bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Effects of Deferiprone and Salinomycin on Lead-Induced Disturbance in the Homeostasis of Intrarenal Essential Elements in Mice
Authors: Gluhcheva Yordanka , Pashkunova-Martic Irena , Schaier Martin , Vladov Ivelin , Stoykova Silviya , Petrova Emilia , Pavlova Ekaterina , Dorkov Peter , Helbich Thomas H. , Keppler Bernhard , Ivanova Juliana
Published: April 2022

Lead (Pb) exposure induces severe nephrotoxic effects in humans and animals. Herein, we compare the effects of two chelating agents, salinomycin and deferiprone, on Pb-induced renal alterations in mice and in the homeostasis of essential elements. Adult male mice (Institute of Cancer Research (ICR)) were randomized into four groups: control (Ctrl)—untreated mice administered distilled water for 28 days; Pb-exposed group (Pb)—mice administered orally an average daily dose of 80 mg/kg body weight (BW) lead (II) nitrate (Pb(NO3)2) during the first two weeks of the experimental protocol followed by the administration of distilled water for another two weeks; salinomycin-treated (Pb + Sal) group—Pb-exposed mice, administered an average daily dose of 16 mg/kg BW salinomycin for two weeks; deferiprone-treated (Pb + Def) group—Pb-exposed mice, administered an average daily dose of 20 mg/kg BW deferiprone for 14 days. The exposure of mice to Pb induced significant accumulation of the toxic metal in the kidneys and elicited inflammation with leukocyte infiltrations near the glomerulus. Biochemical analysis of the sera revealed that Pb significantly altered the renal function markers. Pb-induced renal toxicity was accompanied by a significant decrease in the endogenous renal concentrations of phosphorous (P), calcium (Ca), copper (Cu) and selenium (Se). In contrast to deferiprone, salinomycin significantly improved renal morphology in Pb-treated mice and decreased the Pb content by 13.62% compared to the Pb-exposed group. There was also a mild decrease in the renal endogenous concentration of magnesium (Mg) and elevation of the renal concentration of iron (Fe) in the salinomycin-treated group compared to controls. Overall, the results demonstrated that salinomycin is a more effective chelating agent for the treatment of Pb-induced alterations in renal morphology compared to deferiprone.
CoA in Health and Disease
Authors: Dobrzyn Pawel
Published: April 2022

Coenzyme A (CoA) and its thioester derivatives are crucial components of numerous biosynthetic and degradative pathways of the cellular metabolism (including fatty acid synthesis and oxidation, the Krebs cycle, ketogenesis, cholesterol and acetylcholine biosynthesis, amino acid degradation, and neurotransmitter biosynthesis), post-translational modifications of proteins, and the regulation of gene expression [...]
New Insights into Green Protocols for Oxidative Depolymerization of Lignin and Lignin Model Compounds
Authors: Scimmi Cecilia , Sancineto Luca , Drabowicz Jozef , Santi Claudio
Published: April 2022

Oxidative depolymerization of lignin is a hot topic in the field of biomass valorization. The most recent and green procedures have been herein detailed. Photochemical and electrochemical approaches are reviewed highlighting the pros and cons of each method. Mechanochemistry activated strategies are able to combine oxidation and depolymerization in the deconstruction of lignin. Homogenous and heterogeneous catalytic systems are exemplified stressing the green aspects associated with both the procedures. Solvent-free approaches as well as those carried out in alternative media are listed. Finally, the few examples of selenium catalyzed lignin valorization reported so far are cited.
New Frontiers in Organ Preservation and Hepatoprotection
Authors: Czigany Zoltan , Tolba René Hany
Published: April 2022

This editorial aims to summarize the 13 scientific articles published in the Special Issue entitled “New Frontiers in Organ Preservation and Hepatoprotection” [...]
Neurodevelopmental Disorders Associated with PSD-95 and Its Interaction Partners
Authors: Levy Amanda M. , Gomez-Puertas Paulino , Tümer Zeynep
Published: April 2022

The postsynaptic density (PSD) is a massive protein complex, critical for synaptic strength and plasticity in excitatory neurons. Here, the scaffolding protein PSD-95 plays a crucial role as it organizes key PSD components essential for synaptic signaling, development, and survival. Recently, variants in DLG4 encoding PSD-95 were found to cause a neurodevelopmental disorder with a variety of clinical features including intellectual disability, developmental delay, and epilepsy. Genetic variants in several of the interaction partners of PSD-95 are associated with similar phenotypes, suggesting that deficient PSD-95 may affect the interaction partners, explaining the overlapping symptoms. Here, we review the transmembrane interaction partners of PSD-95 and their association with neurodevelopmental disorders. We assess how the structural changes induced by DLG4 missense variants may disrupt or alter such protein–protein interactions, and we argue that the pathological effect of DLG4 variants is, at least partly, exerted indirectly through interaction partners of PSD-95. This review presents a direction for functional studies to elucidate the pathogenic mechanism of deficient PSD-95, providing clues for therapeutic strategies.
Engineered Neutral Phosphorous Dendrimers Protect Mouse Cortical Neurons and Brain Organoids from Excitotoxic Death
Authors: Posadas Inmaculada , Romero-Castillo Laura , Ronca Rosa-Anna , Karpus Andrii , Mignani Serge , Majoral Jean-Pierre , Muñoz-Fernández Mariángeles , Ceña Valentín
Published: April 2022

Nanoparticles are playing an increasing role in biomedical applications. Excitotoxicity plays a significant role in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s or Parkinson’s disease. Glutamate ionotropic receptors, mainly those activated by N-methyl-D-aspartate (NMDA), play a key role in excitotoxic death by increasing intraneuronal calcium levels; triggering mitochondrial potential collapse; increasing free radicals; activating caspases 3, 9, and 12; and inducing endoplasmic reticulum stress. Neutral phosphorous dendrimers, acting intracellularly, have neuroprotective actions by interfering with NMDA-mediated excitotoxic mechanisms in rat cortical neurons. In addition, phosphorous dendrimers can access neurons inside human brain organoids, complex tridimensional structures that replicate a significant number of properties of the human brain, to interfere with NMDA-induced mechanisms of neuronal death. Phosphorous dendrimers are one of the few nanoparticles able to gain access to the inside of neurons, both in primary cultures and in brain organoids, and to exert pharmacological actions by themselves.
Antiseptic Materials on the Base of Polymer Interpenetrating Networks Microgels and Benzalkonium Chloride
Authors: Kozhunova Elena Yu. , Komarova Galina A. , Vyshivannaya Oxana V. , Nasimova Irina R. , Kuvarina Anastasia E. , Sadykova Vera S.
Published: April 2022

Polymer microgels, including those based on interpenetrating networks (IPNs), are currently vastly studied, and their practical applications are a matter of thriving research. In this work, we show the perspective for the use of polyelectrolyte IPN microgels either as scavengers or carriers of antiseptic substances. Here, we report that poly-N-isopropylacrylamide/polyacrylic acid IPN microgels can efficiently absorb the common bactericidal and virucidal compound benzalkonium chloride. The particles can form a stable aqueous colloidal suspension or be used as building blocks for soft free-standing films. Both materials showed antiseptic efficacy on the examples of Bacillus subtilis and S. aureus, which was approximately equal to the commercial antibiotic. Such polymer biocides can be used as liquid disinfectants, stable surface coatings, or parts of biomedical devices and can enhance the versatility of the possible practical applications of polymer microgels.
Identifying Novel Osteoarthritis-Associated Genes in Human Cartilage Using a Systematic Meta-Analysis and a Multi-Source Integrated Network
Authors: Shorter Emily , Avelar Roberto , Zachariou Margarita , Spyrou George M. , Raina Priyanka , Smagul Aibek , Ashraf Kharaz Yalda , Peffers Mandy , Goljanek-Whysall Kasia , de Magalhães João Pedro , Poulet Blandine
Published: April 2022

Osteoarthritis, the most common joint disorder, is characterised by deterioration of the articular cartilage. Many studies have identified potential therapeutic targets, yet no effective treatment has been determined. The aim of this study was to identify and rank osteoarthritis-associated genes and micro-RNAs to prioritise those most integral to the disease. A systematic meta-analysis of differentially expressed mRNA and micro-RNAs in human osteoarthritic cartilage was conducted. Ingenuity pathway analysis identified cellular senescence as an enriched pathway, confirmed by a significant overlap (p < 0.01) with cellular senescence drivers (CellAge Database). A co-expression network was built using genes from the meta-analysis as seed nodes and combined with micro-RNA targets and SNP datasets to construct a multi-source information network. This accumulated and connected 1689 genes which were ranked based on node and edge aggregated scores. These bioinformatic analyses were confirmed at the protein level by mass spectrometry of the different zones of human osteoarthritic cartilage (superficial, middle, and deep) compared to normal controls. This analysis, and subsequent experimental confirmation, revealed five novel osteoarthritis-associated proteins (PPIB, ASS1, LHDB, TPI1, and ARPC4-TTLL3). Focusing future studies on these novel targets may lead to new therapies for osteoarthritis.
Review of Knowledge of Uranium-Induced Kidney Toxicity for the Development of an Adverse Outcome Pathway to Renal Impairment
Authors: Guéguen Yann , Frerejacques Marie
Published: April 2022

An adverse outcome pathway (AOP) is a conceptual construct of causally and sequentially linked events, which occur during exposure to stressors, with an adverse outcome relevant to risk assessment. The development of an AOP is a means of identifying knowledge gaps in order to prioritize research assessing the health risks associated with exposure to physical or chemical stressors. In this paper, a review of knowledge was proposed, examining experimental and epidemiological data, in order to identify relevant key events and potential key event relationships in an AOP for renal impairment, relevant to stressors such as uranium (U). Other stressors may promote similar pathways, and this review is a necessary step to compare and combine knowledge reported for nephrotoxicants. U metal ions are filtered through the glomerular membrane of the kidneys, then concentrate in the cortical and juxtaglomerular areas, and bind to the brush border membrane of the proximal convoluted tubules. U uptake by epithelial cells occurs through endocytosis and the sodium-dependent phosphate co-transporter (NaPi-IIa). The identified key events start with the inhibition of the mitochondria electron transfer chain and the collapse of mitochondrial membrane potential, due to cytochrome b5/cytochrome c disruption. In the nucleus, U directly interacts with negatively charged DNA phosphate, thereby inducing an adduct formation, and possibly DNA strand breaks or cross-links. U also compromises DNA repair by inhibiting zing finger proteins. Thereafter, U triggers the Nrf2, NF-κB, or endoplasmic reticulum stress pathways. The resulting cellular key events include oxidative stress, DNA strand breaks and chromosomal aberrations, apoptosis, and pro-inflammatory effects. Finally, the main adverse outcome is tubular damage of the S2 and S3 segments of the kidneys, leading to tubular cell death, and then kidney failure. The attribution of renal carcinogenesis due to U is controversial, and specific experimental or epidemiological studies must be conducted. A tentative construction of an AOP for uranium-induced kidney toxicity and failure was proposed.
Neuronal and Brain Maturation
Authors: Bonfanti Luca , Couillard-Després Sébastien
Published: April 2022

Can plasticity be considered as an extension of “immaturity” [...]
Docosahexaenoic Acid Suppresses Oxidative Stress-Induced Autophagy and Cell Death via the AMPK-Dependent Signaling Pathway in Immortalized Fischer Rat Schwann Cells 1
Authors: Tatsumi Yasuaki , Kato Ayako , Niimi Naoko , Yako Hideji , Himeno Tatsuhito , Kondo Masaki , Tsunekawa Shin , Kato Yoshiro , Kamiya Hideki , Nakamura Jiro , Higai Koji , Sango Kazunori , Kato Koichi
Published: April 2022

Autophagy is the process by which intracellular components are degraded by lysosomes. It is also activated by oxidative stress; hence, autophagy is thought to be closely related to oxidative stress, one of the major causes of diabetic neuropathy. We previously reported that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) induced antioxidant enzymes and protected Schwann cells from oxidative stress. However, the relationship between autophagy and oxidative stress-induced cell death in diabetic neuropathy has not been elucidated. Treatment with tert-butyl hydroperoxide (tBHP) decreased the cell survival rate, as measured by an MTT assay in immortalized Fischer rat Schwann cells 1 (IFRS1). A DHA pretreatment significantly prevented tBHP-induced cytotoxicity. tBHP increased autophagy, which was revealed by the ratio of the initiation markers, AMP-activated protein kinase, and UNC51-like kinase phosphorylation. Conversely, the DHA pretreatment suppressed excessive tBHP-induced autophagy signaling. Autophagosomes induced by tBHP in IFRS1 cells were decreased to control levels by the DHA pretreatment whereas autolysosomes were only partially decreased. These results suggest that DHA attenuated excessive autophagy induced by oxidative stress in Schwann cells and may be useful to prevent or reduce cell death in vitro. However, its potentiality to treat diabetic neuropathy must be validated in in vivo studies.
Synergistic Anti-Angiogenic Effect of Combined VEGFR Kinase Inhibitors, Lenvatinib, and Regorafenib: A Therapeutic Potential for Breast Cancer
Authors: Bajbouj Khuloud , Qaisar Rizwan , Alshura Mohammed A. , Ibrahim Zeinab , Alebaji Mohamad B. , Al Ani Amenah W. , Janajrah Hanadi M. , Bilalaga Mariah M. , Omara Abdelrahman I. , Abou Assaleh Rebal S. , Saber-Ayad Maha M. , Elmoselhi Adel B.
Published: April 2022

Background: Breast cancer currently affects more than two million women worldwide, and its incidence is steadily increasing. One of the most essential factors of invasion and metastasis of breast cancer cells is angiogenesis and non-angiogenic vascularization. Lenvatinib and Regorafenib share the same anti-angiogenic effect by inhibiting vascular endothelial growth factor receptors (VEGFRs subtypes 1 to 3) and have been approved for treating different types of cancer. Methods: We investigated Lenvatinib and Regorafenib effects on a well-established in-vitro model of breast cancer using MCF-7 (estrogen, progesterone receptor-positive, and HER2-negative), MDA-MB-231 (triple negative), as well as Human Umbilical Vascular Endothelial Cell line (HUVEC) cell lines. We performed the cell viability assay on four groups of cells, which included a control group, a Lenvatinib treated only group, a Regorafenib treated only group, and a group treated with a combination of both drugs at 24, 48, and 72 h. Data were analyzed as means ± standard deviation, and the drug–drug interactions with Compusyn software. Cellular migration assay, tube formation assay, and Western blots were conducted to determine the functional and the protein expression of downstream signals such as Caspase-9, anti-apoptotic Survivin, P-ERK, and total-ERK in the control and treatment groups. Results: MCF-7 cells showed a reduction in cell survival rates with higher dosing and longer incubation periods with each drug and with the combination of drugs. A synergistic interaction was identified (CI < 1) with both drugs on MCF7 at different dose combinations and at a higher dose in MDA-MB-231 cells. Furthermore, there was a marked decrease in the anti-angiogenic effect of both drugs in tube formation assay using MDA-MB-231 cells and survivin protein expression in MCF-7, and those antitumor markers showed a better outcome in drug combination than the use of each drug alone. Conclusion: Our result is the first to report the synergistic anti-angiogenic potential of combination therapy of Lenvatinib and Regorafenib. Therefore, it shows their therapeutic potential in breast cancer, including the aggressive types. Further studies are warranted to confirm and explore this therapeutic approach.
Molecular Pathways Involved in the Anti-Cancer Activity of Flavonols: A Focus on Myricetin and Kaempferol
Authors: Felice Maria Rosa , Maugeri Alessandro , De Sarro Giovambattista , Navarra Michele , Barreca Davide
Published: April 2022

Natural compounds have always represented valuable allies in the battle against several illnesses, particularly cancer. In this field, flavonoids are known to modulate a wide panel of mechanisms involved in tumorigenesis, thus rendering them worthy candidates for both cancer prevention and treatment. In particular, it was reported that flavonoids regulate apoptosis, as well as hamper migration and proliferation, crucial events for the progression of cancer. In this review, we collect recent evidence concerning the anti-cancer properties of the flavonols myricetin and kaempferol, discussing their mechanisms of action to give a thorough overview of their noteworthy capabilities, which are comparable to those of their most famous analogue, namely quercetin. On the whole, these flavonols possess great potential, and hence further study is highly advised to allow a proper definition of their pharmaco-toxicological profile and assess their potential use in protocols of chemoprevention and adjuvant therapies.
Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases
Authors: Marosi Mate , Arman Parsa , Aceto Giuseppe , D’Ascenzo Marcello , Laezza Fernanda
Published: April 2022

Glycogen synthase kinase 3β (GSK3) is a multifaceted serine/threonine (S/T) kinase expressed in all eukaryotic cells. GSK3β is highly enriched in neurons in the central nervous system where it acts as a central hub for intracellular signaling downstream of receptors critical for neuronal function. Unlike other kinases, GSK3β is constitutively active, and its modulation mainly involves inhibition via upstream regulatory pathways rather than increased activation. Through an intricate converging signaling system, a fine-tuned balance of active and inactive GSK3β acts as a central point for the phosphorylation of numerous primed and unprimed substrates. Although the full range of molecular targets is still unknown, recent results show that voltage-gated ion channels are among the downstream targets of GSK3β. Here, we discuss the direct and indirect mechanisms by which GSK3β phosphorylates voltage-gated Na+ channels (Nav1.2 and Nav1.6) and voltage-gated K+ channels (Kv4 and Kv7) and their physiological effects on intrinsic excitability, neuronal plasticity, and behavior. We also present evidence for how unbalanced GSK3β activity can lead to maladaptive plasticity that ultimately renders neuronal circuitry more vulnerable, increasing the risk for developing neuropsychiatric disorders. In conclusion, GSK3β-dependent modulation of voltage-gated ion channels may serve as an important pharmacological target for neurotherapeutic development.
Protein Tyrosine Phosphatase Receptor Type Z in Central Nervous System Disease
Authors: Nagai Kenichiro , Fujii Masazumi , Kitazume Shinobu
Published: April 2022

Gliomas are among the most common tumors of the central nervous system and include highly malignant subtypes, such as glioblastoma, which are associated with poor prognosis. Effective treatments are therefore urgently needed. Despite the recent advances in neuroimaging technologies, differentiating gliomas from other brain diseases such as multiple sclerosis remains challenging in some patients, and often requires invasive brain biopsy. Protein tyrosine phosphatase receptor type Z (PTPRZ) is a heavily glycosylated membrane protein that is highly expressed in the central nervous system. Several reports analyzing mouse tumor models suggest that PTPRZ may have potential as a therapeutic target for gliomas. A soluble cleaved form of PTPRZ (sPTPRZ) in the cerebrospinal fluid is markedly upregulated in glioma patients, making it another promising diagnostic biomarker. Intriguingly, PTPRZ is also involved in the process of remyelination in multiple sclerosis. Indeed, lowered PTPRZ glycosylation by deletion of the glycosyltransferase gene leads to reduced astrogliosis and enhanced remyelination in mouse models of demyelination. Here, we review the expression, molecular structure, and biological roles of PTPRZ. We also discuss glioma and demyelinating diseases, as well as the pathological role of PTPRZ and its application as a diagnostic marker and therapeutic target.
MdMAPKKK1 Regulates Apple Resistance to Botryosphaeria dothidea by Interacting with MdBSK1
Authors: Wang Nan , Liu Yingshuang , Dong Chaohua , Zhang Yugang , Bai Suhua
Published: April 2022

Plant MAPK cascade performs a critical role in the regulation of plant immunity and disease resistance. Although the function of MAPK cascade in immunity regulation is partially conserved between different species, the mechanism varies in different host and pathogen combinations. To date, the MAPK cascade function of woody plants in the regulation of disease resistance has seldom been reported. Here, we present evidence to show that apple MdMAPKKK1 performed an important role in the regulation of apple resistance to Botryosphaeria dothidea, the causal agent of apple ring rot. B. dothidea infection leads to enhanced MdMAPKKK1 expression and MAPK cascade activation, indicating that the MAPK cascade is involved in the defense against B. dothidea. MdMAPKKK1 overexpression-induced pathogen-independent cell death. MdMAPKKK1 silencing decreases the resistance of apple calli and fruits to B. dothidea. Further analysis indicates that MdMAPKKK1 can bind MdBSK1 and is likely phosphorylated by it. The MdBSK1-mediated phosphorylation of MdMAPKKK1 is important for resistance to B. dothidea. These results collectively indicate that apple resistance to B. dothidea is regulated by the interaction between MAPKKK1 and MdBSK1.
In Vivo Functional Assay in Fish Gills: Exploring Branchial Acid-Excreting Mechanisms in Zebrafish
Authors: Shih Shang-Wu , Yan Jia-Jiun , Tsou Yi-Ling , Lu Shao-Wei , Wang Min-Chen , Chou Ming-Yi , Hwang Pung-Pung
Published: April 2022

Molecular and physiological analyses in ionoregulatory organs (e.g., adult gills and embryonic skin) are essential for studying fish ion regulation. Recent progress in the molecular physiology of fish ion regulation was mostly obtained in embryonic skin; however, studies of ion regulation in adult gills are still elusive and limited because there are no direct methods for in vivo functional assays in the gills. The present study applied the scanning ion-selective electrode technique (SIET) in adult gills to investigate branchial H+-excreting functions in vivo. We removed the opercula from zebrafish and then performed long-term acid acclimation experiments. The results of Western blot and immunofluorescence showed that the protein expression of H+-ATPase (HA) and the number of H+-ATPase-rich ionocytes were increased under acidic situations. The SIET results proved that the H+ excretion capacity is indeed enhanced in the gills acclimated to acidic water. In addition, both HA and Na+/H+ exchanger (Nhe) inhibitors suppressed the branchial H+ excretion capacity, suggesting that H+ is excreted in association with HA and Nhe in zebrafish gills. These results demonstrate that SIET is effective for in vivo detection in fish gills, representing a breakthrough approach for studying the molecular physiology of fish ion regulation.
Anti-Inflammatory and Neuroprotective Mechanisms of GTS-21, an α7 Nicotinic Acetylcholine Receptor Agonist, in Neuroinflammation and Parkinson’s Disease Mouse Models
Authors: Park Jung-Eun , Leem Yea-Hyun , Park Jin-Sun , Kim Do-Yeon , Kang Jihee Lee , Kim Hee-Sun
Published: April 2022

Neuroinflammation is crucial in the progression of neurodegenerative diseases. Thus, controlling neuroinflammation has been proposed as an important therapeutic strategy for neurodegenerative disease. In the present study, we examined the anti-inflammatory and neuroprotective effects of GTS-21, a selective α7 nicotinic acetylcholine receptor (α7 nAChR) agonist, in neuroinflammation and Parkinson’s disease (PD) mouse models. GTS-21 inhibited the expression of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and primary microglia. Further research revealed that GTS-21 has anti-inflammatory properties by inhibiting PI3K/Akt, NF-κB, and upregulating AMPK, Nrf2, CREB, and PPARγ signals. The effects of GTS-21 on these pro-/anti-inflammatory signaling molecules were reversed by treatment with an α7 nAChR antagonist, suggesting that the anti-inflammatory effects of GTS-21 are mediated through α7 nAChR activation. The anti-inflammatory and neuroprotective properties of GTS-21 were then confirmed in LPS-induced systemic inflammation and MPTP-induced PD model mice. In LPS-injected mouse brains, GTS-21 reduced microglial activation and production of proinflammatory markers. Furthermore, in the brains of MPTP-injected mice, GTS-21 restored locomotor activity and dopaminergic neuronal cell death while inhibiting microglial activation and pro-inflammatory gene expression. These findings suggest that GTS-21 has therapeutic potential in neuroinflammatory and neurodegenerative diseases such as PD.
Enzyme-Responsive Hydrogels as Potential Drug Delivery Systems—State of Knowledge and Future Prospects
Authors: Sobczak Marcin
Published: April 2022

Fast advances in polymer science have provided new hydrogels for applications in drug delivery. Among modern drug formulations, polymeric type stimuli-responsive hydrogels (SRHs), also called smart hydrogels, deserve special attention as they revealed to be a promising tool useful for a variety of pharmaceutical and biomedical applications. In fact, the basic feature of these systems is the ability to change their mechanical properties, swelling ability, hydrophilicity, or bioactive molecules permeability, which are influenced by various stimuli, particularly enzymes. Indeed, among a great number of SHRs, enzyme-responsive hydrogels (ERHs) gain much interest as they possess several potential biomedical applications (e.g., in controlled release, drug delivery, etc.). Such a new type of SHRs directly respond to many different enzymes even under mild conditions. Therefore, they show either reversible or irreversible enzyme-induced changes both in chemical and physical properties. This article reviews the state-of-the art in ERHs designed for controlled drug delivery systems (DDSs). Principal enzymes used for biomedical hydrogel preparation were presented and different ERHs were further characterized focusing mainly on glucose oxidase-, β-galactosidase- and metalloproteinases-based catalyzed reactions. Additionally, strategies employed to produce ERHs were described. The current state of knowledge and the discussion were made on successful applications and prospects for further development of effective methods used to obtain ERH as DDSs.
3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature
Authors: Nardecchia Francesca , Caciotti Anna , Giovanniello Teresa , De Leo Sabrina , Ferri Lorenzo , Galosi Serena , Santagata Silvia , Torres Barbara , Bernardini Laura , Carducci Claudia , Morrone Amelia , Leuzzi Vincenzo
Published: April 2022

3-Methylglutaconic aciduria type I (MGCA1) is an inborn error of the leucine degradation pathway caused by pathogenic variants in the AUH gene, which encodes 3-methylglutaconyl-coenzyme A hydratase (MGH). To date, MGCA1 has been diagnosed in 19 subjects and has been associated with a variable clinical picture, ranging from no symptoms to severe encephalopathy with basal ganglia involvement. We report the case of a 31-month-old female child referred to our center after the detection of increased 3-hydroxyisovalerylcarnitine levels at newborn screening, which were associated with increased urinary excretion of 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and 3-methylglutaric acid. A next-generation sequencing (NGS) panel for 3-methylglutaconic aciduria failed to establish a definitive diagnosis. To further investigate the strong biochemical indication, we measured MGH activity, which was markedly decreased. Finally, single nucleotide polymorphism array analysis disclosed the presence of two microdeletions in compound heterozygosity encompassing the AUH gene, which confirmed the diagnosis. The patient was then supplemented with levocarnitine and protein intake was slowly decreased. At the last examination, the patient showed mild clumsiness and an expressive language disorder. This case exemplifies the importance of the biochemical phenotype in the differential diagnosis of metabolic diseases and the importance of collaboration between clinicians, biochemists, and geneticists for an accurate diagnosis.
Genesis of Open States Zones in a DNA Molecule Depends on the Localization and Value of the Torque
Authors: Dzhimak Stepan , Svidlov Alexandr , Elkina Anna , Gerasimenko Eugeny , Baryshev Mikhail , Drobotenko Mikhail
Published: April 2022

The formation and dynamics of the open states in a double-stranded DNA molecule are largely determined by its mechanical parameters. The main one is the torque. However, the experimental study of DNA dynamics and the occurrence of open states is limited by the spatial resolution of available biophysical instruments. Therefore, in this work, on the basis of a mechanical mathematical model of DNA, calculations of the torque effect on the process of occurrence and dynamics of open states were carried out for the interferon alpha 17 gene. It was shown that torsion action leads to the occurrence of rotational movements of nitrogenous bases. This influence is nonlinear, and an increase in the amplitude of the torsion action does not lead to an automatic increase in the amplitude of rotational movements and an increase in the zones’ open states. Calculations with a constant torsion moment demonstrate that open states zones are more often formed at the boundaries of the gen and in regions with a predominance of A–T pairs. It is shown, that for the occurrence of open states in the part of the gene that contains a small number of A–T pairs, a large amount of torque is required. When the torque is applied to a certain region of the gene, the probability of the formation of the open state depends on the content of A–T pairs in this region, the size of this region, and on the exposure time. For this mathematical model, open states zones can be closed when the torsion action stops. The simulation results showed that the values of the torsion moment required for the appearance of open states zones, in some cases, are close to experimentally measured (13–15 pN·nm).
S-Acetyl-Glutathione Attenuates Carbon Tetrachloride-Induced Liver Injury by Modulating Oxidative Imbalance and Inflammation
Authors: Di Paola Rosanna , Modafferi Sergio , Siracusa Rosalba , Cordaro Marika , D’Amico Ramona , Ontario Maria Laura , Interdonato Livia , Salinaro Angela Trovato , Fusco Roberta , Impellizzeri Daniela , Calabrese Vittorio , Cuzzocrea Salvatore
Published: April 2022

Liver fibrosis, depending on the stage of the disease, could lead to organ dysfunction and cirrhosis, and no effective treatment is actually available. Emergent proof supports a link between oxidative stress, liver fibrogenesis and mitochondrial dysfunction as molecular bases of the pathology. A valid approach to protect against the disease would be to replenish the endogenous antioxidants; thus, we investigated the protective mechanisms of the S-acetyl-glutathione (SAG), a glutathione (GSH) prodrug. Preliminary in vitro analyses were conducted on primary hepatic cells. SAG pre-treatment significantly protected against cytotoxicity induced by CCl4. Additionally, CCl4 induced a marked increase in AST and ALT levels, whereas SAG significantly reduced these levels, reaching values found in the control group. For the in vivo analyses, mice were administered twice a week with eight consecutive intraperitoneal injections of 1 mL/kg CCl4 (diluted at 1:10 in olive oil) to induce oxidative imbalance and liver inflammation. SAG (30 mg/kg) was administered orally for 8 weeks. SAG significantly restored SOD activity, GSH levels and GPx activity, while it strongly reduced GSSG levels, lipid peroxidation and H2O2 and ROS levels in the liver. Additionally, CCl4 induced a decrease in anti-oxidants, including Nrf2, HO-1 and NQO-1, which were restored by treatment with SAG. The increased oxidative stress characteristic on liver disfunction causes the impairment of mitophagy and accumulation of dysfunctional and damaged mitochondria. Our results showed the protective effect of SAG administration in restoring mitophagy, as shown by the increased PINK1 and Parkin expressions in livers exposed to CCl4 intoxication. Thus, the SAG administration showed anti-inflammatory effects decreasing pro-inflammatory cytokines TNF-α, IL-6, MCP-1 and IL-1β in both serum and liver, and suppressing the TLR4/NFkB pathway. SAG attenuated reduced fibrosis, collagen deposition, hepatocellular damage and organ dysfunction. In conclusion, our results suggest that SAG administration protects the liver from CCl4 intoxication by restoring the oxidative balance, ameliorating the impairment of mitophagy and leading to reduced inflammation.
A Framework for Online Public Health Debates: Some Design Elements for Visual Analytics Systems
Authors: Ninkov Anton , Sedig Kamran
Published: April 2022

Nowadays, many people are deeply concerned about their physical well-being; as a result, they invest much time and effort investigating health-related topics. In response to this, many online websites and social media profiles have been created, resulting in a plethora of information on such topics. In a given topic, oftentimes, much of the information is conflicting, resulting in online camps that have different positions and arguments. We refer to the collection of all such positionings and entrenched camps on a topic as an online public health debate. The information people encounter regarding such debates can ultimately influence how they make decisions, what they believe, and how they act. Therefore, there is a need for public health stakeholders (i.e., people with a vested interest in public health issues) to be able to make sense of online debates quickly and accurately. In this paper, we present a framework-based approach for investigating online public health debates—a preliminary work that can be expanded upon. We first introduce the concept of online debate entities (ODEs), which is a generalization for those who participate in online debates (e.g., websites and Twitter profiles). We then present the framework ODIN (Online Debate entIty aNalyzer), in which we identify, define, and justify ODE attributes that we consider important for making sense of online debates. Next, we provide an overview of four online public health debates (vaccines, statins, cannabis, and dieting plans) using ODIN. Finally, we showcase four prototype visual analytics systems whose design elements are informed by the ODIN framework.
A Traffic-Load-Based Algorithm for Wireless Sensor Networks’ Lifetime Extension
Authors: Tsoumanis Georgios , Giannakeas Nikolaos , Tzallas Alexandros T. , Glavas Evripidis , Koritsoglou Kyriakos , Karvounis Evaggelos , Bezas Konstantinos , Angelis Constantinos T.
Published: April 2022

It has been shown in the literature that the lifetime of a wireless sensor network is heavily connected to the number of transmissions that network nodes have to undertake. Considering this finding, along with the effects of the energy hole problem where nodes closer to the sink node transmit more than the more distant ones, a node close to the sink node will be the one that transmits the most, while it will also be the node that will deplete its battery first. Taking into consideration that the failure of a single network node to operate, due to its battery being discharged, can lead to a network stopping its operation, the most energy-consuming node in the network will also be the one that will be responsible for the network’s termination. In this sense, the most energy-consuming node’s energy consumption optimization is the main case in this paper. More specifically, in this work, it is firstly shown that the energy consumption of a wireless sensor network is closely related to each network node’s traffic load, that is the transmissions of the packets that are created or forwarded by a node. The minimization of the most energy-consuming node’s energy consumption was studied here, while the implementation of a traffic-load-based algorithm is also proposed. Under the proposed algorithm, given a simple shortest path approach that assigns a parent (i.e., the next hop towards the sink node) in each network node and the knowledge it provides regarding the distance (in hops in this paper’s case) of network nodes from the sink node, the proposed algorithm exploits the shortest path’s results in order to discover, for all network nodes, neighbors that are of the same distance (from the sink node) with the initially assigned parent. Then, if such neighbors exist, all these neighbors are equally burdened with the parenting role. As a result, the traffic load is shared by all of them. To evaluate the proposed algorithm, simulation results are provided, showing that the goals set were achieved; thus, the network lifetime was prolonged. In addition, it is shown that under the algorithm, a fairer distribution of the traffic load takes place.
Artificial Intelligence and Machine Learning Approaches in Digital Education: A Systematic Revision
Authors: Munir Hussan , Vogel Bahtijar , Jacobsson Andreas
Published: April 2022

The use of artificial intelligence and machine learning techniques across all disciplines has exploded in the past few years, with the ever-growing size of data and the changing needs of higher education, such as digital education. Similarly, online educational information systems have a huge amount of data related to students in digital education. This educational data can be used with artificial intelligence and machine learning techniques to improve digital education. This study makes two main contributions. First, the study follows a repeatable and objective process of exploring the literature. Second, the study outlines and explains the literature’s themes related to the use of AI-based algorithms in digital education. The study findings present six themes related to the use of machines in digital education. The synthesized evidence in this study suggests that machine learning and deep learning algorithms are used in several themes of digital learning. These themes include using intelligent tutors, dropout predictions, performance predictions, adaptive and predictive learning and learning styles, analytics and group-based learning, and automation. artificial neural network and support vector machine algorithms appear to be utilized among all the identified themes, followed by random forest, decision tree, naive Bayes, and logistic regression algorithms.
Ant Mortality with Food Competition in Forests along a Temperature Gradient
Authors: Kwon Tae-Sung , Lee Dae-Seong , Park Young-Seuk
Published: April 2022

The authors elucidated the relationship between temperature and mortality due to food competition in ant communities in forests. A field experiment was conducted using four bait types at six different oak forest sites with different mean annual temperatures in South Korea. The mortality rate due to food competition showed a hump-shaped trend, with temperature distribution being higher at study sites with intermediate temperatures and a linear trend increasing or decreasing with temperature along the temperature gradient. In most species, the mortality rate due to interspecific competition was higher than that due to intraspecific competition, but the dominant species, which were less affected by other species, had a higher mortality rate due to intraspecific competition. In subordinate species that are highly affected by other species, the mortality rate due to intraspecific competition increased as the mortality rate due to interspecific competition decreased. The results indicated that mortality due to inter- or intraspecific competition for food was associated by temperature, density of other species, and species characteristics (body size, dominance, feeding strategy, and aggressiveness). Given the relationship between temperature and mortality due to food competition, the authors expect that changes in competition due to climate warming will affect the fitness of ant species.
Implantable Cardioverter Defibrillator in Primary and Secondary Prevention of SCD—What We Still Don′t Know
Authors: Ursaru Andreea Maria , Petris Antoniu Octavian , Costache Irina Iuliana , Nicolae Ana , Crisan Adrian , Tesloianu Nicolae Dan
Published: April 2022

Implantable cardioverter defibrillators (ICDs) are the cornerstone of primary and secondary prevention of sudden cardiac death (SCD) all around the globe. In almost 40 years of technological advances and multiple clinical trials, there has been a continuous increase in the implantation rate. The purpose of this review is to highlight the grey areas related to actual ICD recommendations, focusing specifically on the primary prevention of SCD. We will discuss the still-existing controversies strongly reflected in the differences between the international guidelines regarding ICD indication class in non-ischemic cardiomyopathy, and also address the question of early implantation after myocardial infarction in the absence of clear protocols for patients at high risk of life-threatening arrhythmias. Correlating the insufficient data in the literature for 40-day waiting times with the increased risk of SCD in the first month after myocardial infarction, we review the pros and cons of early ICD implantation.
Correction: Marsh et al. Peptidic Connexin43 Therapeutics in Cardiac Reparative Medicine. J. Cardiovasc. Dev. Dis. 2021, 8, 52
Authors: Marsh Spencer R. , Williams Zachary J. , Pridham Kevin J. , Gourdie Robert G.
Published: April 2022

The authors would like to make corrections to the reference citations in the original article [...]
Mediators of Amylin Action in Metabolic Control
Authors: Boyle Christina N. , Zheng Yi , Lutz Thomas A.
Published: April 2022

Amylin (also called islet amyloid polypeptide (IAPP)) is a pancreatic beta-cell hormone that is co-secreted with insulin in response to nutrient stimuli. The last 35 years of intensive research have shown that amylin exerts important physiological effects on metabolic control. Most importantly, amylin is a physiological control of meal-ending satiation, and it limits the rate of gastric emptying and reduces the secretion of pancreatic glucagon, in particular in postprandial states. The physiological effects of amylin and its analogs are mediated by direct brain activation, with the caudal hindbrain playing the most prominent role. The clarification of the structure of amylin receptors, consisting of the calcitonin core receptor plus receptor-activity modifying proteins, aided in the development of amylin analogs with a broad pharmacological profile. The general interest in amylin physiology and pharmacology was boosted by the finding that amylin is a sensitizer to the catabolic actions of leptin. Today, amylin derived analogs are considered to be among the most promising approaches for the pharmacotherapy against obesity. At least in conjunction with insulin, amylin analogs are also considered important treatment options in diabetic patients, so that new drugs may soon be added to the only currently approved compound pramlintide (Symlin®). This review provides a brief summary of the physiology of amylin’s mode of actions and its role in the control of the metabolism, in particular energy intake and glucose metabolism.
HUS1 as a Potential Therapeutic Target in Urothelial Cancer
Authors: Lindner Andrea Katharina , Furlan Tobias , Orme Jacob J. , Tulchiner Gennadi , Staudacher Nina , D’Andrea David , Culig Zoran , Pichler Renate
Published: April 2022

Platinum-based chemotherapy is the standard of care with concern to first-line systemic therapy for metastatic disease in urothelial cancer (UC). Resistance to chemotherapy despite an initial response is linked with the ability to remove platinum-based DNA adducts and to repair chemotherapy-induced DNA lesions by various DNA repair proteins. The Rad9-Rad1-HUS1 complex that is loaded onto DNA at sites of damage is involved in checkpoint activation as well as DNA repair. Here, we addressed for the first time the potential influence of HUS1 expression in urothelial carcinogenesis (using two human basal urothelial cancer cell lines UM-UC-3 and HT1197) and its role as a potential therapeutic target for predicting responses to platinum-based chemotherapy. Specific inhibition of HUS1 expression in both cell lines was achieved by specific siRNA and validated by Western blot. In order to define the possible importance of HUS1 in the regulation of cellular proliferation, parental and resistant cells were treated with increasing concentrations of either control or HUS1 siRNA. HUS1 protein expression was observed in both human basal urothelial cancer cell lines UM-UC-3 and HT1197. In cisplatin-sensitive cells, knock-down of HUS1 inhibited cellular proliferation in the presence of cisplatin. On the contrary, knock-down of HUS1 in resistant cells did not result in a re-sensitization to cisplatin. Finally, RNAseq data from the Cancer Genome Atlas provided evidence that HUS1 expression is a significant prognostic factor for poor survival in UC patients. In summary, HUS1 may acts as an oncogene in UC and might be a key determinant of the cellular response to cisplatin-based chemotherapy.
Balloon Pulmonary Angioplasty in Patients with Chronic Thromboembolic Pulmonary Hypertension in Greece: Data from the Hellenic Pulmonary Hypertension Registry
Authors: Karyofyllis Panagiotis , Demerouti Eftychia , Giannakoulas George , Anthi Anastasia , Arvanitaki Alexandra , Athanassopoulos George , Feloukidis Christos , Iakovou Ioannis , Kostelidou Theodora , Mitrouska Ioanna , Mouratoglou Sophia-Anastasia , Orfanos Stylianos E. , Pappas Christos , Pitsiou Georgia , Tsetika Eleftheria-Garyfallia , Tsiapras Dimitrios , Voudris Vassilios , Manginas Athanassios
Published: April 2022

Balloon pulmonary angioplasty (BPA) is a novel and promising treatment option for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are ineligible for pulmonary endarterectomy (PEA) and for those with persistent or recurrent pulmonary hypertension after PEA. We present the results of BPA procedures in CTEPH patients included in the Greek Pulmonary Hypertension Registry, evaluating the real-life efficacy and safety. We analyzed data from 180 BPA procedures (2–17/patient, mean 8 ± 4/patient, 1248 dilated vessels, 0–18/session). Significant improvements were observed in mean pulmonary arterial pressure (a reduction by 44%, p < 0.001), pulmonary vascular resistance (reduction by 60%, p < 0.001), and NT-proBNP (decrease by >70%, p: 0.003), while cardiac index improved modestly (9% increase, p = 0.143). We had 37 BPA-related non-fatal complications (20.6% in all interventions), predominantly including hemoptysis. Overall survival was 91%, 75% and 62% at 3, 4 and 5 years, respectively. Therefore, BPA may be a promising therapeutic option in patients with CTEPH in Greece.