bluuebunny/crossref_metadata_2025 huggingface dataset:
N-Acylated and N-Alkylated 2-Aminobenzothiazoles Are Novel Agents That Suppress the Generation of Prostaglandin E2
Authors: Theodoropoulou Maria A. , Psarra Anastasia , Erhardt Martin , Nikolaou Aikaterini , Gerogiannopoulou Anna-Dimitra D. , Hadjipavlou-Litina Dimitra , Hayashi Daiki , Dennis Edward A. , Huwiler Andrea , Kokotos George
Published: February 2022

The quest for novel agents to regulate the generation of prostaglandin E2 (PGE2) is of high importance because this eicosanoid is a key player in inflammatory diseases. We synthesized a series of N-acylated and N-alkylated 2-aminobenzothiazoles and related heterocycles (benzoxazoles and benzimidazoles) and evaluated their ability to suppress the cytokine-stimulated generation of PGE2 in rat mesangial cells. 2-Aminobenzothiazoles, either acylated by the 3-(naphthalen-2-yl)propanoyl moiety (GK510) or N-alkylated by a chain carrying a naphthalene (GK543) or a phenyl moiety (GK562) at a distance of three carbon atoms, stand out in inhibiting PGE2 generation, with EC50 values ranging from 118 nM to 177 nM. Both GK510 and GK543 exhibit in vivo anti-inflammatory activity greater than that of indomethacin. Thus, N-acylated or N-alkylated 2-aminobenzothiazoles are novel leads for the regulation of PGE2 formation.
Mesenchymal Stem Cells Isolated from Paediatric Paravertebral Adipose Tissue Show Strong Osteogenic Potential
Authors: Rožanc Jan , Gradišnik Lidija , Velnar Tomaž , Gregorič Minja , Milojević Marko , Vihar Boštjan , Gole Boris , Maver Uroš
Published: February 2022

Mesenchymal stem cells (MSCs) represent the basis of novel clinical concepts in cellular therapy and tissue regeneration. Therefore, the isolation of MSCs from various tissues has become an important endeavour for stem cell biobanking and the development of regenerative therapies. Paravertebral adipose tissue is readily exposed during spinal procedures in children and could be a viable source of stem cells for therapeutic applications. Here, we describe the first case of MSCs isolated from paravertebral adipose tissue (PV-ADMSCs), obtained during a routine spinal surgery on a child. Using quantitative real-time PCR and flow cytometry, we show that PV-ADMSCs have different levels of stem marker expression compared to the MSCs from other sources while having the highest proliferation rate. Furthermore, we evaluate the multipotency of PV-ADMSCs by the three-lineage (adipogenic, osteogenic and chondrogenic) differentiation and compare it to the multipotency of MSCs from other sources. It was found that the PV-ADMSCs have a strong osteogenic potential in particular. Taken together, our data indicate that PV-ADMSCs meet the criteria for successful cell therapy, defined by the International Society for Cellular Therapy (ISCT), and thus, could provide a source of MSCs that is relatively easy to isolate and expand in culture. Due to their strong osteogenic potential, these cells provide a promising basis, especially for orthopaedic applications.
Bacterial Translocation in Gastrointestinal Cancers and Cancer Treatment
Authors: Kouzu Keita , Tsujimoto Hironori , Kishi Yoji , Ueno Hideki , Shinomiya Nariyoshi
Published: February 2022

In recent years, there has been increasing evidence that gut microbiota is associated with the onset and exacerbation of various diseases, such as gastrointestinal cancer. For instance, it is well known that local inflammation of the intestinal tract in colorectal cancer that is caused by the increased number of Fusobacterium, due to changes in the intestinal bacterial flora, is involved in carcinogenesis. In contrast, gut bacteria or their products, pathogen-associated molecular patterns, not only cause intestinal inflammation but also invade the bloodstream through dysbiosis and gut barrier dysfunction, thereby leading to systemic inflammation, namely bacterial translocation. The involvement of bacterial translocation in the carcinogenesis of gastrointestinal cancers and their prognosis is increasingly being recognized. The Toll-like receptor signaling pathways plays an important role in the carcinogenesis of such cancers. In addition, bacterial translocation influences the treatment of cancers such as surgery and chemotherapy. In this review, we outline the concept of bacterial translocation, summarize the current knowledge on the relationship between gut bacteria and gastrointestinal cancer, and provide future perspectives of this field.
Photodynamic Inactivation of Antibiotic-Resistant and Sensitive Aeromonas hydrophila with Peripheral Pd(II)- vs. Zn(II)-Phthalocyanines
Authors: Mantareva Vanya N. , Kussovski Vesselin , Orozova Petya , Dimitrova Lyudmila , Kulu Irem , Angelov Ivan , Durmus Mahmut , Najdenski Hristo
Published: February 2022

The antimicrobial multidrug resistance (AMR) of pathogenic bacteria towards currently used antibiotics has a remarkable impact on the quality and prolongation of human lives. An effective strategy to fight AMR is the method PhotoDynamic Therapy (PDT). PDT is based on a joint action of a photosensitizer, oxygen, and light within a specific spectrum. This results in the generation of singlet oxygen and other reactive oxygen species that can inactivate the pathogenic cells without further regrowth. This study presents the efficacy of a new Pd(II)- versus Zn(II)-phthalocyanine complexes with peripheral positions of methylpyridiloxy substitution groups (pPdPc and ZnPcMe) towards Gram-negative bacteria Aeromonas hydrophila (A.hydrophila). Zn(II)-phthalocyanine, ZnPcMe was used as a reference compound for in vitro studies, bacause it is well-known with a high photodynamic inactivation ability for different pathogenic microorganisms. The studied new isolates of A.hydrophila were antibiotic-resistant (R) and sensitive (S) strains. The photoinactivation results showed a full effect with 8 µM pPdPc for S strain and with 5 µM ZnPcMe for both R and S strains. Comparison between both new isolates of A.hydrophila (S and R) suggests that the uptakes and more likely photoinactivation efficacy of the applied phthalocyanines are independent of the drug sensitivity of the studied strains.
In Vivo Evaluation of ECP Peptide Analogues for the Treatment of Acinetobacter baumannii Infection
Authors: Li Jiarui , Prats-Ejarque Guillem , Torrent Marc , Andreu David , Brandenburg Klaus , Fernández-Millán Pablo , Boix Ester
Published: February 2022

Antimicrobial peptides (AMPs) are alternative therapeutics to traditional antibiotics against bacterial resistance. Our previous work identified an antimicrobial region at the N-terminus of the eosinophil cationic protein (ECP). Following structure-based analysis, a 30mer peptide (ECPep-L) was designed that combines antimicrobial action against Gram-negative species with lipopolysaccharides (LPS) binding and endotoxin-neutralization activities. Next, analogues that contain non-natural amino acids were designed to increase serum stability. Here, two analogues were selected for in vivo assays: the all-D version (ECPep-D) and the Arg to Orn version that incorporates a D-amino acid at position 2 (ECPep-2D-Orn). The peptide analogues retained high LPS-binding and anti-endotoxin activities. The peptides efficacy was tested in a murine acute infection model of Acinetobacter baumannii. Results highlighted a survival rate above 70% following a 3-day supervision with a single administration of ECPep-D. Moreover, in both ECPep-D and ECPep-2D-Orn peptide-treated groups, clinical symptoms improved significantly and the tissue infection was reduced to equivalent levels to mice treated with colistin, used as a last resort in the clinics. Moreover, treatment drastically reduced serum levels of TNF-α inflammation marker within the first 8 h. The present results support ECP-derived peptides as alternative candidates for the treatment of acute infections caused by Gram-negative bacteria.
New Tricks with Old Dogs: Computational Identification and Experimental Validation of New miRNA–mRNA Regulation in hiPSC-CMs
Authors: Bencun Maja , Britto-Borges Thiago , Eschenbach Jessica , Dieterich Christoph
Published: February 2022

Cardiovascular disease is still the leading cause of morbidity and mortality worldwide. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a valuable widespread in vitro model to study cardiac disease. Herein, we employ the hiPSC-CM model to identify novel miRNA–mRNA interaction partners during cardiac differentiation and β-adrenergic stress. Whole transcriptome and small RNA sequencing data were combined to identify novel miRNA–mRNA interactions. Briefly, mRNA and miRNA expression profiles were integrated with miRNA target predictions to identify significant statistical dependencies between a miRNA and its candidate target set. We show by experimental validation that our approach discriminates true from false miRNA target predictions. Thereby, we identified several differentially expressed miRNAs and focused on the two top candidates: miR-99a-5p in the context of cardiac differentiation and miR-212-3p in the context of β-adrenergic stress. We validated some target mRNA candidates by 3′UTR luciferase assays as well as in transfection experiments in the hiPSC-CM model system. Our data show that iPSC-derived cardiomyocytes and computational modeling can be used to uncover new valid miRNA–mRNA interactions beyond current knowledge.
Loss of atm in Zebrafish as a Model of Ataxia–Telangiectasia Syndrome
Authors: Chen Kehua , Wang Peng , Chen Jingrun , Ying Yiling , Chen Yi , Gilson Eric , Lu Yiming , Ye Jing
Published: February 2022

Ataxia–telangiectasia mutated (ATM) is a key DNA damage signaling kinase that is mutated in humans with ataxia–telangiectasia (A-T) syndrome. This syndrome is characterized by neurodegeneration, immune abnormality, cancer predisposition, and premature aging. To better understand the function of ATM in vivo, we engineered a viable zebrafish model with a mutated atm gene. Zebrafish atm loss-of-function mutants show characteristic features of A-T-like motor disturbance, including coordination disorders, immunodeficiency, and tumorigenesis. The immunological disorder of atm homozygote fish is linked to the developmental blockade of hematopoiesis, which occurs at the adulthood stage and results in a decrease in infection defense but, with little effect on wound healing. Malignant neoplasms found in atm mutant fish were mainly nerve sheath tumors and myeloid leukemia, which rarely occur in A-T patients or Atm−/− mice. These results underscore the importance of atm during immune cell development. This zebrafish A-T model opens up a pathway to an improved understanding of the molecular basis of tumorigenesis in A-T and the cellular role of atm.
Hyperspectral Imaging during Normothermic Machine Perfusion—A Functional Classification of Ex Vivo Kidneys Based on Convolutional Neural Networks
Authors: Sommer Florian , Sun Bingrui , Fischer Julian , Goldammer Miriam , Thiele Christine , Malberg Hagen , Markgraf Wenke
Published: February 2022

Facing an ongoing organ shortage in transplant medicine, strategies to increase the use of organs from marginal donors by objective organ assessment are being fostered. In this context, normothermic machine perfusion provides a platform for ex vivo organ evaluation during preservation. Consequently, analytical tools are emerging to determine organ quality. In this study, hyperspectral imaging (HSI) in the wavelength range of 550–995 nm was applied. Classification of 26 kidneys based on HSI was established using KidneyResNet, a convolutional neural network (CNN) based on the ResNet-18 architecture, to predict inulin clearance behavior. HSI preprocessing steps were implemented, including automated region of interest (ROI) selection, before executing the KidneyResNet algorithm. Training parameters and augmentation methods were investigated concerning their influence on the prediction. When classifying individual ROIs, the optimized KidneyResNet model achieved 84% and 62% accuracy in the validation and test set, respectively. With a majority decision on all ROIs of a kidney, the accuracy increased to 96% (validation set) and 100% (test set). These results demonstrate the feasibility of HSI in combination with KidneyResNet for non-invasive prediction of ex vivo kidney function. This knowledge of preoperative renal quality may support the organ acceptance decision.
Drug Design Targeting the Muscarinic Receptors and the Implications in Central Nervous System Disorders
Authors: Johnson Chad R. , Kangas Brian D. , Jutkiewicz Emily M. , Bergman Jack , Coop Andrew
Published: February 2022

There is substantial evidence that cholinergic system function impairment plays a significant role in many central nervous system (CNS) disorders. During the past three decades, muscarinic receptors (mAChRs) have been implicated in various pathologies and have been prominent targets of drug-design efforts. However, due to the high sequence homology of the orthosteric binding site, many drug candidates resulted in limited clinical success. Although several advances in treating peripheral pathologies have been achieved, targeting CNS pathologies remains challenging for researchers. Nevertheless, significant progress has been made in recent years to develop functionally selective orthosteric and allosteric ligands targeting the mAChRs with limited side effect profiles. This review highlights past efforts and focuses on recent advances in drug design targeting these receptors for Alzheimer’s disease (AD), schizophrenia (SZ), and depression.
Context-Aware Diagnostic Specificity (CADS)
Authors: McLamore Eric S. , Moreira Geisianny , Vanegas Diana C. , Datta Shoumen Palit Austin
Published: February 2022

Rapid detection of proteins is critical in a vast array of diagnostic or monitoring applications [...]
Cognitive Impairment in Anti-Phospholipid Syndrome and Anti-Phospholipid Antibody Carriers
Authors: Hassan Fadi , Naffaa Mohammad E. , Saab Amir , Putterman Chaim
Published: February 2022

Cognitive impairment is frequently reported among anti-phospholipid syndrome (APS) patients as well as anti-phospholipid antibody (aPL) carriers, but it is less studied than other manifestations of this condition. Moreover, the exact prevalence of cognitive impairment in these patients has not been accurately determined, mainly due to inconsistency in the tools used to identify impairment, small sample sizes, and variability in the anti-phospholipid antibodies measured and positivity cutoffs. The notion of a direct pathogenic effect is supported by the observation that the higher the number of aPLs present and the higher the load of the specific antibody, the greater the risk of cognitive impairment. There is some evidence to suggest that besides the thrombotic process, inflammation-related pathways play a role in the pathogenesis of cognitive impairment in APS. The cornerstone treatments of APS are anti-coagulant and anti-thrombotic medications. These treatments have shown some favorable effects in reversing cognitive impairment, but solid evidence for the efficacy and safety of these treatments in the context of cognitive impairment is still lacking. In this article, we review the current knowledge regarding the epidemiology, pathophysiology, clinical associations, and treatment of cognitive impairment associated with APS and aPL positivity.
Does Where You Live Predict What You Say? Associations between Neighborhood Factors, Child Sleep, and Language Development
Authors: Li Queenie K. W. , MacKinnon Anna L. , Tough Suzanne , Graham Susan , Tomfohr-Madsen Lianne
Published: February 2022

Language ability is strongly related to important child developmental outcomes. Family-level socioeconomic status influences child language ability; it is unclear if, and through which mechanisms, neighborhood-level factors impact child language. The current study investigated the association between neighborhood factors (deprivation and disorder) assessed before birth and child language outcomes at age 5, with sleep duration as a potential underlying pathway. Secondary analysis was conducted on data collected between 2008 and 2018 on a subsample of 2444 participants from the All Our Families cohort study (Calgary, Canada) for whom neighborhood information from pregnancy could be geocoded. Neighborhood deprivation was determined using the Vancouver Area Neighborhood Deprivation Index (VANDIX), and disorder was assessed using crime reports. Mothers reported on their children’s sleep duration and language ability. Multilevel modeling indicated that greater neighborhood deprivation and disorder during pregnancy were predictive of lower scores on the Child Communication Checklist–2 (CCC–2) at 5 years. Path analyses revealed an indirect effect of neighborhood disorder on language through child sleep duration at 12 months. These results add to growing evidence that child development should be considered within the context of multiple systems. Sleep duration as an underlying link between environmental factors and child language ability warrants further study as a potential target for intervention.
Co-Inhibition of Androgen Receptor and PARP as a Novel Treatment Paradigm in Prostate Cancer—Where Are We Now?
Authors: Rao Arpit , Moka Nagaishwarya , Hamstra Daniel A. , Ryan Charles J.
Published: February 2022

Metastatic prostate cancer remains lethal with a 5-year survival rate of about 30%, indicating the need for better treatment options. Novel antiandrogens (NAA)—enzalutamide and abiraterone—have been the mainstay of treatment for advanced disease since 2011. In patients who progress on the first NAA, responses to the second NAA are infrequent (25–30%) and short-lasting (median PFS ~3 months). With the growing adoption of NAA therapy in pre-metastatic castration-resistant settings, finding better treatment options for first-line mCRPC has become an urgent clinical need. The regulatory approval of two PARP inhibitors in 2020—rucaparib and olaparib—has provided the first targeted therapy option for patients harboring defects in selected DNA damage response and repair (DDR) pathway genes. However, a growing body of preclinical and clinical data shows that co-inhibition of AR and PARP induces synthetic lethality and could be a promising therapy for patients without any DDR alterations. In this review article, we will investigate the limitations of NAA monotherapy, the mechanistic rationale for synthetic lethality induced by co-inhibition of AR and PARP, the clinical data that have led to the global development of a number of these AR and PARP combination therapies, and how this may impact patient care in the next 2–10 years.
RAS Mutation Conversion in Bevacizumab-Treated Metastatic Colorectal Cancer Patients: A Liquid Biopsy Based Study
Authors: Nicolazzo Chiara , Belardinilli Francesca , Vestri Annarita , Magri Valentina , De Renzi Gianluigi , De Meo Michela , Caponnetto Salvatore , Di Nicolantonio Federica , Cortesi Enrico , Giannini Giuseppe , Gazzaniga Paola
Published: February 2022

Liquid biopsies have shown that, in RAS mutant colorectal cancer, the conversion to RAS wild-type * status during the course of the disease is a frequent event, supporting the concept that the evolutionary landscape of colorectal cancer can lead to an unexpected negative selection of RAS mutant clones. The aim of the present study was to clarify whether the negative selection of RAS mutation in plasma might be drug-dependent. For this purpose, we used liquid biopsy to compare the rate of conversion from RAS mutant to RAS wild-type * in two groups of originally RAS mutant mCRC patients: the first treated with chemotherapy alone, while the second was treated with chemotherapy combined with bevacizumab. Serial liquid biopsies were performed at 3 months (T1), 6 months (T2), 9 months (T3), and 12 months (T4) after starting first line treatments. We found that the only independent variable significantly associated to RAS status conversion was the use of bevacizumab. RAS conversion was not found associated to tumor burden reduction, although bevacizumab-treated patients who converted to RAS wild-type * had a significantly longer PFS compared to patients who remained RAS mutant. The appearance of a “RAS wild-type * window”, mainly in bevacizumab-treated patients, might present them as candidates for second line treatment with anti-EGFR, which was otherwise precluded.
Statins Reduce Hepatocellular Carcinoma Risk in Patients with Chronic Kidney Disease and End-Stage Renal Disease: A 17-Year Longitudinal Study
Authors: Sung Fung-Chang , Yeh Yi-Ting , Muo Chih-Hsin , Hsu Chih-Cheng , Tsai Wen-Chen , Hsu Yueh-Han
Published: February 2022

Hepatocellular carcinoma (HCC) is the most common cancer in end-stage renal disease (ESRD) patients in Taiwan. Whether statin therapy associated with the HCC risk in hyperlipidemic patients with chronic kidney disease (CKD) and ESRD is unclear. Using population-based insurance claim data from Taiwan, we identified from hyperlipidemic patients taking statins or not (677,364 versus 867,707) in 1999–2015. Among them, three pairs of propensity score matched statin and non-statin cohorts were established by renal function: 413,867 pairs with normal renal function (NRF), 46,851 pairs with CKD and 6372 pairs with ESRD. Incidence rates of HCC were compared, by the end of 2016, between statin and non-statin cohorts, between hydrophilic statins (HS) and lipophilic statins (LS) users, and between statin-ezetimibe combination therapy (SECT) and statin monotherapy (SM) users. The HCC incidence increased progressively from NRF to CKD and ESRD groups, was lower in the statin cohort than in the non-statin cohort, with the differences of incidence per 10,000 person-years increased from (7.77 vs. 21.4) in NRF group to (15.8 vs. 37.1) in CKD group to (19.1 vs. 47.8) in ESRD group. The incidence increased with age, but the Cox method estimated hazard ratios showed a greater statin effectiveness in older patients. Among statin users, the HCC incidence was lower in HS users than in LS users, and lower in SECT users than in SM users, but the difference was significant only in the NRF group. Hyperlipidemic patients with CKD and ESRD receiving statins are at reduced HCC risks; the treatment effectiveness is superior for HS users than for LS users, and for SECT users than for SM users, but not significant.
A Comprehensive Commentary on the Multilocular Cystic Renal Neoplasm of Low Malignant Potential: A Urologist’s Perspective
Authors: Pitra Tomas , Pivovarcikova Kristyna , Alaghehbandan Reza , Bartos Vesela Adriena , Tupy Radek , Hora Milan , Hes Ondrej
Published: February 2022

Multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) is a cystic renal tumor with indolent clinical behavior. In most of cases, it is an incidental finding during the examination of other health issues. The true incidence rate is estimated to be between 1.5% and 4% of all RCCs. These lesions are classified according to the Bosniak classification as Bosniak category III. There is a wide spectrum of diagnostic tools that can be utilized in the identification of this tumor, such as computed tomography (CT), magnetic resonance (MRI) or contrast-enhanced ultrasonography (CEUS). Management choices of these lesions range from conservative approaches, such as clinical follow-up, to surgery. Minimally invasive techniques (i.e., robotic surgery and laparoscopy) are preferred, with an emphasis on nephron sparing surgery, if clinically feasible.
Identification of a Gene-Expression-Based Surrogate of Genomic Instability during Oral Carcinogenesis
Authors: Truchard Eléonore , Bertolus Chloé , Martinez Pierre , Thomas Emilie , Saintigny Pierre , Foy Jean-Philippe
Published: February 2022

Background: Our goal was to identify a gene-expression-based surrogate of genomic instability (GI) associated with the transformation of oral potentially malignant disorder (OPMD) into oral squamous cell carcinoma (OSCC). Methods: GI was defined as the fraction of genome altered (FGA). Training sets included the CCLE and TCGA databases. The relevance of the enrichment score of the top correlated genes, referred to as the GIN score, was evaluated in eight independent public datasets from the GEO repository, including a cohort of patients with OPMD with available outcome. Results: A set of 20 genes correlated with FGA in head and neck SCC were identified. A significant correlation was found between the 20-gene based GIN score and FGA in 95 esophagus SCC (r = 0.59) and 501 lung SCC (r = 0.63), and in 33 OPMD/OSCC (r = 0.38). A significantly increased GIN score was observed at different stages of oral carcinogenesis (normal–dysplasia –OSCC) in five independent datasets. The GIN score was higher in 10 OPMD that transformed into oral cancer compared to 10 nontransforming OPMD (p = 0.0288), and was associated with oral-cancer-free survival in 86 patients with OPMD (p = 0.0081). Conclusions: The GIN score is a gene-expression surrogate of GI, and is associated with oral carcinogenesis and OPMD malignant transformation.
Are Cell Junctions Implicated in the Regulation of Vitellogenin Uptake? Insights from an RNAseq-Based Study in Eel, Anguilla australis
Authors: Babio Lucila , Lokman P. Mark , Damsteegt Erin L. , Dutoit Ludovic
Published: February 2022

At the onset of puberty, ovarian follicles become competent to incorporate large amounts of vitellogenin (Vtg). Using an RNAseq-based approach, transcriptomes from pre-vitellogenic (PV) and early vitellogenic (EV) ovaries from wild-caught eel, Anguilla australis, were compared to investigate the expression of specific genes encoding cell junction proteins that could be involved in regulating Vtg uptake. Partial support was found for the mechanical barrier hypothesis proposing that the access of Vtg to the oolemma is restricted by a tight junction (TJ) network within the granulosa cell layer, which changes between the PV and EV stage. Among 25 genes encoding TJ-constituting proteins, five were down-regulated and two were up-regulated. A chemical barrier hypothesis stating that gap junctions (GJs) are involved in modulating Vtg uptake was not supported, as only five GJs were found to be expressed in the ovary with no significant changes in expression between stages. Furthermore, the endocytic pathway was found to be up-regulated during the PV-EV transition. Finally, the study showed that gene expression patterns may help identify suitable candidates involved in the regulation of Vtg uptake, and provided novel sequence data for A. australis, including putative Vtg receptors corresponding to Lr8 and Lrp13 members of the low-density lipoprotein receptor family.
Oxidative Stress in Human Pathology and Aging: Molecular Mechanisms and Perspectives
Authors: Hajam Younis Ahmad , Rani Raksha , Ganie Shahid Yousuf , Sheikh Tariq Ahmad , Javaid Darakhshan , Qadri Syed Sanober , Pramodh Sreepoorna , Alsulimani Ahmad , Alkhanani Mustfa F. , Harakeh Steve , Hussain Arif , Haque Shafiul , Reshi Mohd Salim
Published: February 2022

Reactive oxygen and nitrogen species (RONS) are generated through various endogenous and exogenous processes; however, they are neutralized by enzymatic and non-enzymatic antioxidants. An imbalance between the generation and neutralization of oxidants results in the progression to oxidative stress (OS), which in turn gives rise to various diseases, disorders and aging. The characteristics of aging include the progressive loss of function in tissues and organs. The theory of aging explains that age-related functional losses are due to accumulation of reactive oxygen species (ROS), their subsequent damages and tissue deformities. Moreover, the diseases and disorders caused by OS include cardiovascular diseases [CVDs], chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases and cancer. OS, induced by ROS, is neutralized by different enzymatic and non-enzymatic antioxidants and prevents cells, tissues and organs from damage. However, prolonged OS decreases the content of antioxidant status of cells by reducing the activities of reductants and antioxidative enzymes and gives rise to different pathological conditions. Therefore, the aim of the present review is to discuss the mechanism of ROS-induced OS signaling and their age-associated complications mediated through their toxic manifestations in order to devise effective preventive and curative natural therapeutic remedies.
Influence of the Metabolism on Myeloid Cell Functions in Cancers: Clinical Perspectives
Authors: Boyer Thomas , Blaye Céline , Larmonier Nicolas , Domblides Charlotte
Published: February 2022

Tumor metabolism plays a crucial role in sustaining tumorigenesis. There have been increasing reports regarding the role of tumor metabolism in the control of immune cell functions, generating a potent immunosuppressive contexture that can lead to immune escape. The metabolic reprogramming of tumor cells and the immune escape are two major hallmarks of cancer, with several instances of crosstalk between them. In this paper, we review the effects of tumor metabolism on immune cells, focusing on myeloid cells due to their important role in tumorigenesis and immunosuppression from the early stages of the disease. We also discuss ways to target this specific crosstalk in cancer patients.
C53 Interacting with UFM1-Protein Ligase 1 Regulates Microtubule Nucleation in Response to ER Stress
Authors: Klebanovych Anastasiya , Vinopal Stanislav , Dráberová Eduarda , Sládková Vladimíra , Sulimenko Tetyana , Sulimenko Vadym , Vosecká Věra , Macůrek Libor , Legido Agustin , Dráber Pavel
Published: February 2022

ER distribution depends on microtubules, and ER homeostasis disturbance activates the unfolded protein response resulting in ER remodeling. CDK5RAP3 (C53) implicated in various signaling pathways interacts with UFM1-protein ligase 1 (UFL1), which mediates the ufmylation of proteins in response to ER stress. Here we find that UFL1 and C53 associate with γ-tubulin ring complex proteins. Knockout of UFL1 or C53 in human osteosarcoma cells induces ER stress and boosts centrosomal microtubule nucleation accompanied by γ-tubulin accumulation, microtubule formation, and ER expansion. C53, which is stabilized by UFL1, associates with the centrosome and rescues microtubule nucleation in cells lacking UFL1. Pharmacological induction of ER stress by tunicamycin also leads to increased microtubule nucleation and ER expansion. Furthermore, tunicamycin suppresses the association of C53 with the centrosome. These findings point to a novel mechanism for the relief of ER stress by stimulation of centrosomal microtubule nucleation.
Treatment of Pheochromocytoma Cells with Recurrent Cycles of Hypoxia: A New Pseudohypoxic In Vitro Model
Authors: Helm Jana , Drukewitz Stephan , Poser Isabel , Richter Susan , Friedemann Markus , William Doreen , Mohr Hermine , Nölting Svenja , Robledo Mercedes , Bornstein Stefan R. , Eisenhofer Graeme , Bechmann Nicole
Published: February 2022

Continuous activation of hypoxia pathways in pheochromocytomas and paragangliomas (PPGLs) is associated with higher disease aggressiveness, for which effective treatment strategies are still missing. Most of the commonly used in vitro models lack characteristics of these pseudohypoxic tumors, including elevated expression of hypoxia-inducible factor (HIF) 2α. To address this shortcoming, we investigated whether recurrent hypoxia cycles lead to continuous activation of hypoxia pathways under normoxic conditions and whether this pseudohypoxia is associated with increased cellular aggressiveness. Rat pheochromocytoma cells (PC12) were incubated under hypoxia for 24 h every 3–4 days, up to 20 hypoxia–reoxygenation cycles, resulting in PC12 Z20 cells. PC12 Z20 control cells were obtained by synchronous cultivation under normoxia. RNA sequencing revealed upregulation of HIF2α in PC12 Z20 cells and a pseudohypoxic gene signature that overlapped with the gene signature of pseudohypoxic PPGLs. PC12 Z20 cells showed a higher growth rate, and the migration and adhesion capacity were significantly increased compared with control cells. Changes in global methylation, together with the pseudohypoxic conditions, may be responsible for the increased aggressiveness of this new model. The established sub-cell line with characteristics of pseudohypoxic PPGLs represent a complementary model for further investigations, for example, with regard to new therapeutic approaches.
Metabolomics of Acute vs. Chronic Spinach Intake in an Apc–Mutant Genetic Background: Linoleate and Butanoate Metabolites Targeting HDAC Activity and IFN–γ Signaling
Authors: Chen Ying-Shiuan , Li Jia , Neja Sultan , Kapoor Sabeeta , Tovar Perez Jorge , Tripathi Chakrapani , Menon Rani , Jayaraman Arul , Lee Kyongbum , Dashwood Wan , Wang Shan , Zhang Ke , Kobayashi Koichi , Rajendran Praveen , Dashwood Roderick
Published: February 2022

There is growing interest in the crosstalk between the gut microbiome, host metabolomic features, and disease pathogenesis. The current investigation compared long–term (26 week) and acute (3 day) dietary spinach intake in a genetic model of colorectal cancer. Metabolomic analyses in the polyposis in rat colon (Pirc) model and in wild–type animals corroborated key contributions to anticancer outcomes by spinach–derived linoleate bioactives and a butanoate metabolite linked to increased α–diversity of the gut microbiome. Combining linoleate and butanoate metabolites in human colon cancer cells revealed enhanced apoptosis and reduced cell viability, paralleling the apoptosis induction in colon tumors from rats given long–term spinach treatment. Mechanistic studies in cell–based assays and in vivo implicated the linoleate and butanoate metabolites in targeting histone deacetylase (HDAC) activity and the interferon–γ (IFN–γ) signaling axis. Clinical translation of these findings to at–risk patients might provide valuable quality–of–life benefits by delaying surgical interventions and drug therapies with adverse side effects.
Development of Fluorescent Carbon Nanoparticle-Based Probes for Intracellular pH and Hypochlorite Sensing
Authors: Lin Yu-Syuan , Chuang Li-Wei , Lin Yu-Feng , Hu Shun-Ruei , Huang Chih-Ching , Huang Yu-Fen , Chang Huan-Tsung
Published: February 2022

Acid-base and redox reactions are important mechanisms that affect the optical properties of fluorescent probes. Fluorescent carbon nanoparticles (CNPs) that possess tailored surface functionality enable a prompt response to regional stimuli, offering a useful platform for detection, sensing, and imaging. In this study, mPA CNPs were developed through one-pot hydrothermal reaction as a novel fluorescent probe (quantum yield = 10%) for pH and hypochlorite sensing. m-Phenylenediamine was chosen as the major component of CNPs for pH and hypochlorite responsiveness. Meanwhile, ascorbic acid with many oxygen-containing groups was introduced to generate favorable functionalities for improved water solubility and enhanced sensing response. Thus, the mPA CNPs could serve as a pH probe and a turn-off sensor toward hypochlorite at neutral pH through fluorescence change. The as-prepared mPA CNPs exhibited a linear fluorescence response over the pH ranges from pH 5.5 to 8.5 (R2 = 0.989), and over the concentration range of 0.125–1.25 μM for hypochlorite (R2 = 0.985). The detection limit (LOD) of hypochlorite was calculated to be 0.029 μM at neutral pH. The mPA CNPs were further applied to the cell imaging. The positively charged surface and nanoscale dimension of the mPA CNPs lead to their efficient intracellular delivery. The mPA CNPs were also successfully used for cell imaging and sensitive detection of hypochlorite as well as pH changes in biological systems. Given these desirable performances, the as-synthesized fluorescent mPA CNPs shows great potential as an optical probe for real-time pH and hypochlorite monitoring in living cells.
3D Printing Technologies in Biosensors Production: Recent Developments
Authors: Remaggi Giulia , Zaccarelli Alessandro , Elviri Lisa
Published: February 2022

Recent advances in 3D printing technologies and materials have enabled rapid development of innovative sensors for applications in different aspects of human life. Various 3D printing technologies have been adopted to fabricate biosensors or some of their components thanks to the advantages of these methodologies over the traditional ones, such as end-user customization and rapid prototyping. In this review, the works published in the last two years on 3D-printed biosensors are considered and grouped on the basis of the 3D printing technologies applied in different fields of application, highlighting the main analytical parameters. In the first part, 3D methods are discussed, after which the principal achievements and promising aspects obtained with the 3D-printed sensors are reported. An overview of the recent developments on this current topic is provided, as established by the considered works in this multidisciplinary field. Finally, future challenges on the improvement and innovation of the 3D printing technologies utilized for biosensors production are discussed.
The Role of Urotensin-II in Obesity and Metabolic Syndrome in Pediatric Population
Authors: Simunovic Marko , Jukic Andrija , Paradzik Martina , Supe-Domic Daniela , Stanisic Lada , Degoricija Marina , Hillestad Anna Hummelvoll , Skrabic Veselin , Bozic Josko
Published: February 2022

Background: Urotensin-II (U-II) is a short cyclic peptide that is widely recognized as one of the most potent vasoconstrictors. U-II plays a role in the pathophysiology of MS, participating in the development of essential hypertension, insulin resistance, hyperglycemia, and a proinflammatory state. Methods: This study comprised 52 obese children and adolescents with a body mass index (BMI) z score > 2, aged 10 to 18 years. Serum levels of U-II were assessed using an enzyme-linked immunosorbent assay along with other standard biochemical parameters. Results: Elevated serum levels of U-II were recorded in the group of obese subjects with MS when compared with the group of obese subjects without MS (4.99 (8.97–3.16) vs. 4.17 (5.17–2.03) ng/mL, median and IQR, p = 0.026). Furthermore, a subgroup of study subjects with high blood pressure had significantly higher U-II levels in comparison with the normotensive subgroup (4.98 (7.19–3.22) vs. 3.32 (5.06–1.97) ng/mL, p = 0.027), while the subgroup with a positive family history of high blood pressure had significantly higher U-II levels when compared with subjects who had a negative family history of elevated blood pressure (5.06 (6.83–4.45) vs. 3.32 (6.13–2.21) ng/mL, p = 0.039). Conclusions: To the best of the author’s knowledge, this is the first study on the levels of U-II in obese children and adolescents, including a possible link to MS.
Effects of Vision Therapy on Bilateral Amblyopia Unresponsive to Conventional Treatment: A Retrospective Comparative Study
Authors: Huang Yu-Te , Lin Hui-Ju , Liao Wen-Ling , Tsai Yi-Yu , Hsieh Yi-Ching
Published: February 2022

Background: In this study we aim to determines the effect of our vision therapy program for 7- to 10-year-old patients who exhibit bilateral amblyopia that is no longer responsive to conventional treatment. Methods: Children with bilateral amblyopia between the ages of 7 and 10 treated with vision therapy at the China Medical University Hospital between 2016 and 2019 were retrospectively reviewed. Age and visual acuity-matched bilateral amblyopes are included as a control group. The visual acuity for both groups showed no improvement for more than 3 months with part-time patching and full refraction correction. The initial and final visual acuity, stereopsis, and refractive status were analyzed. Results: Here, 15 cases were included as the treatment group and 16 cases as a control group. At the endpoint, the study group shows a significant improvement in BCVA, with a mean of 0.32 ± 0.15 logMAR (3 lines improvement) versus 0.003 ± 0.19 logMAR (nearly no improvement) for the control group (p < 0.001). The benefits of treatment are most obvious in the first 3 months after treatment (p < 0.001) and last until the end point. Stereoacuity also improves from 190.00 ± 163.34 to 85.00 ± 61.24 arc seconds, which is a 55.26% improvement. Conclusions: Vision therapy, comprising orthoptic therapy, perceptual learning and dichoptic training, is a successful program for increasing visual acuity and stereoacuity in 7- to 10-year-old children with bilateral amblyopia that is unresponsive to conventional treatment.
Subtyping of Internalizing and Externalizing Behaviors in Japanese Community-Based Children: A Latent Class Analysis and Association with Family Activities
Authors: Li Xiang , Zhu Yan-Tong , Jiao Dan-Dan , Sawada Yuko , Tanaka Emiko , Watanabe Taeko , Tomisaki Etsuko , Zhu Zhu , Ajmal Ammara , Matsumoto Munenori , Zhang Jin-Rui , Banu Alpona Afsari , Liu Yang , Cui Ming-Yu , Graça Yolanda , Wang Yan-Lin , Qian Mei-Ling , Anme Tokie
Published: February 2022

Externalizing and internalizing behavioral problems occurs at a high rate among children. However, this has rarely been examined among Japanese children using a person-oriented method. Hence, this study aims to explore its subtypes and clarify their association with family-based group activities. We conducted a cross-sectional survey in a typical community-based suburban area for all families with primary school children in Japan. We investigated children’s internalizing and externalizing behaviors based on the Japanese version of the Strengths and Difficulties Questionnaire (SDQ), and different types of activities that family members frequently engaged in. Data from 206 families were collected and used for the analysis. The subtypes were explored using latent class analysis (LCA). The relationship between family activities and latent class membership was analyzed using a logistic regression model. Moreover, three latent class models and their probabilities were identified, namely, risk group (31.3%), moderate group (44.9%), and normal group (23.8%). Frequent family activities including play sports, traveling or hiking, watching TV and communicating, cooking or making a dessert, and doing housework, which were significantly related to the normal group. These results would add evidence to potential types of children’s behavioral problems and preventive childcare practices needed in the primary gate of families.
Early Skin-to-Skin Contact Does Not Affect Cerebral Tissue Oxygenation in Preterm Infants <32 Weeks of Gestation
Authors: Hanke Kathrin , Rausch Tanja K. , Sosnowski Runa , Paul Pia , Spiegler Juliane , Müller Mirja , König Inke R. , Göpel Wolfgang , Herting Egbert , Härtel Christoph
Published: February 2022

Aim: It was the aim of our study to determine the regional cerebral tissue oxygenation saturation (rcSO2) as an additional monitoring parameter during early skin-to-skin contact (SSC) in preterm infants with a gestational age of <32 gestational weeks. Methods: We conducted two observational convenience sample studies using additional monitoring with near-infrared spectroscopy (NIRS) in the first 120 h of life: (a) NIRS 1 (gestational age of 26 0/7 to 31 6/7 weeks) and (b) NIRS 2 (gestational age of 24 0/7 to 28 6/7 weeks). The rcSO2 values were compared between resting time in the incubator (period I), SSC (period II) and handling nursing care (period III). For the comparison, we separated the sequential effects by including a “wash-out phase” of 1 h between each period. Results: During the first 120 h of life 38/53 infants in NIRS 1 and 15/23 infants in NIRS 2 received SSC, respectively. We found no remarkable differences for rcSO2 values of NIRS 1 patients between SSC time and period I (95% confidence interval (CI) for the difference in %: SSC vs. period I [1; 3]). In NIRS 2, rcSO2 values during SSC were only 2% lower compared with period I [median [1. quartile; 3. quartile] in %; 78 [73; 82] vs. 80 [74; 85]] but were similar to period III [78 [72; 83]]. In a combined analysis, a small difference in rcSO2 values between SSC and resting times was found using a generalized linear mixed model that included gender and gestational age (OR 95% CI; 1.178 [1.103; 1.253], p < 0.0001). Episodes below the cut-off for “hypoxia”; e.g., <55%, were comparable during SSC and periods I and III (0.3–2.1%). No FiO2 adjustment was required in the vast majority of SSC episodes. Conclusions: Our observational data indicate that rcSO2 values of infants during SSC were comparable to rcSO2 values during incubator care and resting time. This additional monitoring supports a safe implementation of early SSC in extremely preterm infants in NICUs.
Iraq Is Moving Forward to Achieve Global Targets in Nutrition
Authors: Sabeeh Hind Khalid , Ali Saadulddin Hussein , Al-Jawaldeh Ayoub
Published: February 2022

From the 1990s and after 2003, Iraq suffered many difficulties which affected its population negatively in different ways; from embargo to political instabilities, conflicts, and wars, collectively leading to food insecurity especially among the internally displaced people. The Ministry of Health and International Organizations worked collectively to improve the nutritional situation among the most vulnerable groups: children under five, and women in reproductive age. This study aims to review the nutrition situation for Iraq in relation to the Global Nutrition Targets and for Sustainable Development Goals. The data used for comparison was obtained from nationally representative surveys conducted in Iraq from 1996 to 2018, including urban and rural areas for all 18 governorates. Results of these surveys showed a gradual decline in undernutrition indicators for children under five, and an emergence of overweight and obesity, indicating an urgent need for collective action from all sectors and related Ministries regarding malnutrition in its different forms. It also revealed a decline in the prevalence of anemia among the targeted women, but an increase of low birth weight in newborn infants. Exclusive breastfeeding though, is still staggering and in need of urgent action. Iraq is transferring from a generalized state of insecurity to a more secure one, emphasizing the need to strengthen systems for efficient monitoring and evaluation. There is also a need for more recent surveys representing Iraq, as the available data is scant, particularly dietary intake studies within the normal population and internally displaced families in camps or scattered shelters.
Transcription of the Envelope Protein by 1-L Protein–RNA Recognition Code Leads to Genes/Proteins That Are Relevant to the SARS-CoV-2 Life Cycle and Pathogenesis
Authors: Nahalka Jozef
Published: February 2022

The theoretical protein–RNA recognition code was used in this study to research the compatibility of the SARS-CoV-2 envelope protein (E) with mRNAs in the human transcriptome. According to a review of the literature, the spectrum of identified genes showed that the virus post-transcriptionally promotes or represses the genes involved in the SARS-CoV-2 life cycle. The identified genes/proteins are also involved in adaptive immunity, in the function of the cilia and wound healing (EMT and MET) in the pulmonary epithelial tissue, in Alzheimer’s and Parkinson’s disease and in type 2 diabetes. For example, the E-protein promotes BHLHE40, which switches off the IL-10 inflammatory “brake” and inhibits antiviral THαβ cells. In the viral cycle, E supports the COPII-SCAP-SREBP-HSP90α transport complex by the lowering of cholesterol in the ER and by the repression of insulin signaling, which explains the positive effect of HSP90 inhibitors in COVID-19 (geldanamycin), and E also supports importin α/β-mediated transport to the nucleus, which explains the positive effect of ivermectin, a blocker of importins α/β. In summary, transcription of the envelope protein by the 1-L protein–RNA recognition code leads to genes/proteins that are relevant to the SARS-CoV-2 life cycle and pathogenesis.