. Analysis of CORT levels revealed that females of both rat lines had higher blood levels of CORT compared to males. Alcohol consumption reduced CORT in females but not in males. Overall, these findings indicate that selective blockade of GR selectively reduces alcohol SA, and genetically selected msP rats are less sensitive to this pharmacological manipulation compared to heterogeneous Wistars. Moreover, results suggest sex differences in response to GR antagonism and the ability of alcohol to regulate GR transmission.
Role of Adaptor Protein Myeloid Differentiation 88 (MyD88) in Post-Subarachnoid Hemorrhage Inflammation: A Systematic Review
Authors: Ahmed Hammad , Khan Mahtab Ahmad , Kahlert Ulf Dietrich , Niemelä Mika , Hänggi Daniel , Chaudhry Shafqat Rasul , Muhammad Sajjad
Published: April 2021

Myeloid differentiation 88 (MyD88) is a well-established inflammatory adaptor protein. It is one of the essential downstream proteins of the toll-like receptor 4 (TLR4) signaling pathway. TLRs are pattern recognition receptors that are usually activated by the damage-associated molecular pattern molecules (DAMPs). Sterile inflammation is triggered by the endogenous DAMPs released in response to global cerebral ischemia and from extravasated blood after subarachnoid hemorrhage (SAH). In this review, we highlight the importance of the neuroinflammatory role of the MyD88 in the SAH. We also explore a few possible pharmacological agents that can be used to decrease SAH-associated neuroinflammation by modulating the MyD88 dependent functions. Pharmacological agents such as flavonoids, melatonin, fluoxetine, pentoxifylline and progesterone have been investigated experimentally to reduce the SAH-associated inflammation. Inhibition of the MyD88 not only reduces the expression of pro-inflammatory cytokines, but also potentially inhibits other processes that can augment the SAH associated inflammation. Further investigations are required to translate these findings in the clinical setting.
Molecular Pathways of Cellular Senescence and Placental Aging in Late Fetal Growth Restriction and Stillbirth
Authors: Kajdy Anna , Modzelewski Jan , Cymbaluk-Płoska Aneta , Kwiatkowska Ewa , Bednarek-Jędrzejek Magdalena , Borowski Dariusz , Stefańska Katarzyna , Rabijewski Michał , Torbé Andrzej , Kwiatkowski Sebastian
Published: April 2021

Abnormally accelerated, premature placental senescence plays a crucial role in the genesis of pregnancy pathologies. Abnormal growth in the third trimester can present as small for gestational age fetuses or fetal growth restriction. One differs from the other by the presence of signs of placental insufficiency and the risk of stillbirth. The majority of stillbirths occur in normally grown fetuses and are classified as “unexplained”, which often leads to conclusions that they were unpreventable. The main characteristic of aging is a gradual decline in the function of cells, tissues, and organs. These changes result in the accumulation of senescent cells in mitotic tissues. These cells begin the aging process that disrupts tissues’ normal functions by affecting neighboring cells, degrading the extracellular matrix, and reducing tissues’ regeneration capacity. Different degrees of abnormal placentation result in the severity of fetal growth restriction and its sequelae, including fetal death. This review aims to present the current knowledge and identify future research directions to understand better placental aging in late fetal growth restriction and unexplained stillbirth. We hypothesized that the final diagnosis of placental insufficiency can be made only using markers of placental senescence.
Development in the Mammalian Auditory System Depends on Transcription Factors
Authors: Elliott Karen L. , Pavlínková Gabriela , Chizhikov Victor V. , Yamoah Ebenezer N. , Fritzsch Bernd
Published: April 2021

We review the molecular basis of several transcription factors (Eya1, Sox2), including the three related genes coding basic helix–loop–helix (bHLH; see abbreviations) proteins (Neurog1, Neurod1, Atoh1) during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires Neurog1, followed by its downstream target Neurod1, to cross-regulate Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 expression for interactions with Atoh1. Upregulation of Atoh1 following Neurod1 loss changes some vestibular neurons’ fate into “hair cells”, highlighting the significant interplay between the bHLH genes. Further work showed that replacing Atoh1 by Neurog1 rescues some hair cells from complete absence observed in Atoh1 null mutants, suggesting that bHLH genes can partially replace one another. The inhibition of Atoh1 by Neurod1 is essential for proper neuronal cell fate, and in the absence of Neurod1, Atoh1 is upregulated, resulting in the formation of “intraganglionic” HCs. Additional genes, such as Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b, play a role in the auditory system. Finally, both Lmx1a and Lmx1b genes are essential for the cochlear organ of Corti, spiral ganglion neuron, and cochlear nuclei formation. We integrate the mammalian auditory system development to provide comprehensive insights beyond the limited perception driven by singular investigations of cochlear neurons, cochlear hair cells, and cochlear nuclei. A detailed analysis of gene expression is needed to understand better how upstream regulators facilitate gene interactions and mammalian auditory system development.
Type I Interferon Production of Plasmacytoid Dendritic Cells under Control
Authors: Bencze Dóra , Fekete Tünde , Pázmándi Kitti
Published: April 2021

One of the most powerful and multifaceted cytokines produced by immune cells are type I interferons (IFNs), the basal secretion of which contributes to the maintenance of immune homeostasis, while their activation-induced production is essential to effective immune responses. Although, each cell is capable of producing type I IFNs, plasmacytoid dendritic cells (pDCs) possess a unique ability to rapidly produce large amounts of them. Importantly, type I IFNs have a prominent role in the pathomechanism of various pDC-associated diseases. Deficiency in type I IFN production increases the risk of more severe viral infections and the development of certain allergic reactions, and supports tumor resistance; nevertheless, its overproduction promotes autoimmune reactions. Therefore, the tight regulation of type I IFN responses of pDCs is essential to maintain an adequate level of immune response without causing adverse effects. Here, our goal was to summarize those endogenous factors that can influence the type I IFN responses of pDCs, and thus might serve as possible therapeutic targets in pDC-associated diseases. Furthermore, we briefly discuss the current therapeutic approaches targeting the pDC-type I IFN axis in viral infections, cancer, autoimmunity, and allergy, together with their limitations defined by the Janus-faced nature of pDC-derived type I IFNs.
Caffeine-Cyclodextrin Complexes as Solids: Synthesis, Biological and Physicochemical Characterization
Authors: Szmeja Sebastian , Gubica Tomasz , Ostrowski Andrzej , Zalewska Aldona , Szeleszczuk Łukasz , Zawada Katarzyna , Zielińska-Pisklak Monika , Skowronek Krzysztof , Wiweger Małgorzata
Published: April 2021

Mechanochemical and in-solution synthesis of caffeine complexes with α-, β-, and γ-cyclodextrins was optimized. It was found that short-duration, low-energy cogrinding, and evaporation (instead of freeze-drying) are effective methods for the formation and isolation of these complexes. The products obtained, their pure components, and their mixtures were examined by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), FT-IR and Raman spectroscopy. Moreover, molecular modeling provided an improved understanding of the association process between the guest and host molecules in these complexes. The complexes were found to exhibit high toxicity in zebrafish (Danio rerio) embryos, in contrast to pure caffeine and cyclodextrins at the same molar concentrations. HPLC measurements of the caffeine levels in zebrafish embryos showed that the observed cytotoxicity is not caused by an increased caffeine concentration in the body of the organism, as the concentrations are similar regardless of the administered caffeine form. Therefore, the observed high toxicity could be the result of the synergistic effect of caffeine and cyclodextrins.
Lipopolysaccharide-Enhanced Responses against Aryl Hydrocarbon Receptor in FcgRIIb-Deficient Macrophages, a Profound Impact of an Environmental Toxin on a Lupus-Like Mouse Model
Authors: Udompornpitak Kanyarat , Bhunyakarnjanarat Thansita , Charoensappakit Awirut , Dang Cong Phi , Saisorn Wilasinee , Leelahavanichkul Asada
Published: April 2021

Fc gamma receptor IIb (FcgRIIb) is the only inhibitory-FcgR in the FcgR family, and FcgRIIb-deficient (FcgRIIb−/−) mice develop a lupus-like condition with hyper-responsiveness against several stimulations. The activation of aryl hydrocarbon receptor (Ahr), a cellular environmental sensor, might aggravate activity of the lupus-like condition. As such, 1,4-chrysenequinone (1,4-CQ), an Ahr-activator, alone did not induce supernatant cytokines from macrophages, while the 24 h pre-treatment by lipopolysaccharide (LPS), a representative inflammatory activator, prior to 1,4-CQ activation (LPS/1,4-CQ) predominantly induced macrophage pro-inflammatory responses. Additionally, the responses from FcgRIIb−/− macrophages were more prominent than wild-type (WT) cells as determined by (i) supernatant cytokines (TNF-α, IL-6, and IL-10), (ii) expression of the inflammation associated genes (NF-κB, aryl hydrocarbon receptor, iNOS, IL-1β and activating-FcgRIV) and cell-surface CD-86 (a biomarker of M1 macrophage polarization), and (iii) cell apoptosis (Annexin V), with the lower inhibitory-FcgRIIb expression. Moreover, 8-week-administration of 1,4-CQ in 8 week old FcgRIIb−/− mice, a genetic-prone lupus-like model, enhanced lupus characteristics as indicated by anti-dsDNA, serum creatinine, proteinuria, endotoxemia, gut-leakage (FITC-dextran), and glomerular immunoglobulin deposition. In conclusion, an Ahr activation worsened the disease severity in FcgRIIb−/− mice possibly through the enhanced inflammatory responses. The deficiency of inhibitory-FcgRIIb in these mice, at least in part, prominently enhanced the pro-inflammatory responses. Our data suggest that patients with lupus might be more vulnerable to environmental pollutants.
Differences in PARP Inhibitors for the Treatment of Ovarian Cancer: Mechanisms of Action, Pharmacology, Safety, and Efficacy
Authors: Valabrega Giorgio , Scotto Giulia , Tuninetti Valentina , Pani Arianna , Scaglione Francesco
Published: April 2021

Poly(ADP-ribose) polymerases (PARP) are proteins responsible for DNA damage detection and signal transduction. PARP inhibitors (PARPi) are able to interact with the binding site for PARP cofactor (NAD+) and trapping PARP on the DNA. In this way, they inhibit single-strand DNA damage repair. These drugs have been approved in recent years for the treatment of ovarian cancer. Although they share some similarities, from the point of view of the chemical structure and pharmacodynamic, pharmacokinetic properties, these drugs also have some substantial differences. These differences may underlie the different safety profiles and activity of PARPi.
Infiltration of Immune Competent Cells into Primary Tumors and Their Surrounding Connective Tissues in Xenograft and Syngeneic Mouse Models
Authors: Metzen Marlon , Bruns Michael , Deppert Wolfgang , Schumacher Udo
Published: April 2021

To fight cancer more efficiently with cell-based immunotherapy, more information about the cells of the immune system and their interaction with cancer cells in vivo is needed. Therefore paraffin wax embedded primary breast cancers from the syngeneic mouse WAP-T model and from xenografted tumors of breast, colon, melanoma, ovarian, neuroblastoma, pancreatic, prostate, and small cell lung cancer were investigated for the infiltration of immunocompetent cells by immunohistochemistry using antibodies against leukocyte markers. The following markers were used: CD45 as a pan-leukocyte marker, BSA-I as a dendritic cell marker, CD11b as an NK cell marker, and CD68 as a marker for macrophages. The labeled immune cells were attributed to the following locations: adjacent adipose tissue, tumor capsule, intra-tumoral septae, and cancer cells directly. In xenograft tumors, the highest score of CD45 and CD11b positive, NK, and dendritic cells were found in the adjacent adipose tissue, followed by lesser infiltration directly located at the cancer cells themselves. The detected numbers of CD45 positive cells differed between the tumor entities: few infiltrating cells in breast cancer, small cell lung cancer, neuroblastoma, a moderate infiltration in colon cancer, melanoma and ovarian cancer, strongest infiltration in prostate and pancreatic cancer. In the syngeneic tumors, the highest score of CD45 and CD11b positive, NK and dendritic cells were observed in the tumor capsule, followed by a lesser infiltration of the cancer tissue. Our findings argue for paying more attention to investigate how immune-competent cells can reach the tumor cells directly.
Method for the Production and Purification of Plant Immuno-Active Xylanase from Trichoderma
Authors: Anand Gautam , Leibman-Markus Meirav , Elkabetz Dorin , Bar Maya
Published: April 2021

Plants lack a circulating adaptive immune system to protect themselves against pathogens. Therefore, they have evolved an innate immune system based upon complicated and efficient defense mechanisms, either constitutive or inducible. Plant defense responses are triggered by elicitors such as microbe-associated molecular patterns (MAMPs). These components are recognized by pattern recognition receptors (PRRs) which include plant cell surface receptors. Upon recognition, PRRs trigger pattern-triggered immunity (PTI). Ethylene Inducing Xylanase (EIX) is a fungal MAMP protein from the plant-growth-promoting fungi (PGPF)–Trichoderma. It elicits plant defense responses in tobacco (Nicotiana tabacum) and tomato (Solanum lycopersicum), making it an excellent tool in the studies of plant immunity. Xylanases such as EIX are hydrolytic enzymes that act on xylan in hemicellulose. There are two types of xylanases: the endo-1, 4-β-xylanases that hydrolyze within the xylan structure, and the β-d-xylosidases that hydrolyze the ends of the xylan chain. Xylanases are mainly synthesized by fungi and bacteria. Filamentous fungi produce xylanases in high amounts and secrete them in liquid cultures, making them an ideal system for xylanase purification. Here, we describe a method for cost- and yield-effective xylanase production from Trichoderma using wheat bran as a growth substrate. Xylanase produced by this method possessed xylanase activity and immunogenic activity, effectively inducing a hypersensitive response, ethylene biosynthesis, and ROS burst.
Obesity, Nutrition and Heart Rate Variability
Authors: Strüven Anna , Holzapfel Christina , Stremmel Christopher , Brunner Stefan
Published: April 2021

Heart rate variability (HRV) represents the activity and balance of the autonomic nervous system and its capability to react to internal and external stimuli. As a measure of general body homeostasis, HRV is linked to lifestyle factors and it is associated with morbidity and mortality. It is easily accessible by heart rate monitoring and gains interest in the era of smart watches and self-monitoring. In this review, we summarize effects of weight loss, training, and nutrition on HRV with a special focus on obesity. Besides weight reduction, effects of physical activity and dietary intervention can be monitored by parameters of HRV, including its time and frequency domain components. In the future, monitoring of HRV should be included in any weight reduction program as it provides an additional tool to analyze the effect of body weight on general health and homeostasis. HRV parameters could, for example, be monitored easily by implementation of an electrocardiogram (ECG) every two to four weeks during weight reduction period. Indices presumibly showing beneficial changes could be a reduction in heart rate and the number of premature ventricular complexes as well as an increase in standard deviation of normal-to-normal beat intervals (SDNN), just to name some.
Current Strategies in Assessment of Nanotoxicity: Alternatives to In Vivo Animal Testing
Authors: Huang Hung-Jin , Lee Yu-Hsuan , Hsu Yung-Ho , Liao Chia-Te , Lin Yuh-Feng , Chiu Hui-Wen
Published: April 2021

Millions of experimental animals are widely used in the assessment of toxicological or biological effects of manufactured nanomaterials in medical technology. However, the animal consciousness has increased and become an issue for debate in recent years. Currently, the principle of the 3Rs (i.e., reduction, refinement, and replacement) is applied to ensure the more ethical application of humane animal research. In order to avoid unethical procedures, the strategy of alternatives to animal testing has been employed to overcome the drawbacks of animal experiments. This article provides current alternative strategies to replace or reduce the use of experimental animals in the assessment of nanotoxicity. The currently available alternative methods include in vitro and in silico approaches, which can be used as cost-effective approaches to meet the principle of the 3Rs. These methods are regarded as non-animal approaches and have been implemented in many countries for scientific purposes. The in vitro experiments related to nanotoxicity assays involve cell culture testing and tissue engineering, while the in silico methods refer to prediction using molecular docking, molecular dynamics simulations, and quantitative structure–activity relationship (QSAR) modeling. The commonly used novel cell-based methods and computational approaches have the potential to help minimize the use of experimental animals for nanomaterial toxicity assessments.
ATF3 Promotes Arsenic-Induced Apoptosis and Oppositely Regulates DR5 and Bcl-xL Expression in Human Bronchial Epithelial Cells
Authors: Shi Qiwen , Hu Bei , Yang Chen , Zhao Lan , Wu Jing , Qi Nan
Published: April 2021

Arsenic is one of the most common environmental pollutants eliciting serious public health issues; however, it is also a well-recognized chemotherapeutic agent for acute promyelocytic leukemia. The association between arsenic exposure and lung diseases has been established, but underlying molecular mechanisms are poorly defined. Here we investigated the toxicology of arsenic in airway epithelium. Arsenic rapidly induced the activating transcription factor ATF3 expression through the JNK and p38 pathways. The ATF3-deficient BEAS-2B cells were relatively resistant to apoptosis upon arsenic exposure, indicating a facilitatory role of ATF3 in arsenic-induced apoptosis. We further showed that ATF3 oppositely regulated the transcription of death receptor (DR5) and Bcl2-like 1 (Bcl-xL) by directly binding to the promoter DR5 and Bcl-xL. Altogether, our findings establish ATF3 as a pro-apoptotic protein in arsenic-induced airway epithelial apoptosis through transcriptionally regulating DR5 and Bcl-xL, highlighting the potential of ATF3 as an early and sensitive biomarker for arsenic-caused lung injury.
Core RNA Interference Genes Involved in miRNA and Ta-siRNA Biogenesis in Hops and Their Expression Analysis after Challenging with Verticillium nonalfalfae
Authors: Kunej Urban , Jakše Jernej , Radišek Sebastjan , Štajner Nataša
Published: April 2021

RNA interference is an evolutionary conserved mechanism by which organisms regulate the expression of genes in a sequence-specific manner to modulate defense responses against various abiotic or biotic stresses. Hops are grown for their use in brewing and, in recent years, for the pharmaceutical industry. Hop production is threatened by many phytopathogens, of which Verticillium, the causal agent of Verticillium wilt, is a major contributor to yield losses. In the present study, we performed identification, characterization, phylogenetic, and expression analyses of three Argonaute, two Dicer-like, and two RNA-dependent RNA polymerase genes in the susceptible hop cultivar Celeia and the resistant cultivar Wye Target after infection with Verticillium nonalfalfae. Phylogeny results showed clustering of hop RNAi proteins with their orthologues from the closely related species Cannabis sativa, Morus notabilis and Ziziphus jujuba which form a common cluster with species of the Rosaceae family. Expression analysis revealed downregulation of argonaute 2 in both cultivars on the third day post-inoculation, which may result in reduced AGO2-siRNA-mediated posttranscriptional gene silencing. Both cultivars may also repress ta-siRNA biogenesis at different dpi, as we observed downregulation of argonaute 7 in the susceptible cultivar on day 1 and downregulation of RDR6 in the resistant cultivar on day 3 after inoculation.
Role of Adipose Tissue in Inflammatory Bowel Disease
Authors: Karaskova Eva , Velganova-Veghova Maria , Geryk Milos , Foltenova Hana , Kucerova Veronika , Karasek David
Published: April 2021

Inflammatory bowel diseases (IBDs), chronic inflammatory disorders affecting the gastrointestinal tract, include Crohn’s disease and ulcerative colitis. There are increasing clinical and experimental data showing that obesity, especially visceral adiposity, plays a substantial role in the pathogenesis of IBD. Obesity seems to be an important risk factor also for IBD disease severity and clinical outcomes. Visceral adipose tissue is an active multifunctional metabolic organ involved in lipid storage and immunological and endocrine activity. Bowel inflammation penetrates the surrounding adipose tissue along the mesentery. Mesenteric fat serves as a barrier to inflammation and controls immune responses to the translocation of gut bacteria. At the same time, mesenteric adipose tissue may be the principal source of cytokines and adipokines responsible for inflammatory processes associated with IBD. This review is particularly focusing on the potential role of adipokines in IBD pathogenesis and their possible use as promising therapeutic targets.
Comparative Analysis of the Microbiome across the Gut–Skin Axis in Atopic Dermatitis
Authors: Park Dong Hoon , Kim Joo Wan , Park Hi-Joon , Hahm Dae-Hyun
Published: April 2021

Atopic dermatitis (AD) is a refractory and relapsing skin disease with a complex and multifactorial etiology. Various congenital malformations and environmental factors are thought to be involved in the onset of the disease. The etiology of the disease has been investigated, with respect to clinical skin symptoms and systemic immune response factors. A gut microbiome–mediated connection between emotional disorders such as depression and anxiety, and dermatologic conditions such as acne, based on the comorbidities of these two seemingly unrelated disorders, has long been hypothesized. Many aspects of this gut–brain–skin integration theory have recently been revalidated to identify treatment options for AD with the recent advances in metagenomic analysis involving powerful sequencing techniques and bioinformatics that overcome the need for isolation and cultivation of individual microbial strains from the skin or gut. Comparative analysis of microbial clusters across the gut–skin axis can provide new information regarding AD research. Herein, we provide a historical perspective on the modern investigation and clinical implications of gut–skin connections in AD in terms of the integration between the two microbial clusters.
The Gut Microbiota Affects Corticosterone Production in the Murine Small Intestine
Authors: Ergang Peter , Vagnerová Karla , Hermanová Petra , Vodička Martin , Jágr Michal , Šrůtková Dagmar , Dvořáček Václav , Hudcovic Tomáš , Pácha Jiří
Published: April 2021

Glucocorticoids (GCs) are hormones that are released in response to stressors and exhibit many activities, including immunomodulatory and anti-inflammatory activities. They are primarily synthesized in the adrenal gland but are also produced in peripheral tissues via regeneration of adrenal 11-oxo metabolites or by de novo synthesis from cholesterol. The present study investigated the influence of the microbiota on de novo steroidogenesis and regeneration of corticosterone in the intestine of germ-free (GF) and specific pathogen-free mice challenged with a physical stressor (anti-CD3 antibody i.p. injection). In the small intestine, acute immune stress resulted in increased mRNA levels of the proinflammatory cytokines IL1β, IL6 and Tnfα and genes involved in de novo steroidogenesis (Stard3 and Cyp11a1), as well as in regeneration of active GCs from their 11-oxo metabolites (Hsd11b1). GF mice showed a generally reduced transcriptional response to immune stress, which was accompanied by decreased intestinal corticosterone production and reduced expression of the GC-sensitive marker Fkbp5. In contrast, the interaction between stress and the microbiota was not detected at the level of plasma corticosterone or the transcriptional response of adrenal steroidogenic enzymes. The results indicate a differential immune stress-induced intestinal response to proinflammatory stimuli and local corticosterone production driven by the gut microbiota.
Attenuating Effects of Dieckol on Hypertensive Nephropathy in Spontaneously Hypertensive Rats
Authors: Son Myeongjoo , Oh Seyeon , Choi Junwon , Jang Ji Tae , Son Kuk Hui , Byun Kyunghee
Published: April 2021

Hypertension induces renal fibrosis or tubular interstitial fibrosis, which eventually results in end-stage renal disease. Epithelial-to-mesenchymal transition (EMT) is one of the underlying mechanisms of renal fibrosis. Though previous studies showed that Ecklonia cava extracts (ECE) and dieckol (DK) had inhibitory action on angiotensin (Ang) I-converting enzyme, which converts Ang I to Ang II. It is known that Ang II is involved in renal fibrosis; however, it was not evaluated whether ECE or DK attenuated hypertensive nephropathy by decreasing EMT. In this study, the effect of ECE and DK on decreasing Ang II and its down signal pathway of angiotensin type 1 receptor (AT1R)/TGFβ/SMAD, which is related with the EMT and restoring renal function in spontaneously hypertensive rats (SHRs), was investigated. Either ECE or DK significantly decreased the serum level of Ang II in the SHRs. Moreover, the renal expression of AT1R/TGFβ/SMAD was decreased by the administration of either ECE or DK. The mesenchymal cell markers in the kidney of SHRs was significantly decreased by ECE or DK. The fibrotic tissue of the kidney of SHRs was also significantly decreased by ECE or DK. The ratio of urine albumin/creatinine of SHRs was significantly decreased by ECE or DK. Overall, the results of this study indicate that ECE and DK decreased the serum levels of Ang II and expression of AT1R/TGFβ/SMAD, and then decreased the EMT and renal fibrosis in SHRs. Furthermore, the decrease in EMT and renal fibrosis could lead to the restoration of renal function. It seems that ECE or DK could be beneficial for decreasing hypertensive nephropathy by decreasing EMT and renal fibrosis.
Biochemical and Biophysical Characterization of Recombinant Human 3-Phosphoglycerate Dehydrogenase
Authors: Murtas Giulia , Marcone Giorgia Letizia , Peracchi Alessio , Zangelmi Erika , Pollegioni Loredano
Published: April 2021

The human enzyme D-3-phosphoglycerate dehydrogenase (hPHGDH) catalyzes the reversible dehydrogenation of 3-phosphoglycerate (3PG) into 3-phosphohydroxypyruvate (PHP) using the NAD+/NADH redox cofactor, the first step in the phosphorylated pathway producing L-serine. We focused on the full-length enzyme that was produced in fairly large amounts in E. coli cells; the effect of pH, temperature and ligands on hPHGDH activity was studied. The forward reaction was investigated on 3PG and alternative carboxylic acids by employing two coupled assays, both removing the product PHP; 3PG was by far the best substrate in the forward direction. Both PHP and α-ketoglutarate were efficiently reduced by hPHGDH and NADH in the reverse direction, indicating substrate competition under physiological conditions. Notably, neither PHP nor L-serine inhibited hPHGDH, nor did glycine and D-serine, the coagonists of NMDA receptors related to L-serine metabolism. The investigation of NADH and phosphate binding highlights the presence in solution of different conformations and/or oligomeric states of the enzyme. Elucidating the biochemical properties of hPHGDH will enable the identification of novel approaches to modulate L-serine levels and thus to reduce cancer progression and treat neurological disorders.
Detection of Antimicrobial Peptides in Stratum Corneum by Mass Spectrometry
Authors: Jenei Adrienn , Kalló Gergő , Dajnoki Zsolt , Gáspár Krisztián , Szegedi Andrea , Kapitány Anikó , Csősz Éva
Published: April 2021

Antimicrobial and immunomodulatory peptides (AMPs) are considered as the key players in the maintenance of skin barrier functions. Here, we developed a novel approach for the examination of AMPs in the outermost layer of the epidermis, namely stratum corneum (SC). The SC sample collection by tape stripping was coupled with detection by highly specific and sensitive parallel reaction monitoring (PRM)-based mass spectrometry. We found that hexane-free processing of SC samples produced higher protein yield compared to hexane-based extraction. Of the 18 investigated peptides, 9 could be detected either in healthy or in inflamed skin specimens. Regarding the amount of S100A8, LCN2, LACRT and LYZ significant topographical differences were described among gland poor (GP), sebaceous gland rich (SGR) and apocrine gland rich (AGR) healthy skin regions. We applied a minimally invasive, reproducible approach for sampling, which can be assessed for research and diagnostic purposes and for monitoring the effectiveness of therapies in skin diseases.
An Overview of Long Non-Coding (lnc)RNAs in Neuroblastoma
Authors: Baldini Francesca , Calderoni Matilde , Vergani Laura , Modesto Paola , Florio Tullio , Pagano Aldo
Published: April 2021

Neuroblastoma (NB) is a heterogeneous developmental tumor occurring in childhood, which arises from the embryonic sympathoadrenal cells of the neural crest. Although the recent progress that has been done on this tumor, the mechanisms involved in NB are still partially unknown. Despite some genetic aberrations having been identified, the sporadic cases represent the majority. Due to its wide heterogeneity in clinical behavior and etiology, NB represents a challenge in terms of prevention and treatment. Since a definitive therapy is lacking so far, there is an urgent necessity to unveil the molecular mechanisms behind NB onset and progression to develop new therapeutic approaches. Long non-coding RNAs (lncRNAs) are a group of RNAs longer than 200 nucleotides. Whether lncRNAs are destined to become a protein or not, they exert multiple biological functions such as regulating gene expression and functions. In recent decades, different research has highlighted the possible role of lncRNAs in the pathogenesis of many diseases, including cancer. Moreover, lncRNAs may represent potential markers or targets for diagnosis and treatment of diseases. This mini-review aimed to briefly summarize the most recent findings on the involvement of some lncRNAs in NB disease by focusing on their mechanisms of action and possible role in unveiling NB onset and progression.
Role of Microbiota-Derived Extracellular Vesicles in Gut-Brain Communication
Authors: Cuesta Carlos M. , Guerri Consuelo , Ureña Juan , Pascual María
Published: April 2021

Human intestinal microbiota comprise of a dynamic population of bacterial species and other microorganisms with the capacity to interact with the rest of the organism and strongly influence the host during homeostasis and disease. Commensal and pathogenic bacteria coexist in homeostasis with the intestinal epithelium and the gastrointestinal tract’s immune system, or GALT (gut-associated lymphoid tissue), of the host. However, a disruption to this homeostasis or dysbiosis by different factors (e.g., stress, diet, use of antibiotics, age, inflammatory processes) can cause brain dysfunction given the communication between the gut and brain. Recently, extracellular vesicles (EVs) derived from bacteria have emerged as possible carriers in gut-brain communication through the interaction of their vesicle components with immune receptors, which lead to neuroinflammatory immune response activation. This review discusses the critical role of bacterial EVs from the gut in the neuropathology of brain dysfunctions by modulating the immune response. These vesicles, which contain harmful bacterial EV contents such as lipopolysaccharide (LPS), peptidoglycans, toxins and nucleic acids, are capable of crossing tissue barriers including the blood-brain barrier and interacting with the immune receptors of glial cells (e.g., Toll-like receptors) to lead to the production of cytokines and inflammatory mediators, which can cause brain impairment and behavioral dysfunctions.
MiRNAs and Muscle Regeneration: Therapeutic Targets in Duchenne Muscular Dystrophy
Authors: Aránega Amelia Eva , Lozano-Velasco Estefanía , Rodriguez-Outeiriño Lara , Ramírez de Acuña Felicitas , Franco Diego , Hernández-Torres Francisco
Published: April 2021

microRNAs (miRNAs) are small non-coding RNAs required for the post-transcriptional control of gene expression. MicroRNAs play a critical role in modulating muscle regeneration and stem cell behavior. Muscle regeneration is affected in muscular dystrophies, and a critical point for the development of effective strategies for treating muscle disorders is optimizing approaches to target muscle stem cells in order to increase the ability to regenerate lost tissue. Within this framework, miRNAs are emerging as implicated in muscle stem cell response in neuromuscular disorders and new methodologies to regulate the expression of key microRNAs are coming up. In this review, we summarize recent advances highlighting the potential of miRNAs to be used in conjunction with gene replacement therapies, in order to improve muscle regeneration in the context of Duchenne Muscular Dystrophy (DMD).
Neuromedin U, a Key Molecule in Metabolic Disorders
Authors: Teranishi Hitoshi , Hanada Reiko
Published: April 2021

Obesity is now a public health concern. The leading cause of obesity is an energy imbalance between ingested and expended calories. The mechanisms of feeding behavior and energy metabolism are regulated by a complex of various kinds of molecules, including anorexigenic and orexigenic neuropeptides. One of these neuropeptides, neuromedin U (NMU), was isolated in the 1980s, and its specific receptors, NMUR1 and NMUR2, were defined in 2000. A series of subsequent studies has revealed many of the physiological roles of the NMU system, including in feeding behavior, energy expenditure, stress responses, circadian rhythmicity, and inflammation. Particularly over the past decades, many reports have indicated that the NMU system plays an essential and direct role in regulating body weight, feeding behavior, energy metabolism, and insulin secretion, which are tightly linked to obesity pathophysiology. Furthermore, another ligand of NMU receptors, NMS (neuromedin S), was identified in 2005. NMS has physiological functions similar to those of NMU. This review summarizes recent observations of the NMU system in relation to the pathophysiology of obesity in both the central nervous systems and the peripheral tissues.
Harnessing the Endogenous Plasticity of Pancreatic Islets: A Feasible Regenerative Medicine Therapy for Diabetes?
Authors: Lorenzo Petra I. , Cobo-Vuilleumier Nadia , Martín-Vázquez Eugenia , López-Noriega Livia , Gauthier Benoit R.
Published: April 2021

Diabetes is a chronic metabolic disease caused by an absolute or relative deficiency in functional pancreatic β-cells that leads to defective control of blood glucose. Current treatments for diabetes, despite their great beneficial effects on clinical symptoms, are not curative treatments, leading to a chronic dependence on insulin throughout life that does not prevent the secondary complications associated with diabetes. The overwhelming increase in DM incidence has led to a search for novel antidiabetic therapies aiming at the regeneration of the lost functional β-cells to allow the re-establishment of the endogenous glucose homeostasis. Here we review several aspects that must be considered for the development of novel and successful regenerative therapies for diabetes: first, the need to maintain the heterogeneity of islet β-cells with several subpopulations of β-cells characterized by different transcriptomic profiles correlating with differences in functionality and in resistance/behavior under stress conditions; second, the existence of an intrinsic islet plasticity that allows stimulus-mediated transcriptome alterations that trigger the transdifferentiation of islet non-β-cells into β-cells; and finally, the possibility of using agents that promote a fully functional/mature β-cell phenotype to reduce and reverse the process of dedifferentiation of β-cells during diabetes.
An Overview of the Sorption Studies of Contaminants on Poly(Ethylene Terephthalate) Microplastics in the Marine Environment
Authors: Lionetto Francesca , Esposito Corcione Carola
Published: April 2021

Marine pollution is one of the biggest environmental problems, mainly due to single-use or disposable plastic waste fragmenting into microplastics (MPs) and nanoplastics (NPs) and entering oceans from the coasts together with human-made MPs. A rapidly growing worry concerning environmental and human safety has stimulated research interest in the potential risks induced by the chemicals associated with MPs/NPs. In this framework, the present review analyzes the recent advances in adsorption and desorption studies of different contaminants species, both organic and metallic, on MPs made of Poly(Ethylene terephthalate). The choice of PET is motivated by its great diffusion among plastic items and, unfortunately, also in marine plastic pollution. Due to the ubiquitous presence of PET MPS/NPs, the interest in its role as a vector of contaminants has abruptly increased in the last three years, as demonstrated by the very high number of recent papers on sorption studies in different environments. The present review relies on a chemical engineering approach aimed at providing a deeper overview of both the sorption mechanisms of organic and metal contaminants to PET MPs/NPs and the most used adsorption kinetic models to predict the mass transfer process from the liquid phase to the solid adsorbent.
Exploring the Species Diversity of Edible Mushrooms in Yunnan, Southwestern China, by DNA Barcoding
Authors: Zhang Ying , Mo Meizi , Yang Liu , Mi Fei , Cao Yang , Liu Chunli , Tang Xiaozhao , Wang Pengfei , Xu Jianping
Published: April 2021

Yunnan Province, China, is famous for its abundant wild edible mushroom diversity and a rich source of the world’s wild mushroom trade markets. However, much remains unknown about the diversity of edible mushrooms, including the number of wild edible mushroom species and their distributions. In this study, we collected and analyzed 3585 mushroom samples from wild mushroom markets in 35 counties across Yunnan Province from 2010 to 2019. Among these samples, we successfully obtained the DNA barcode sequences from 2198 samples. Sequence comparisons revealed that these 2198 samples likely belonged to 159 known species in 56 different genera, 31 families, 11 orders, 2 classes, and 2 phyla. Significantly, 51.13% of these samples had sequence similarities to known species at lower than 97%, likely representing new taxa. Further phylogenetic analyses on several common mushroom groups including 1536 internal transcribed spacer (ITS) sequences suggested the existence of 20 new (cryptic) species in these groups. The extensive new and cryptic species diversity in wild mushroom markets in Yunnan calls for greater attention for the conservation and utilization of these resources. Our results on both the distinct barcode sequences and the distributions of these sequences should facilitate new mushroom species discovery and forensic authentication of high-valued mushrooms and contribute to the scientific inventory for the management of wild mushroom markets.
Green Leaf Volatile Confers Management of Late Blight Disease: A Green Vaccination in Potato
Authors: Najdabbasi Neda , Mirmajlessi Seyed Mahyar , Dewitte Kevin , Ameye Maarten , Mänd Marika , Audenaert Kris , Landschoot Sofie , Haesaert Geert
Published: April 2021

Yield losses of crops due to plant pathogens are a major threat in all agricultural systems. In view of environmental issues and legislative limitations for chemical crop protection products, the need to design new environmentally friendly disease management strategies has gained interest. Despite the unique capability of green leaf volatiles (GLVs) to suppress a broad spectrum of plant pathogens, their capacity to control the potato late-blight-causing agent Phytophthora infestans has not been well studied. This study addresses the potential role of the GLV Z-3-hexenyl acetate (Z-3-HAC) in decreasing the severity of late blight and the underlying gene-based evidence leading to this effect. Nine-week-old potato plants (Solanum tuberosum L.) were exposed to Z-3-HAC before they were inoculated with P. infestans genotypes at different time points. These pre-exposed potato plants exhibited slower disease development after infection with the highly pathogenic genotype of P. infestans (EU-13-A2) over time. Qualitative assessment showed that the exposed, infected plants possessed significantly lower sporulation intensity and disease severity compared to the control plants. Hypersensitive response (HR)-like symptoms were observed on the treated leaves when inoculated with different pathogen genotypes. No HR-like lesions were detected on the untreated leaves after infection. It was shown that the transcript levels of several defense-related genes, especially those that are involved in reactive oxygen species (ROS) production pathways were significantly expressed in plants at 48 and 72 h postexposure to the Z-3-HAC. The current work provides evidence on the role of Z-3-HAC in the increased protection of potato plants against late blight through plant immunity and offers new opportunities for the sustainable control of potato diseases.