bluuebunny/crossref_metadata_2025 huggingface dataset:
Decreased Levels of Soluble CD44 in a High-Risk Population following a Smoking Cessation Program
Authors: Smith Drew H. , Raslan Shahm , Reis Isildinha M. , Al-Awady Abdurrahman , Buitron Isabella , Perez Melanie , Liu Huaping , Halgowich Jerri , Gordon Claudia , Webb Hooper Monica , Barengo Noël C. , Franzmann Elizabeth J.
Published: December 2021

Tobacco is a risk factor of head and neck cancer (HNC) and smoking cessation alone may reduce HNC risk by 70%. Soluble CD44 (solCD44), a cell surface receptor linked to cell proliferation and migration, and total protein (TP) levels can detect early HNC. This study aims to determine whether salivary solCD44 and TP levels in oral rinses change following a smoking cessation program. 150 smokers provided oral rinse samples at baseline and at a 12-month follow-up after participation in a smoking cessation program. Assays to measure levels of solCD44, TP, and cotinine, a metabolite used as a biomarker of tobacco exposure, were completed. A paired-samples t-test was used to determine whether there was a statistically significant (p < 0.05) mean difference in biomarker levels before and after the program. Baseline and at 12-month follow-up data were available for 88 subjects, 21 of whom quit smoking entirely. Mean levels of solCD44 significantly decreased by 0.412 ng/mL from baseline to the 12-month follow-up, p = 0.010. There was no significant difference in mean TP levels, p = 0.975. Mean cotinine levels decreased significantly by 74.7 ng/mL, p = 0.035. This is the first work demonstrating an association between smoking cessation and decreased solCD44 levels in oral rinses. Decreased expression of the tumorigenic CD44 may be one mechanism by which smoking cessation lowers cancer risk.
Correction: Cazzoletti et al. Risk Factors Associated with Nursing Home COVID-19 Outbreaks: A Retrospective Cohort Study. Int. J. Environ. Res. Public Health 2021, 18, 8434
Authors: Cazzoletti Lucia , Zanolin Maria Elisabetta , Tocco Tussardi Ilaria , Alemayohu Mulubirhan Assefa , Zanetel Ernesto , Visentin Donatella , Fabbri Luca , Giordani Massimo , Ruscitti Giancarlo , Benetollo Pier Paolo , Tardivo Stefano , Torri Emanuele
Published: December 2021

The authors would like to make the following corrections to this paper [...]
Evaluation of Lower Limb Muscle Electromyographic Activity during 400 m Indoor Sprinting among Elite Female Athletes: A Cross-Sectional Study
Authors: Pietraszewski Przemysław , Gołaś Artur , Krzysztofik Michał , Śrutwa Marta , Zając Adam
Published: December 2021

The purpose of this cross-sectional study was to analyze changes in normalized surface electromyography (sEMG) signals for the gastrocnemius medialis, biceps femoris, gluteus maximus, tibialis anterior, and vastus lateralis muscles occurring during a 400 m indoor sprint between subsequent curved sections of the track. Ten well-trained female sprinters (age: 21 ± 4 years; body mass: 47 ± 5 kg; body height: 161 ± 7 cm; 400 m personal best: 52.4 ± 1.1 s) performed an all-out 400 m indoor sprint. Normalized sEMG signals were recorded bilaterally from the selected lower limb muscles. The two-way ANOVA (curve × side) revealed no statistically significant interaction. However, the main effect analysis showed that normalized sEMG signals significantly increased in subsequent curves run for all the studied muscles: gastrocnemius medialis (p = 0.003), biceps femoris (p < 0.0001), gluteus maximus (p = 0.044), tibialis anterior (p = 0.001), and vastus lateralis (p = 0.023), but differences between limbs were significant only for the gastrocnemius medialis (p = 0.012). The results suggest that the normalized sEMG signals for the lower limb muscles increased in successive curves during the 400 m indoor sprint. Moreover, the gastrocnemius medialis of the inner leg is highly activated while running curves; therefore, it should be properly prepared for high demands, and attention should be paid to the possibility of the occurrence of a negative adaptation, such as asymmetries.
The Relationships among Anxiety, Subjective Well-Being, Media Consumption, and Safety-Seeking Behaviors during the COVID-19 Epidemic
Authors: Luo Yi-Fang , Shen Heng-Yu , Yang Shu-Ching , Chen Liang-Ching
Published: December 2021

The COVID-19 epidemic has been confirmed as the largest scale outbreak of atypical pneumonia since the outbreak of severe acute respiratory syndrome (SARS) in 2003 and it has become a public health emergency of international concern. It exacerbated public confusion and anxiety, and the impact of COVID-19 on people needs to be better understood. Indeed, prior studies that conducted meta-analysis of longitudinal cohort research compared mental health before versus during the COVID-19 pandemic and proved that public health polices (e.g., city lockdowns, quarantines, avoiding gatherings, etc.) and COVID-19-related information that circulates on new media platforms directly affected citizen’s mental health and well-being. Hence, this research aims to explore Taiwanese people’s health status, anxiety, media sources for obtaining COVID-19 information, subjective well-being, and safety-seeking behavior during the COVID-19 epidemic and how they are associated. Online surveys were conducted through new media platforms, and 342 responses were included in the analysis. The research results indicate that the participants experienced different aspects of COVID-19 anxiety, including COVID-19 worry and perceived COVID-19 risk. Among the given media sources, the more participants searched for COVID-19 information on new media, the greater they worried about COVID-19. Furthermore, COVID-19 worry was positively related to safety-seeking behavior, while perceived COVID-19 risk was negatively related to subjective well-being. This paper concludes by offering some suggestions for future studies and pointing out limitations of the present study.
Developmental Origins of Cardiovascular Disease: Understanding High Mortality Rates in the American South
Authors: Senney Garrett T. , Steckel Richard H.
Published: December 2021

While many social scientists view heart disease as the outcome of current conditions, this cannot fully explain the significant geographic disparities in cardiovascular disease (CVD) mortality rates in the USA. The developmental origins hypothesis proposes that CVD vulnerability is created by poor conditions in utero that underbuilds major organs relative to those needed to process lush nutrition later in life. The American South underwent an economic transformation from persistent poverty to rapid economic growth in the post-World War II era. We use state-level data on income growth and current conditions to explain variation in CVD mortality rates in 2010–2011. Our proxy for unbalanced physical growth, the ratio of median household income in 1980 to that in 1950, has a large systematic influence on CVD mortality, an impact that increases dramatically with age. The income ratio combined with smoking, obesity, healthcare access, and education explain more than 70% of the variance in CVD mortality rates.
Cationic Phenosafranin Photosensitizers Based on Polyhedral Oligomeric Silsesquioxanes for Inactivation of Gram-Positive and Gram-Negative Bacteria
Authors: Rozga-Wijas Krystyna , Bak-Sypien Irena , Turecka Katarzyna , Narajczyk Magdalena , Waleron Krzysztof
Published: December 2021

The high photodynamic effect of the Newman strain of the S. aureus and of clinical strains of S. aureus MRSA 12673 and E. coli 12519 are observed for new cationic light-activated phenosafranin polyhedral oligomeric silsesquioxane (POSS) conjugates in vitro. Killing of bacteria was achieved at low concentrations of silsesquioxanes (0.38 µM) after light irradiation (λem. max = 522 nm, 10.6 mW/cm2) for 5 min. Water-soluble POSS-photosensitizers are synthesized by chemically coupling a phenosafranin dye (PSF) (3,7-diamino-5-phenylphenazine chloride) to an inorganic silsesquioxane cage activated by attachment of succinic anhydride rings. The chemical structure of conjugates is confirmed by 1H, 13C NMR, HRMS, IR, fluorescence spectroscopy and UV-VIS analyzes. The APDI and daunorubicin (DAU) synergy is investigated for POSSPSFDAU conjugates. Confocal microscopy experiments indicate a site of intracellular accumulation of the POSSPSF, whereas iBuPOSSPSF and POSSPSFDAU accumulate in the cell wall or cell membrane. Results from the TEM study show ruptured S. aureus cells with leaking cytosolic mass and distorted cells of E. coli. Bacterial cells are eradicated by ROS produced upon irradiation of the covalent conjugates that can kill the bacteria by destruction of cellular membranes, intracellular proteins and DNA through the oxidative damage of bacteria.
Systematic Review of Calcium Channels and Intracellular Calcium Signaling: Relevance to Pesticide Neurotoxicity
Authors: Costas-Ferreira Carmen , Faro Lilian R. F.
Published: December 2021

Pesticides of different chemical classes exert their toxic effects on the nervous system by acting on the different regulatory mechanisms of calcium (Ca2+) homeostasis. Pesticides have been shown to alter Ca2+ homeostasis, mainly by increasing its intracellular concentration above physiological levels. The pesticide-induced Ca2+ overload occurs through two main mechanisms: the entry of Ca2+ from the extracellular medium through the different types of Ca2+ channels present in the plasma membrane or its release into the cytoplasm from intracellular stocks, mainly from the endoplasmic reticulum. It has also been observed that intracellular increases in the Ca2+ concentrations are maintained over time, because pesticides inhibit the enzymes involved in reducing its levels. Thus, the alteration of Ca2+ levels can lead to the activation of various signaling pathways that generate oxidative stress, neuroinflammation and, finally, neuronal death. In this review, we also discuss some proposed strategies to counteract the detrimental effects of pesticides on Ca2+ homeostasis.
A Study on How Methionine Restriction Decreases the Body’s Hepatic and Lipid Deposition in Rice Field Eel (Monopterus albus)
Authors: Hu Yajun , Cai Minglang , Zhong Huan , Chu Wuying , Hu Yi
Published: December 2021

Methionine restriction reduces animal lipid deposition. However, the molecular mechanism underlying how the body reacts to the condition and regulates lipid metabolism remains unknown. In this study, a feeding trial was performed on rice field eel Monopterus albus with six isonitrogenous and isoenergetic feeds that included different levels of methionine (0, 2, 4, 6, 8, and 10 g/kg). Compared with M0 (0 g/kg), the crude lipid and crude protein of M. albus increased markedly in M8 (8 g/kg) (p < 0.05), serum (total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and non-esterified free fatty acids), and hepatic contents (hepatic lipase, apolipoprotein-A, fatty acid synthetase, total cholesterol, triglyceride, and lipoprteinlipase). However, in the serum, very-low-density lipoprotein and hepatic contents (hormone-sensitive triglyceride lipase, Acetyl CoA carboxylase, carnitine palmitoyltransterase, and mirosomal triglygeride transfer protein) decreased markedly in M8 (p < 0.05). The contents of hepatic C18:2n-6, C22:6n-3, and n-3PUFA in the M8 group were significantly higher than those in M0 (p < 0.05), and the contents of lipid droplets in M8 were higher than those in M0. Compared with M0, the hepatic gcn2, eif2α, hsl, mttp, ldlrap, pparα, cpt1, and cpt2 were remarkably downregulated in M8, while srebf2, lpl, moat2, dgat2, hdlbp, srebf1, fas, fads2, me1, pfae, and icdh were markedly upregulated in M8. Moreover, hepatic SREBP1 and FAS protein expression were upregulated significantly in M8 (p < 0.01). In short, methionine restriction decreased the lipid deposition of M. albus, especially for hepatic lipid deposition, and mainly downregulated hepatic fatty acid metabolism. Besides, gcn2 could be activated under methionine restriction.
New Frontiers in Peripheral Nerve Regeneration: Concerns and Remedies
Authors: Klimovich Polina , Rubina Kseniya , Sysoeva Veronika , Semina Ekaterina
Published: December 2021

Topical advances in studying molecular and cellular mechanisms responsible for regeneration in the peripheral nervous system have highlighted the ability of the nervous system to repair itself. Still, serious injuries represent a challenge for the morphological and functional regeneration of peripheral nerves, calling for new treatment strategies that maximize nerve regeneration and recovery. This review presents the canonical view of the basic mechanisms of nerve regeneration and novel data on the role of exosomes and their transferred microRNAs in intracellular communication, regulation of axonal growth, Schwann cell migration and proliferation, and stromal cell functioning. An integrated comprehensive understanding of the current mechanistic underpinnings will open the venue for developing new clinical strategies to ensure full regeneration in the peripheral nervous system.
The Eclectic Nature of Glioma-Infiltrating Macrophages and Microglia
Authors: Arrieta Víctor A. , Najem Hinda , Petrosyan Edgar , Lee-Chang Catalina , Chen Peiwen , Sonabend Adam M. , Heimberger Amy B.
Published: December 2021

Glioblastomas (GBMs) are complex ecosystems composed of highly multifaceted tumor and myeloid cells capable of responding to different environmental pressures, including therapies. Recent studies have uncovered the diverse phenotypical identities of brain-populating myeloid cells. Differences in the immune proportions and phenotypes within tumors seem to be dictated by molecular features of glioma cells. Furthermore, increasing evidence underscores the significance of interactions between myeloid cells and glioma cells that allow them to evolve in a synergistic fashion to sustain tumor growth. In this review, we revisit the current understanding of glioma-infiltrating myeloid cells and their dialogue with tumor cells in consideration of their increasing recognition in response and resistance to immunotherapies as well as the immune impact of the current chemoradiotherapy used to treat gliomas.
Review on the Use of Heavy Metal Deposits from Water Treatment Waste towards Catalytic Chemical Syntheses
Authors: Das Tushar Kanti , Poater Albert
Published: December 2021

The toxicity and persistence of heavy metals has become a serious problem for humans. These heavy metals accumulate mainly in wastewater from various industries’ discharged effluents. The recent trends in research are now focused not only on the removal efficiency of toxic metal particles, but also on their effective reuse as catalysts. This review discusses the types of heavy metals obtained from wastewater and their recovery through commonly practiced physico-chemical pathways. In addition, it covers the advantages of the new system for capturing heavy metals from wastewater, as compared to older conventional technologies. The discussion also includes the various structural aspects of trapping systems and their hypothesized mechanistic approaches to immobilization and further rejuvenation of catalysts. Finally, it concludes with the challenges and future prospects of this research to help protect the ecosystem.
Mitochondrial Oxidative Stress—A Causative Factor and Therapeutic Target in Many Diseases
Authors: Kowalczyk Paweł , Sulejczak Dorota , Kleczkowska Patrycja , Bukowska-Ośko Iwona , Kucia Marzena , Popiel Marta , Wietrak Ewa , Kramkowski Karol , Wrzosek Karol , Kaczyńska Katarzyna
Published: December 2021

The excessive formation of reactive oxygen species (ROS) and impairment of defensive antioxidant systems leads to a condition known as oxidative stress. The main source of free radicals responsible for oxidative stress is mitochondrial respiration. The deleterious effects of ROS on cellular biomolecules, including DNA, is a well-known phenomenon that can disrupt mitochondrial function and contribute to cellular damage and death, and the subsequent development of various disease processes. In this review, we summarize the most important findings that implicated mitochondrial oxidative stress in a wide variety of pathologies from Alzheimer disease (AD) to autoimmune type 1 diabetes. This review also discusses attempts to affect oxidative stress as a therapeutic avenue.
A Fibrin Coating Method of Polypropylene Meshes Enables the Adhesion of Menstrual Blood-Derived Mesenchymal Stromal Cells: A New Delivery Strategy for Stem Cell-Based Therapies
Authors: Marinaro Federica , Silva Joana M. , Barros Alexandre A. , Aroso Ivo M. , Gómez-Blanco Juan C. , Jardin Isaac , Lopez Jose J. , Pulido María , de Pedro María Ángeles , Reis Rui L. , Sánchez-Margallo Francisco Miguel , Casado Javier G. , López Esther
Published: December 2021

Polypropylene (PP) mesh is well-known as a gold standard of all prosthetic materials of choice for the reinforcement of soft tissues in case of hernia, organ prolapse, and urinary incontinence. The adverse effects that follow surgical mesh implantation remain an unmet medical challenge. Herein, it is outlined a new approach to allow viability and adhesion of human menstrual blood-derived mesenchymal stromal cells (MenSCs) on PP surgical meshes. A multilayered fibrin coating, based on fibrinogen and thrombin from a commercial fibrin sealant, was optimized to guarantee a homogeneous and stratified film on PP mesh. MenSCs were seeded on the optimized fibrin-coated meshes and their adhesion, viability, phenotype, gene expression, and immunomodulatory capacity were fully evaluated. This coating guaranteed MenSC viability, adhesion and did not trigger any change in their stemness and inflammatory profile. Additionally, MenSCs seeded on fibrin-coated meshes significantly decreased CD4+ and CD8+ T cell proliferation, compared to in vitro stimulated lymphocytes (p < 0.0001). Hence, the proposed fibrin coating for PP surgical meshes may allow the local administration of stromal cells and the reduction of the exacerbated inflammatory response following mesh implantation surgery. Reproducible and easy to adapt to other cell types, this method undoubtedly requires a multidisciplinary and translational approach to be improved for future clinical uses.
GPCRs Are Optimal Regulators of Complex Biological Systems and Orchestrate the Interface between Health and Disease
Authors: Leysen Hanne , Walter Deborah , Christiaenssen Bregje , Vandoren Romi , Harputluoğlu İrem , Van Loon Nore , Maudsley Stuart
Published: December 2021

GPCRs arguably represent the most effective current therapeutic targets for a plethora of diseases. GPCRs also possess a pivotal role in the regulation of the physiological balance between healthy and pathological conditions; thus, their importance in systems biology cannot be underestimated. The molecular diversity of GPCR signaling systems is likely to be closely associated with disease-associated changes in organismal tissue complexity and compartmentalization, thus enabling a nuanced GPCR-based capacity to interdict multiple disease pathomechanisms at a systemic level. GPCRs have been long considered as controllers of communication between tissues and cells. This communication involves the ligand-mediated control of cell surface receptors that then direct their stimuli to impact cell physiology. Given the tremendous success of GPCRs as therapeutic targets, considerable focus has been placed on the ability of these therapeutics to modulate diseases by acting at cell surface receptors. In the past decade, however, attention has focused upon how stable multiprotein GPCR superstructures, termed receptorsomes, both at the cell surface membrane and in the intracellular domain dictate and condition long-term GPCR activities associated with the regulation of protein expression patterns, cellular stress responses and DNA integrity management. The ability of these receptorsomes (often in the absence of typical cell surface ligands) to control complex cellular activities implicates them as key controllers of the functional balance between health and disease. A greater understanding of this function of GPCRs is likely to significantly augment our ability to further employ these proteins in a multitude of diseases.
Safety and Danger Considerations of Novel Treatments for Atopic Dermatitis in Context of Primary Cutaneous Lymphomas
Authors: Kołkowski Karol , Trzeciak Magdalena , Sokołowska-Wojdyło Małgorzata
Published: December 2021

The impact of new and emerging therapies on the microenvironment of primary cutaneous lymphomas (PCLs) has been recently raised in the literature. Concomitantly, novel treatments are already used or registered (dupilumab, upadacitinib) and others seem to be added to the armamentarium against atopic dermatitis. Our aim was to review the literature on interleukins 4, 13, 22, and 31, and JAK/STAT pathways in PCLs to elucidate the safety of using biologics (dupilumab, tralokinumab, fezakinumab, nemolizumab) and small molecule inhibitors (upadacitinib, baricitinib, abrocitinib, ruxolitinib, tofacitinib) in the treatment of atopic dermatitis. We summarized the current state of knowledge on this topic based on the search of the PubMed database and related references published before 21 October 2021. Our analysis suggests that some of the mentioned agents (dupilumab, ruxolitinib) and others may have a direct impact on the progression of cutaneous lymphomas. This issue requires further study and meticulous monitoring of patients receiving these drugs to ensure their safety, especially in light of the FDA warning on tofacitinib. In conclusion, in the case of the rapid progression of atopic dermatitis/eczema, especially in patients older than 40 years old, there is a necessity to perform a biopsy followed by a very careful pathological examination.
Identification of Co-Expressed Genes Related to Theacrine Synthesis in Tea Flowers at Different Developmental Stages
Authors: Chen Xiaomin , Shao Shuxian , Yang Ruxing , Gu Mengya , Wang Pengjie , Zhao Feng , Ye Naixing
Published: December 2021

Jiaocheng kucha is the first reported tea germplasm resource which contains theacrine founded in Fujian Province. Currently, the anabolic mechanism of theacrine within tea leaves is clear, but there are few studies focused on its flowers. In order to further explore the mechanism of theacrine synthesis and related genes in flowers, current study applied Jiaocheng kucha flowers (JC) as test materials and Fuding Dabaicha flowers (FD) as control materials to make transcriptome sequencing, and determination of purine alkaloid content in three different developmental periods (flower bud stage, whitening stage and full opening stage). The results showed that the flower in all stages of JC contained theacrine. The theacrine in the flower bud stage was significantly higher than in the other stages. The differentially expressed genes (DEGs) at three different developmental stages were screened from the transcriptome data, and were in a total of 5642, 8640 and 8465. These DEGs related to the synthesis of theacrine were primarily annotated to the pathways of purine alkaloids. Among them, the number of DEGs in xanthine synthesis pathway was the largest and upregulated in JC, while it was the smallest in caffeine synthesis pathway and downregulated in JC. Further weighted gene co-expression network (WGCNA) indicated that ADSL (CsTGY03G0002327), ADSL (CsTGY09G0001824) and UAZ (CsTGY06G0002694) may be a hub gene for the regulation of theacrine metabolism in JC. Our results will contribute to the identification of candidate genes related to the synthesis of theacrine in tea flowers, and explore the molecular mechanism of theacrine synthesis in JC at different developmental stages.
Structural Insights Support Targeting ASK1 Kinase for Therapeutic Interventions
Authors: Obsilova Veronika , Honzejkova Karolina , Obsil Tomas
Published: December 2021

Apoptosis signal-regulating kinase (ASK) 1, a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, modulates diverse responses to oxidative and endoplasmic reticulum (ER) stress and calcium influx. As a crucial cellular stress sensor, ASK1 activates c-Jun N-terminal kinases (JNKs) and p38 MAPKs. Their excessive and sustained activation leads to cell death, inflammation and fibrosis in various tissues and is implicated in the development of many neurological disorders, such as Alzheimer’s, Parkinson’s and Huntington disease and amyotrophic lateral sclerosis, in addition to cardiovascular diseases, diabetes and cancer. However, currently available inhibitors of JNK and p38 kinases either lack efficacy or have undesirable side effects. Therefore, targeted inhibition of their upstream activator, ASK1, stands out as a promising therapeutic strategy for treating such severe pathological conditions. This review summarizes recent structural findings on ASK1 regulation and its role in various diseases, highlighting prospects for ASK1 inhibition in the treatment of these pathologies.
Fluorescence Recognition of Anions Using a Heteroditopic Receptor: Homogenous and Two-Phase Sensing
Authors: Zaleskaya-Hernik Marta , Dobrzycki Łukasz , Karbarz Marcin , Romański Jan
Published: December 2021

In contrast to monotopic receptor 3, the anthracene functionalized squaramide dual-host receptor 1 is capable of selectively extracting sulfate salts, as was evidenced unambiguously by DOSY, mass spectrometry, fluorescent and ion chromatography measurements. The receptors were investigated in terms of anion and ion pair binding using the UV–vis and 1H NMR titrations method in acetonitrile. The reference anion receptor 3, lacking a crown ether unit, was found to lose the enhancement in anion binding induced by the presence of cations. Besides the ability to bind anions in an enhanced manner exhibited by ion pair receptors 2 and 4, changing the 1-aminoanthracene substituent resulted in their exhibiting a lower anion affinity than receptor 1. By using receptor 1 and adjusting the water content in organic phase it was possible to selectively detect sulfates both by “turn-off” and “turn-on” fluorescence, and to do so homogenously and under interfacial conditions. Such properties of receptor 1 have allowed the development of a new type of sensor capable of recognizing and extracting potassium sulfate from the aqueous medium across a phase boundary, resulting in an appropriate fluorescent response in the organic solution.
The Influence of an Adrenergic Antagonist Guanethidine (GUA) on the Distribution Pattern and Chemical Coding of Dorsal Root Ganglia (DRG) Neurons Supplying the Porcine Urinary Bladder
Authors: Janikiewicz Paweł , Wasilewska Barbara , Mazur Urszula , Franke-Radowiecka Amelia , Majewski Mariusz , Bossowska Agnieszka
Published: December 2021

Although guanethidine (GUA) was used in the past as a drug to suppress hyperactivity of the sympathetic nerve fibers, there are no available data concerning the possible action of this substance on the sensory component of the peripheral nervous system supplying the urinary bladder. Thus, the present study was aimed at disclosing the influence of intravesically instilled GUA on the distribution, relative frequency, and chemical coding of dorsal root ganglion neurons associated with the porcine urinary bladder. The investigated sensory neurons were visualized with a retrograde tracing method using Fast Blue (FB), while their chemical profile was disclosed with single-labeling immunohistochemistry using antibodies against substance P (SP), calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase activating polypeptide (PACAP), galanin (GAL), neuronal nitric oxide synthase (nNOS), somatostatin (SOM), and calbindin (CB). After GUA treatment, a slight decrease in the number of FB+ neurons containing SP was observed when compared with untreated animals (34.6 ± 6.5% vs. 45.6 ± 1.3%), while the number of retrogradely traced cells immunolabeled for GAL, nNOS, and CB distinctly increased (12.3 ± 1.0% vs. 7.4 ± 0.6%, 11.9 ± 0.6% vs. 5.4 ± 0.5% and 8.6 ± 0.5% vs. 2.7 ± 0.4%, respectively). However, administration of GUA did not change the number of FB+ neurons containing CGRP, PACAP, or SOM. The present study provides evidence that GUA significantly modifies the sensory innervation of the porcine urinary bladder wall and thus may be considered a potential tool for studying the plasticity of this subdivision of the bladder innervation.
Origin of Increased Solvent Accessibility of Peptide Bonds in Mutual Synergetic Folding Proteins
Authors: Magyar Csaba , Mentes Anikó , Cserző Miklós , Simon István
Published: December 2021

Mutual Synergetic Folding (MSF) proteins belong to a recently discovered class of proteins. These proteins are disordered in their monomeric but ordered in their oligomeric forms. Their amino acid composition is more similar to globular proteins than to disordered ones. Our preceding work shed light on important structural aspects of the structural organization of these proteins, but the background of this behavior is still unknown. We suggest that solvent accessibility is an important factor, especially solvent accessibility of the peptide bonds can be accounted for this phenomenon. The side chains of the amino acids which form a peptide bond have a high local contribution to the shielding of the peptide bond from the solvent. During the oligomerization step, other non-local residues contribute to the shielding. We investigated these local and non-local effects of shielding based on Shannon information entropy calculations. We found that MSF and globular homodimeric proteins have different local contributions resulting from different amino acid pair frequencies. Their non-local distribution is also different because of distinctive inter-subunit contacts.
Investigation of Shape Transformations of Vesicles, Induced by Their Adhesion to Flat Substrates Characterized by Different Adhesion Strength
Authors: Raval Jeel , Iglič Aleš , Góźdź Wojciech
Published: December 2021

The adhesion of lipid vesicles to a rigid flat surface is investigated. We examine the influence of the membrane spontaneous curvature, adhesion strength, and the reduced volume on the stability and shape transformations of adhered vesicles. The minimal strength of the adhesion necessary to stabilize the shapes of adhered vesicles belonging to different shape classes is determined. It is shown that the budding of an adhered vesicle may be induced by the change of the adhesion strength. The importance of the free vesicle shape for its susceptibility to adhesion is discussed.
SLC22 Transporters in the Fly Renal System Regulate Response to Oxidative Stress In Vivo
Authors: Zhang Patrick , Azad Priti , Engelhart Darcy C. , Haddad Gabriel G. , Nigam Sanjay K.
Published: December 2021

Several SLC22 transporters in the human kidney and other tissues are thought to regulate endogenous small antioxidant molecules such as uric acid, ergothioneine, carnitine, and carnitine derivatives. These transporters include those from the organic anion transporter (OAT), OCTN/OCTN-related, and organic cation transporter (OCT) subgroups. In mammals, it has been difficult to show a clear in vivo role for these transporters during oxidative stress. Ubiquitous knockdowns of related Drosophila SLC22s—including transporters homologous to those previously identified by us in mammals such as the “Fly-Like Putative Transporters” FLIPT1 (SLC22A15) and FLIPT2 (SLC22A16)—have shown modest protection against oxidative stress. However, these fly transporters tend to be broadly expressed, and it is unclear if there is an organ in which their expression is critical. Using two tissue-selective knockdown strategies, we were able to demonstrate much greater and longer protection from oxidative stress compared to previous whole fly knockdowns as well as both parent and WT strains (CG6126: p < 0.001, CG4630: p < 0.01, CG16727: p < 0.0001 and CG6006: p < 0.01). Expression in the Malpighian tubule and likely other tissues as well (e.g., gut, fat body, nervous system) appear critical for managing oxidative stress. These four Drosophila SLC22 genes are similar to human SLC22 transporters (CG6126: SLC22A16, CG16727: SLC22A7, CG4630: SLC22A3, and CG6006: SLC22A1, SLC22A2, SLC22A3, SLC22A6, SLC22A7, SLC22A8, SLC22A11, SLC22A12 (URAT1), SLC22A13, SLC22A14)—many of which are highly expressed in the kidney. Consistent with the Remote Sensing and Signaling Theory, this indicates an important in vivo role in the oxidative stress response for multiple SLC22 transporters within the fly renal system, perhaps through interaction with SLC22 counterparts in non-renal tissues. We also note that many of the human relatives are well-known drug transporters. Our work not only indicates the importance of SLC22 transporters in the fly renal system but also sets the stage for in vivo studies by examining their role in mammalian oxidative stress and organ crosstalk.
Whole Exome Sequencing-Based Identification of a Novel Gene Involved in Root Hair Development in Barley (Hordeum vulgare L.)
Authors: Gajek Katarzyna , Janiak Agnieszka , Korotko Urszula , Chmielewska Beata , Marzec Marek , Szarejko Iwona
Published: December 2021

Root hairs play a crucial role in anchoring plants in soil, interaction with microorganisms and nutrient uptake from the rhizosphere. In contrast to Arabidopsis, there is a limited knowledge of root hair morphogenesis in monocots, including barley (Hordeum vulgare L.). We have isolated barley mutant rhp1.e with an abnormal root hair phenotype after chemical mutagenesis of spring cultivar ‘Sebastian’. The development of root hairs was initiated in the mutant but inhibited at the very early stage of tip growth. The length of root hairs reached only 3% of the length of parent cultivar. Using a whole exome sequencing (WES) approach, we identified G1674A mutation in the HORVU1Hr1G077230 gene, located on chromosome 1HL and encoding a cellulose synthase-like C1 protein (HvCSLC1) that might be involved in the xyloglucan (XyG) synthesis in root hairs. The identified mutation led to the retention of the second intron and premature termination of the HvCSLC1 protein. The mutation co-segregated with the abnormal root hair phenotype in the F2 progeny of rhp1.e mutant and its wild-type parent. Additionally, different substitutions in HORVU1Hr1G077230 were found in four other allelic mutants with the same root hair phenotype. Here, we discuss the putative role of HvCSLC1 protein in root hair tube elongation in barley.
Identification of African Swine Fever Virus Inhibitors through High Performance Virtual Screening Using Machine Learning
Authors: Choi Jiwon , Tark Dongseob , Lim Yun-Sook , Hwang Soon B.
Published: December 2021

African swine fever virus (ASFV) is a highly contagious virus that causes severe hemorrhagic viral disease resulting in high mortality in domestic and wild pigs, until few antiviral agents can inhibit ASFV infections. Thus, new anti-ASFV drugs need to be urgently identified. Recently, we identified pentagastrin as a potential antiviral drug against ASFVs using molecular docking and machine learning models. However, the scoring functions are easily influenced by properties of protein pockets, resulting in a scoring bias. Here, we employed the 5′-P binding pocket of AsfvPolX as a potential binding site to identify antiviral drugs and classified 13 AsfvPolX structures into three classes based on pocket parameters calculated by the SiteMap module. We then applied principal component analysis to eliminate this scoring bias, which was effective in making the SP Glide score more balanced between 13 AsfvPolX structures in the dataset. As a result, we identified cangrelor and fostamatinib as potential antiviral drugs against ASFVs. Furthermore, the classification of the pocket properties of AsfvPolX protein can provide an alternative approach to identify novel antiviral drugs by optimizing the scoring function of the docking programs. Here, we report a machine learning-based novel approach to generate high binding affinity compounds that are individually matched to the available classification of the pocket properties of AsfvPolX protein.
Zebrafish Embryos and Larvae as Alternative Animal Models for Toxicity Testing
Authors: Bauer Benedikt , Mally Angela , Liedtke Daniel
Published: December 2021

Prerequisite to any biological laboratory assay employing living animals is consideration about its necessity, feasibility, ethics and the potential harm caused during an experiment. The imperative of these thoughts has led to the formulation of the 3R-principle, which today is a pivotal scientific standard of animal experimentation worldwide. The rising amount of laboratory investigations utilizing living animals throughout the last decades, either for regulatory concerns or for basic science, demands the development of alternative methods in accordance with 3R to help reduce experiments in mammals. This demand has resulted in investigation of additional vertebrate species displaying favourable biological properties. One prominent species among these is the zebrafish (Danio rerio), as these small laboratory ray-finned fish are well established in science today and feature outstanding biological characteristics. In this review, we highlight the advantages and general prerequisites of zebrafish embryos and larvae before free-feeding stages for toxicological testing, with a particular focus on cardio-, neuro, hepato- and nephrotoxicity. Furthermore, we discuss toxicokinetics, current advances in utilizing zebrafish for organ toxicity testing and highlight how advanced laboratory methods (such as automation, advanced imaging and genetic techniques) can refine future toxicological studies in this species.
Neuroprotective Effect of Glatiramer Acetate on Neurofilament Light Chain Leakage and Glutamate Excess in an Animal Model of Multiple Sclerosis
Authors: Aharoni Rina , Eilam Raya , Lerner Shaul , Shavit-Stein Efrat , Dori Amir , Chapman Joab , Arnon Ruth
Published: December 2021

Axonal and neuronal pathologies are a central constituent of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), induced by the myelin oligodendrocyte glycoprotein (MOG) 35–55 peptide. In this study, we investigated neurodegenerative manifestations in chronic MOG 35–55 induced EAE and the effect of glatiramer acetate (GA) treatment on these manifestations. We report that the neuronal loss seen in this model is not attributed to apoptotic neuronal cell death. In EAE-affected mice, axonal damage prevails from the early disease phase, as revealed by analysis of neurofilament light (NFL) leakage into the sera along the disease duration, as well as by immunohistological examination. Elevation of interstitial glutamate concentrations measured in the cerebrospinal fluid (CSF) implies that glutamate excess plays a role in the damage processes inflicted by this disease. GA applied as a therapeutic regimen to mice with apparent clinical symptoms significantly reduces the pathological manifestations, namely apoptotic cell death, NFL leakage, histological tissue damage, and glutamate excess, thus corroborating the neuroprotective consequences of this treatment.
Role of Organic Cation Transporter 3 and Plasma Membrane Monoamine Transporter in the Rewarding Properties and Locomotor Sensitizing Effects of Amphetamine in Male andFemale Mice
Authors: Clauss Nikki J. , Koek Wouter , Daws Lynette C.
Published: December 2021

A lack of effective treatment and sex-based disparities in psychostimulant addiction and overdose warrant further investigation into mechanisms underlying the abuse-related effects of amphetamine-like stimulants. Uptake-2 transporters such as organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT), lesser studied potential targets for the actions of stimulant drugs, are known to play a role in monoaminergic neurotransmission. Our goal was to examine the roles of OCT3 and PMAT in mediating amphetamine (1 mg/kg)-induced conditioned place preference (CPP) and sensitization to its locomotor stimulant effects, in males and females, using pharmacological, decynium-22 (D22; 0.1 mg/kg, a blocker of OCT3 and PMAT) and genetic (constitutive OCT3 and PMAT knockout (−/−) mice) approaches. Our results show that OCT3 is necessary for the development of CPP to amphetamine in males, whereas in females, PMAT is necessary for the ability of D22 to prevent the development of CPP to amphetamine. Both OCT3 and PMAT appear to be important for development of sensitization to the locomotor stimulant effect of amphetamine in females, and PMAT in males. Taken together, these findings support an important, sex-dependent role of OCT3 and PMAT in the rewarding and locomotor stimulant effects of amphetamine.
Distal Lung Microenvironment Triggers Release of Mediators Recognized as Potential Systemic Biomarkers for Idiopathic Pulmonary Fibrosis
Authors: Kalafatis Dimitrios , Löfdahl Anna , Näsman Per , Dellgren Göran , Wheelock Åsa M. , Elowsson Rendin Linda , Sköld Magnus , Westergren-Thorsson Gunilla
Published: December 2021

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with an unmet need of biomarkers that can aid in the diagnostic and prognostic assessment of the disease and response to treatment. In this two-part explorative proteomic study, we demonstrate how proteins associated with tissue remodeling, inflammation and chemotaxis such as MMP7, CXCL13 and CCL19 are released in response to aberrant extracellular matrix (ECM) in IPF lung. We used a novel ex vivo model where decellularized lung tissue from IPF patients and healthy donors were repopulated with healthy fibroblasts to monitor locally released mediators. Results were validated in longitudinally collected serum samples from 38 IPF patients and from 77 healthy controls. We demonstrate how proteins elevated in the ex vivo model (e.g., MMP7), and other serum proteins found elevated in IPF patients such as HGF, VEGFA, MCP-3, IL-6 and TNFRSF12A, are associated with disease severity and progression and their response to antifibrotic treatment. Our study supports the model’s applicability in studying mechanisms involved in IPF and provides additional evidence for both established and potentially new biomarkers in IPF.
Molecular Morphology and Function of Stromal Cells
Authors: Manetti Mirko
Published: December 2021

The term “stromal cells” refers to a highly heterogeneous class of connective tissue cells that build the infrastructure of any organ and fulfill a variety of fundamental roles in health and disease [...]
It Is High Time Physicians Thought of Natural Products for Alleviating NAFLD. Is There Sufficient Evidence to Use Them?
Authors: Tarantino Giovanni , Balsano Clara , Santini Silvano Junior , Brienza Giovanni , Clemente Irma , Cosimini Benedetta , Sinatti Gaia
Published: December 2021

Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease all over the world due to the obesity pandemic; currently, therapeutic options for NAFLD are scarce, except for diet recommendations and physical activity. NAFLD is characterized by excessive accumulation of fat deposits (>5%) in the liver with subsequent inflammation and fibrosis. Studies in the literature show that insulin resistance (IR) may be considered as the key mechanism in the onset and progression of NAFLD. Recently, using natural products as an alternative approach in the treatment of NAFLD has drawn growing attention among physicians. In this review, the authors present the most recent randomized controlled trials (RCTs) and lines of evidence from animal models about the efficacy of nutraceutics in alleviating NAFLD. Among the most studied substances in the literature, the following molecules were chosen because of their presence in the literature of both clinical and preclinical studies: spirulina, oleuropein, garlic, berberine, resveratrol, curcumin, ginseng, glycyrrhizin, coffee, cocoa powder, epigallocatechin-3-gallate, and bromelain.
Hippo Pathway in Regulating Drug Resistance of Glioblastoma
Authors: Casati Giacomo , Giunti Laura , Iorio Anna Lisa , Marturano Arianna , Galli Luisa , Sardi Iacopo
Published: December 2021

Glioblastoma (GBM) represents the most common and malignant tumor of the Central Nervous System (CNS), affecting both children and adults. GBM is one of the deadliest tumor types and it shows a strong multidrug resistance (MDR) and an immunosuppressive microenvironment which remain a great challenge to therapy. Due to the high recurrence of GBM after treatment, the understanding of the chemoresistance phenomenon and how to stimulate the antitumor immune response in this pathology is crucial. The deregulation of the Hippo pathway is involved in tumor genesis, chemoresistance and immunosuppressive nature of GBM. This pathway is an evolutionarily conserved signaling pathway with a kinase cascade core, which controls the translocation of YAP (Yes-Associated Protein)/TAZ (Transcriptional Co-activator with PDZ-binding Motif) into the nucleus, leading to regulation of organ size and growth. With this review, we want to highlight how chemoresistance and tumor immunosuppression work in GBM and how the Hippo pathway has a key role in them. We linger on the role of the Hippo pathway evaluating the effect of its de-regulation among different human cancers. Moreover, we consider how different pathways are cross-linked with the Hippo signaling in GBM genesis and the hypothetical mechanisms responsible for the Hippo pathway activation in GBM. Furthermore, we describe various drugs targeting the Hippo pathway. In conclusion, all the evidence described largely support a strong involvement of the Hippo pathway in gliomas progression, in the activation of chemoresistance mechanisms and in the development of an immunosuppressive microenvironment. Therefore, this pathway is a promising target for the treatment of high grade gliomas and in particular of GBM.
Verteporfin-Loaded Mesoporous Silica Nanoparticles’ Topical Applications Inhibit Mouse Melanoma Lymphangiogenesis and Micrometastasis In Vivo
Authors: Clemente Nausicaa , Miletto Ivana , Gianotti Enrica , Sabbatini Maurizio , Invernizzi Marco , Marchese Leonardo , Dianzani Umberto , Renò Filippo
Published: December 2021

Photodynamic therapy (PDT) has been pointed out as a candidate for improving melanoma treatment. Nanotechnology application in PDT has increased its efficacy by reducing side effects. Herein, mesoporous silica nanoparticles (MSNs) conjugated with verteporfin (Ver-MSNs), in use with PDT, were administered in mice to evaluate their efficacy on lymphoangiogenesis and micrometastasis in melanoma. Melanoma was induced in mice by the subcutaneous injection of B16-F10 cells. The mice were transcutaneously treated with MSNs, Ver-MSNs, or glycerol and exposed to red light. The treatment was carried out four times until day 20. Lymphangiogenesis and micrometastasis were identified by the immunohistochemical method. Lymphoangiogenesis was halved by MSN treatment compared with the control animals, whereas the Ver-MSN treatment almost abolished it. A similar reduction was also observed in lung micrometastasis. PDT with topically administrated Ver-MSNs reduced melanoma lymphoangiogenesis and lung micrometastasis, as well as tumor mass and angiogenesis, and therefore their use could be an innovative and useful tool in melanoma clinical therapy.