bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of the COVID-19 Pandemic on Gyne-Oncological Treatment—A Retrospective Single-Center Analysis of a German University Hospital with 30,525 Patients
Authors: Griewing Sebastian , Kalder Matthias , Lingenfelder Michael , Wagner Uwe , Gremke Niklas
Published: November 2022

The study pursues the objective of drawing a comparison between the data of gyne-oncology, gynecology, and obstetrics patient collectives of a German university hospital regarding the progression of patient number and corresponding treatment data during the five-year period of 2017–2021 to assess the impact of the COVID-19 pandemic on gyne-oncological treatment. Descriptive assessment is based on data extracted from the database of the hospital controlling system QlikView® for patients hospitalized at the Department of Gynecology and Obstetrics of Marburg University Hospital. Gynecology and gyne-oncology experience a maintained decline in patient number (nGynecology: −6% 2019 to 2020, −5% 2019 to 2021; nGyne-Oncology: −6% 2019 to 2020, −2% 2019 to 2021) with varying effects on the specific gyne-oncological main diagnoses. Treatment parameters remain unchanged in relative assessment, but as gyne-oncology constitutes the dominating revenue contributor in gynecology (35.1% of patients, 52.9% of revenue, 2021), the extent of the decrease in total revenue (−18%, 2019 to 2020, −14%, 2019 to 2021) surpasses the decline in patient number. The study displays a negative impact on the gynecology care situation of a German university hospital for the entire pandemic, with an even greater extent on gyne-oncology. This development not only endangers the quality of medical service provision but collaterally pressurizes gynecology service providers.
Effect of Pirfenidone on Risk of Pulmonary Fibrosis in COVID-19 Patients Experiencing Cytokine Storm
Authors: Boshra Marian S. , Abou Warda Ahmed E. , Sayed Mahmoud Abdulbasser , Elkomy Mohammed H. , Alotaibi Nasser H. , Mohsen Marwa , Sarhan Rania M.
Published: November 2022

Objectives: Severe stages of COVID-19 infection have been associated with the excessive discharge of pro-inflammatory mediators such as cytokines, resulting in lung deterioration, which progresses rapidly to lung fibrosis leading to acute respiratory distress syndrome. In this investigation, the efficacy and safety of the novel antifibrotic and anti-inflammatory agent, Pirfenidone, were assessed in COVID-19 patients with pulmonary fibrosis secondary to cytokine storm. In this randomized controlled study, we assigned 100 adult COVID-19 patients cytokine storm and admitted to the intensive care isolation unit into either pirfenidone added to the standard therapy (n = 47), or the standard protocol only (n = 53). High-resolution computed tomography of the chest was performed in all patients to evaluate fibrotic lesions and their progression. The results showed that the percentage of patients who developed pulmonary fibrosis during cytokine storm onset in the pirfenidone group relative to the standard group was 29.8% and 35.8%, respectively, with no significant difference between the two groups; while there was a significant increase in the proportion of patients discharged from the isolation unit with pulmonary fibrosis without progression in fibrotic lesions in the pirfenidone group compared to the standard group (21.3% and 5.7%, respectively). Furthermore, there was a significant difference concerning liver enzyme elevation and GIT disturbance incidences in the studied groups (p = 0.006 and 0.01, respectively). Our findings show that Pirfenidone inhibits fibrosis advancement in COVID-19 patients with pulmonary fibrosis and is associated with hepatotoxicity and GI distress. It may be beneficial in patients with mild to moderate COVID-19-induced pulmonary fibrosis; however, additional research is necessary.
Biodegradable Recycled Paper Mulch Reduces Strawberry Water Consumption and Crop Coefficient
Authors: Pinto João Pedro , da Cunha Fernando França , da Silva Gustavo Henrique , Condé Saulo Borges , Guimarães Gabriel Fernandes Costa , Ribeiro Marcos Caldeira
Published: November 2022

Mulching with recycled paper has the potential to be used in agricultural production and can be adopted in strawberry cultivation. Therefore, the objective of this study was to evaluate the agronomic characteristics, water consumption and technical coefficients of strawberry cultivated with recycled paper as mulch. The treatments consisted of strawberry cultivation in lysimeters with recycled paper mulch and without soil cover. The recycled paper used was 187 μm-thick. The irrigation system was installed with drippers whose flow rate was 2 L h−1. Strawberry irrigation requirements were 317 and 394 mm, with and without mulch, respectively. Mulching with recycled paper did not have a significant effect on the average number of fruits, fresh fruit mass, fruit waste per plant, average fruit yield and water productivity. In relation to the technical coefficients, maximum values of the evaporation coefficient (Ke) of 0.40 (calculated with the evapotranspiration of the grass—L) and 0.28 (calculated with the Penman–Monteith ETo—PM) were obtained for OPM. The Kc values for the initial and full development stages were 0.31 and 0.84 (L) and 0.24 and 0.66 (PM), respectively. NDVI can be used to estimate strawberry Kc values. Recycled paper as mulch reduces the water consumption of strawberry crops and does not alter the agronomic characteristics.
Are the Benefits of a High-Emission Vehicle Driving Area Restriction Policy Greater than the Costs?
Authors: Zhou Jia , Jiang Hongqiang , Cheng Xi , Lu Yaling , Zhang Wei , Dong Zhanfeng
Published: November 2022

China implemented a vehicle driving area restriction policy to control air pollution by delimiting a no-driving area for high-emission vehicles (HEVs). Current academic research does not evaluate the benefits and costs of this policy based on vehicle level and lacks evidence at the regional level. Therefore, a cost–benefit analysis method is developed to evaluate the benefits and the costs of this policy, based on 2.128 million HEVs in the Beijing-Tianjin-Hebei (BTH) region from 2008 to 2015. The benefits, the costs, and net benefits of this policy were CNY 98.49, CNY 5.80 and CNY 92.69 billion. The cost–benefit ratios of the BTH region, Beijing, Tianjin and Hebei were 1:16.98, 1:20.88, 1:14.52 and 1:16.55, respectively. Beijing’s cost–benefit ratio was the maximum at the city scale. This work can provide scientific support for promoting driving area restriction policies on older gasoline vehicles and older diesel vehicles, the improvement of cost–benefit analysis and efficient decision-making for the Chinese government.
An Automatic Generalization Method for a Dense Road Network Area Considering Spatial Structural Features as Constraints
Authors: Wu Pengda , Yin Yong , Wu Chuangqi , Bai Xiaofei , Zhang Chunxiao , Dai Zhaoxin
Published: November 2022

Road networks are the skeletal elements of topographic maps at different scales, and road selection is a prerequisite for implementing continuous multiscale spatial representations of road networks. The mesh-based approach is a common, advanced and powerful method for road selection in dense road areas in which small meshes are removed and road segments with the least importance in each mesh are eliminated. However, small meshes in a map can be classified into two types: aggregated small meshes and isolated small meshes. The number of the former is small, and that of the latter is large. Existing methods are generally applicable for the latter, and some or even most spatial characteristics will be lost when they are applied to the former; as a result, the road selection quality will be affected. Therefore, as a supplement to the mesh-based selection method, this paper proposed an automatic generalization method of dense road network areas (areas formed by aggregated small meshes) considering spatial structural features as constraints. First, the aggregated areas of small meshes were identified based on the number of adjoining small meshes, and the boundaries of aggregated areas are extracted and used as hard constraints during mesh elimination. Second, the starting meshes were redefined by simultaneously considering the edge features and mesh density of small meshes, and an ordinal elimination algorithm was proposed to eliminate the meshes in the stroke connection direction. Third, road selection was implemented by identifying the starting meshes and sequentially processing the related mesh pairs. This iterative process continued until all mesh densities of the newly formed meshes are beyond the threshold or the problem becomes a simple elimination problem involving two adjoining small meshes or one isolated small mesh. Finally, a 1:10,000 standard topographic road map for Jiangsu Province, China, was used for validation. The experimental results showed that in the aggregated areas with two small meshes, 31% of the areas obtained the same selection results by using the mesh-based method and the proposed method, and the remaining 69% obtained a more compact result with the proposed method. Moreover, for all aggregated areas with more than two small meshes, the spatial distribution structure of small meshes was preserved better by the proposed method.
Cerebral Blood Flow in Predator Stress-Resilient and -Susceptible Rats and Mechanisms of Resilience
Authors: Kondashevskaya Marina V. , Downey H. Fred , Tseilikman Vadim E. , Alexandrin Valery V. , Artem’yeva Kseniya A. , Aleksankina Valentina V. , Tseilikman Olga B. , Pashkov Anton A. , Goryacheva Anna V. , Ivleva Irina S. , Karpenko Marina N. , Shatilov Vladislav A. , Manukhina Eugenia B.
Published: November 2022

Stress-induced conditions are associated with impaired cerebral blood flow (CBF) and increased risk of dementia and stroke. However, these conditions do not develop in resilient humans and animals. Here the effects of predator stress (PS, cat urine scent, ten days) on CBF and mechanisms of CBF regulation were compared in PS-susceptible (PSs) and PS-resilient (PSr) rats. Fourteen days post-stress, the rats were segregated into PSs and PSr groups based on a behavior-related anxiety index (AI). CBF and its endothelium-dependent changes were measured in the parietal cortex by laser Doppler flowmetry. The major findings are: (1) PS susceptibility was associated with reduced basal CBF and endothelial dysfunction. In PSr rats, the basal CBF was higher, and endothelial dysfunction was attenuated. (2) CBF was inversely correlated with the AI of PS-exposed rats. (3) Endothelial dysfunction was associated with a decrease in eNOS mRNA in PSs rats compared to the PSr and control rats. (4) Brain dopamine was reduced in PSs rats and increased in PSr rats. (5) Plasma corticosterone of PSs was reduced compared to PSr and control rats. (6) A hypercoagulation state was present in PSs rats but not in PSr rats. Thus, potential stress resilience mechanisms that are protective for CBF were identified.
Cigarette Smoke Extract Induces p38 MAPK-Initiated, Fas-Mediated Eryptosis
Authors: Restivo Ignazio , Attanzio Alessandro , Giardina Ilenia Concetta , Di Gaudio Francesca , Tesoriere Luisa , Allegra Mario
Published: November 2022

Eryptosis is a physiological mechanism for the clearance of senescent or damaged erythrocytes by phagocytes. Excessive eryptosis is stimulated under several pathologies and associated with endothelial injury and thrombosis. Cigarette smoke (CS) is an established risk factor for vascular diseases and cigarette smokers have high-levels of eryptotic erythrocytes. This study, for the first time, investigates the mechanism by which CS damages red blood cells (RBCs). CS extract (CSE) from commercial cigarettes was prepared and standardized for nicotine content. Cytofluorimetric analysis demonstrated that treatment of human RBCs with CSE caused dose-dependent, phosphatidylserine externalization and cell shrinkage, hallmarks of apoptotic death. CSE did not affect cellular levels of Ca2+, reactive oxygen species (ROS) or glutathione (GSH). Immununoprecipitation and immunoblotting revealed the assembly of the death-inducing signaling complex (DISC) and oligomerization of Fas receptor as well as cleaved caspase-8 and caspase-3 within 6 h from the treatment. At the same time-interval, CSE elicited neutral sphyngomielinase (nSMase) activity-dependent ceramide formation and phosphorylation of p38 MAPK. Through specific inhibitors’ nSMase, caspase-8 or p38 MAPK activities, we demonstrated that p38 MAPK activation is required for caspase-8-mediated eryptosis and that ceramide generation is initiator caspase-dependent. Finally, ex vivo analysis detected phosphorylated p38 MAPK (p-p38) and Fas-associated signaling complex in erythrocytes from cigarette smokers. In conclusion, our study demonstrates that CSE exposure induces in erythrocytes an extrinsic apoptotic pathway involving p38 MAPK-initiated DISC formation followed by activation of caspase-8/caspase-3 via ceramide formation.
Pharmaceutical Functionalization of Monomeric Ionic Liquid for the Preparation of Ionic Graft Polymer Conjugates
Authors: Mazur Aleksy , Niesyto Katarzyna , Neugebauer Dorota
Published: November 2022

Polymerizable choline-based ionic liquid (IL), i.e., [2-(methacryloyloxy)ethyl]-trimethylammonium (TMAMA/Cl¯), was functionalized by an ion exchange reaction with pharmaceutical anions, i.e., cloxacillin (CLX¯) and fusidate (FUS¯), as the antibacterial agents. The modified biocompatible IL monomers (TMAMA/CLX¯, TMAMA/FUS¯) were copolymerized with methyl methacrylate (MMA) to prepare the graft copolymers (19–50 mol% of TMAMA units) serving as the drug (co)delivery systems. The in vitro drug release, which was driven by the exchange reaction of the pharmaceutical anions to phosphate ones in PBS medium, was observed for 44% of CLX¯ (2.7 μg/mL) and 53% of FUS¯ (3.6 μg/mL) in the single systems. Similar amounts of released drugs were detected for the dual system, i.e., 41% of CLX¯ (2.2 μg/mL) and 33% of FUS¯ (2.0 μg/mL). The investigated drug ionic polymer conjugates were examined for their cytotoxicity by MTT test, showing a low toxic effect against human bronchial epithelial cells (BEAS-2B) and normal human dermal fibroblasts (NHDF) as the normal cell lines. The satisfactory drug contents and the release profiles attained for the well-defined graft polymers with ionically bonded pharmaceuticals in the side chains make them promising drug carriers in both separate and combined drug delivery systems.
Metabolic and Oxidative Changes in the Fern Adiantum raddianum upon Foliar Application of Metals
Authors: Kováčik Jozef , Husáková Lenka , Babula Petr , Matušíková Ildikó
Published: November 2022

Cadmium (Cd) or nickel (Ni) were applied as a foliar spray (1 µM solution over one month) to mimic air pollution and to monitor metabolic responses and oxidative stress in the pteridophyte species. Exogenous metals did not affect the metal content of the soil and had relatively little effect on the essential elements in leaves or rhizomes. The amounts of Cd and Ni were similar in treated leaves (7.2 µg Cd or 5.3 µg Ni/g DW in mature leaves compared with 0.4 µg Cd or 1.2 µg Ni/g DW in the respective control leaves), but Ni was more abundant in rhizomes (56.6 µg Ni or 3.4 µg Cd/g DW), resulting in a higher Cd translocation and bioaccumulation factor. The theoretical calculation revealed that ca. 4% of Cd and 5.5% of Ni from the applied solution per plant/pot was absorbed. Excess Cd induced stronger ROS production followed by changes in SOD and CAT activities, whereas nitric oxide (NO) stimulation was less intense, as detected by confocal microscopy. The hadrocentric vascular bundles in the petioles also showed higher ROS and NO signals under metal excess. This may be a sign of increased ROS formation, and high correlations were observed. Proteins and amino acids were stimulated by Cd or Ni application in individual organs, whereas phenols and flavonols were almost unaffected. The data suggest that even low levels of exogenous metals induce an oxidative imbalance, although no visible damage is observed, and that the responses of ferns to metals are similar to those of seed plants or algae.
Targeting Mitochondrial Dynamics Proteins for the Development of Therapies for Cardiovascular Diseases
Authors: Blagov Alexander , Kozlov Sergey , Blokhina Tatiana , Sukhorukov Vasily , Orekhov Alexander
Published: November 2022

Cardiovascular diseases are one of the leading causes of death worldwide. The identification of new pathogenetic targets contributes to more efficient development of new types of drugs for the treatment of cardiovascular diseases. This review highlights the problem of mitochondrial dynamics disorders, in the context of cardiovascular diseases. A change in the normal function of mitochondrial dynamics proteins is one of the reasons for the development of the pathological state of cardiomyocytes. Based on this, therapeutic targeting of these proteins may be a promising strategy in the development of cardiac drugs. Here we will consider changes for each process of mitochondrial dynamics in cardiovascular diseases: fission and fusion of mitochondria, mitophagy, mitochondrial transport and biogenesis, and also analyze the prospects of the considered protein targets based on existing drug developments.
Increased Expression of the RBPMS Splice Variants Inhibits Cell Proliferation in Ovarian Cancer Cells
Authors: Rabelo-Fernández Robert J. , Noriega Rivera Ricardo A. , Rivera Yasmarie Santana , Tous-Beveraggi José , Valiyeva Fatima , Vivas-Mejia Pablo E.
Published: November 2022

RNA-Binding Protein with Multiple Splicing (RBPMS) is a member of family proteins that bind to nascent RNA transcripts and regulate their splicing, localization, and stability. Evidence indicates that RBPMS controls the activity of transcription factors associated with cell growth and proliferation, including AP-1 and Smads. Three major RBPMS protein splice variants (RBPMSA, RBPMSB, and RBPMSC) have been described in the literature. We previously reported that reduced RBPMS levels decreased the sensitivity of ovarian cancer cells to cisplatin treatment. However, little is known about the biological role of the RBPMS splice variants in ovarian cancer cells. We performed RT-PCR and Western blots and observed that both RBPMSA and RBPMSC are reduced at the mRNA and protein levels in cisplatin resistant as compared with cisplatin sensitive ovarian cancer cells. The mRNA and protein levels of RBPMSB were not detectable in any of the ovarian cancer cells tested. To better understand the biological role of each RBPMSA and RBPMSC, we transfected these two splice variants in the A2780CP20 and OVCAR3CIS cisplatin resistant ovarian cancer cells and performed cell proliferation, cell migration, and invasion assays. Compared with control clones, a significant reduction in the number of colonies, colony size, cell migration, and invasion was observed with RBPMSA and RBPMSC overexpressed cells. Moreover, A2780CP20-RBPMSA and A2780CP20-RBPMSC clones showed reduced senescence-associated β-galactosidase (β-Gal)-levels when compared with control clones. A2780CP20-RBPMSA clones were more sensitive to cisplatin treatment as compared with A2780CP20-RBPMSC clones. The A2780CP20-RBPMSA and A2780CP20-RBPMSC clones subcutaneously injected into athymic nude mice formed smaller tumors as compared with A2780CP20-EV control group. Additionally, immunohistochemical analysis showed lower proliferation (Ki67) and angiogenesis (CD31) staining in tissue sections of A2780CP20-RBPMSA and A2780CP20-RBPMSC tumors compared with controls. RNAseq studies revealed many common RNA transcripts altered in A2780CP20-RBPMSA and A2780CP20-RBPMSC clones. Unique RNA transcripts deregulated by each RBPMS variant were also observed. Kaplan–Meier (KM) plotter database information identified clinically relevant RBPMSA and RBPMSC downstream effectors. These studies suggest that increased levels of RBPMSA and RBPMSC reduce cell proliferation in ovarian cancer cells. However, only RBPMSA expression levels were associated with the sensitivity of ovarian cancer cells to cisplatin treatment.
Carboxymethyl-Dextran-Coated Superparamagnetic Iron Oxide Nanoparticles for Drug Delivery: Influence of the Coating Thickness on the Particle Properties
Authors: Turrina Chiara , Milani Davide , Klassen Anna , Rojas-González Diana M. , Cookman Jennifer , Opel Matthias , Sartori Barbara , Mela Petra , Berensmeier Sonja , Schwaminger Sebastian P.
Published: November 2022

Carboxymethyl-dextran (CMD)-coated iron oxide nanoparticles (IONs) are of great interest in nanomedicine, especially for applications in drug delivery. To develop a magnetically controlled drug delivery system, many factors must be considered, including the composition, surface properties, size and agglomeration, magnetization, cytocompatibility, and drug activity. This study reveals how the CMD coating thickness can influence these particle properties. ION@CMD are synthesized by co-precipitation. A higher quantity of CMD leads to a thicker coating and a reduced superparamagnetic core size with decreasing magnetization. Above 12.5–25.0 g L−1 of CMD, the particles are colloidally stable. All the particles show hydrodynamic diameters < 100 nm and a good cell viability in contact with smooth muscle cells, fulfilling two of the most critical characteristics of drug delivery systems. New insights into the significant impact of agglomeration on the magnetophoretic behavior are shown. Remarkable drug loadings (62%) with the antimicrobial peptide lasioglossin and an excellent efficiency (82.3%) were obtained by covalent coupling with the EDC/NHS (N-ethyl-N′-(3-(dimethylamino)propyl)carbodiimide/N-hydroxysuccinimide) method in comparison with the adsorption method (24% drug loading, 28% efficiency). The systems showed high antimicrobial activity with a minimal inhibitory concentration of 1.13 µM (adsorption) and 1.70 µM (covalent). This system successfully combines an antimicrobial peptide with a magnetically controllable drug carrier.
Pathogenesis of α-Synuclein in Parkinson’s Disease: From a Neuron-Glia Crosstalk Perspective
Authors: Yi Shuanglong , Wang Linfang , Wang Honglei , Ho Margaret S. , Zhang Shiping
Published: November 2022

Parkinson’s disease (PD) is a progressive neurodegenerative disorder. The classical behavioral defects of PD patients involve motor symptoms such as bradykinesia, tremor, and rigidity, as well as non-motor symptoms such as anosmia, depression, and cognitive impairment. Pathologically, the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) and the accumulation of α-synuclein (α-syn)-composed Lewy bodies (LBs) and Lewy neurites (LNs) are key hallmarks. Glia are more than mere bystanders that simply support neurons, they actively contribute to almost every aspect of neuronal development and function; glial dysregulation has been implicated in a series of neurodegenerative diseases including PD. Importantly, amounting evidence has added glial activation and neuroinflammation as new features of PD onset and progression. Thus, gaining a better understanding of glia, especially neuron-glia crosstalk, will not only provide insight into brain physiology events but also advance our knowledge of PD pathologies. This review addresses the current understanding of α-syn pathogenesis in PD, with a focus on neuron-glia crosstalk. Particularly, the transmission of α-syn between neurons and glia, α-syn-induced glial activation, and feedbacks of glial activation on DA neuron degeneration are thoroughly discussed. In addition, α-syn aggregation, iron deposition, and glial activation in regulating DA neuron ferroptosis in PD are covered. Lastly, we summarize the preclinical and clinical therapies, especially targeting glia, in PD treatments.
Kelulut Honey Regulates Sex Steroid Receptors in a Polycystic Ovary Syndrome Rat Model
Authors: Kamal Datu Agasi Mohd , Ibrahim Siti Fatimah , Ugusman Azizah , Mokhtar Mohd Helmy
Published: November 2022

Reproductive and metabolic anomalies in polycystic ovary syndrome (PCOS) have been associated with the dysregulation of sex steroid receptors. Kelulut honey (KH) has been shown to be beneficial in PCOS-induced rats by regulating folliculogenesis and the oestrus cycle. However, no study has been conducted to evaluate KH’s effect on sex steroid receptors in PCOS. Therefore, the current study examined the effects of KH, metformin, or clomiphene alone and in combination on the mRNA expression and protein distribution of androgen receptor (AR), oestrogen receptor α (ERα), oestrogen receptor β (ERβ), and progesterone receptor (PR) in PCOS-induced rats. The study used female Sprague-Dawley rats, which were treated orally with 1 mg/kg/day of letrozole for 21 days to develop PCOS. PCOS-induced rats were then divided and treated orally for 35 days with KH, metformin, clomiphene, KH + metformin, KH+ clomiphene and distilled water. In this study, we observed aberrant AR, ERα, ERβ and PR expression in PCOS-induced rats compared with the normal control rats. The effects of KH treatment were comparable with clomiphene and metformin in normalizing the expression of AR, ERα, and ERβ mRNA. However, KH, clomiphene and metformin did not affect PR mRNA expression and protein distribution. Hence, this study confirms the aberrant expression of sex steroid receptors in PCOS and demonstrates that KH treatment could normalise the sex steroid receptors profile. The findings provide a basis for future clinical trials to utilize KH as a regulator of sex steroid receptors in patients with PCOS.
Purinergic Receptors P2X7 and P2X4 as Markers of Disease Progression in the rd10 Mouse Model of Inherited Retinal Dystrophy
Authors: Martínez-Gil Natalia , Kutsyr Oksana , Noailles Agustina , Fernández-Sánchez Laura , Vidal Lorena , Sánchez-Sáez Xavier , Sánchez-Castillo Carla , Lax Pedro , Cuenca Nicolás , García Antonio G. , Maneu Victoria
Published: November 2022

The purinergic receptor P2X7 (P2X7R) is implicated in all neurodegenerative diseases of the central nervous system. It is also involved in the retinal degeneration associated with glaucoma, age-related macular degeneration, and diabetic retinopathy, and its overexpression in the retina is evident in these disorders. Retinitis pigmentosa is a progressive degenerative disease that ultimately leads to blindness. Here, we investigated the expression of P2X7R during disease progression in the rd10 mouse model of RP. As the purinergic receptor P2X4 is widely co-expressed with P2X7R, we also studied its expression in the retina of rd10 mice. The expression of P2X7R and P2X4R was examined by immunohistochemistry, flow cytometry, and western blotting. In addition, we analyzed retinal functionality by electroretinographic recordings of visual responses and optomotor tests and retinal morphology. We found that the expression of P2X7R and P2X4R increased in rd10 mice concomitant with disease progression, but with different cellular localization. Our findings suggest that P2X7R and P2X4R might play an important role in RP progression, which should be further analyzed for the pharmacological treatment of inherited retinal dystrophies.
Recent Advances in Proteomics-Based Approaches to Studying Age-Related Macular Degeneration: A Systematic Review
Authors: García-Quintanilla Laura , Rodríguez-Martínez Lorena , Bandín-Vilar Enrique , Gil-Martínez María , González-Barcia Miguel , Mondelo-García Cristina , Fernández-Ferreiro Anxo , Mateos Jesús
Published: November 2022

Age-related macular degeneration (AMD) is a common ocular disease characterized by degeneration of the central area of the retina in the elderly population. Progression and response to treatment are influenced by genetic and non-genetic factors. Proteomics is a powerful tool to study, at the molecular level, the mechanisms underlying the progression of the disease, to identify new therapeutic targets and to establish biomarkers to monitor progression and treatment effectiveness. In this work, we systematically review the use of proteomics-based approaches for the study of the molecular mechanisms underlying the development of AMD, as well as the progression of the disease and on-treatment patient monitoring. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guidelines were followed. Proteomic approaches have identified key players in the onset of the disease, such as complement components and proteins involved in lipid metabolism and oxidative stress, but also in the progression to advanced stages, including factors related to extracellular matrix integrity and angiogenesis. Although anti-vascular endothelial growth factor (anti-VEGF)-based therapy has been crucial in the treatment of neovascular AMD, it is necessary to deepen our understanding of the underlying disease mechanisms to move forward to next-generation therapies for later-stage forms of this multifactorial disease.
Down-Regulation of Neogenin Decreases Proliferation and Differentiation of Spermatogonia during the Early Phase of Spermatogenesis
Authors: Park Jin Woo , Kim Yu Jin , Lee Sang Jin , Ko Jung Jae , Kim Dae Keun , Lee Jae Ho
Published: November 2022

Non-obstructive azoospermia is a major clinical issue associated with male infertility that remains to be addressed. Although neogenin is reportedly abundantly expressed in the testis, its role in mammalian spermatogenesis is unknown. We systematically investigated the role of neogenin during spermatogenesis by performing loss-of-function studies. Testis-specific neogenin conditional knock-out (cKO) mice were generated using CRISPR/Cas9 and neogenin-targeting guide RNAs. We analyzed the expression profiles of germ cell factors by RT-PCR and Western blotting. Neogenin localized mainly to spermatogonia in seminiferous tubules of mouse testes. RT-PCR and Western blot analyses further demonstrated that neogenin expression varied during spermatogenesis and was dramatically increased at postnatal day 12–25 during the pubertal stage. In neogenin-cKO mouse testes, the ratio of primary and secondary spermatocytes was significantly decreased compared with the control, while the number of apoptotic testicular cells was significantly increased. Taken together, these results suggest that neogenin plays a pivotal role in the maintenance and proliferation of spermatogonia during the early stage of spermatogenesis in mice.
A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development
Authors: Wu Jingyun , Möhle Luisa , Brüning Thomas , Eiriz Iván , Rafehi Muhammad , Stefan Katja , Stefan Sven Marcel , Pahnke Jens
Published: November 2022

Huntington’s disease (HD) is a lethal neurodegenerative disorder without efficient therapeutic options. The inefficient translation from preclinical and clinical research into clinical use is mainly attributed to the lack of (i) understanding of disease initiation, progression, and involved molecular mechanisms; (ii) knowledge of the possible HD target space and general data awareness; (iii) detailed characterizations of available disease models; (iv) better suitable models; and (v) reliable and sensitive biomarkers. To generate robust HD-like symptoms in a mouse model, the neomycin resistance cassette was excised from zQ175 mice, generating a new line: zQ175Δneo. We entirely describe the dynamics of behavioral, neuropathological, and immunohistological changes from 15–57 weeks of age. Specifically, zQ175Δneo mice showed early astrogliosis from 15 weeks; growth retardation, body weight loss, and anxiety-like behaviors from 29 weeks; motor deficits and reduced muscular strength from 36 weeks; and finally slight microgliosis at 57 weeks of age. Additionally, we collected the entire bioactivity network of small-molecule HD modulators in a multitarget dataset (HD_MDS). Hereby, we uncovered 358 unique compounds addressing over 80 different pharmacological targets and pathways. Our data will support future drug discovery approaches and may serve as useful assessment platform for drug discovery and development against HD.
Plethora of Non-Covalent Interactions in Coordination and Organometallic Chemistry Are Modern Smart Tool for Materials Science, Catalysis, and Drugs Design
Authors: Novikov Alexander S.
Published: November 2022

Non-covalent interactions are one of the key topics in coordination and organometallic chemistry. Examples of such weak interactions are hydrogen, halogen, and chalcogen bonds, stacking interactions, metallophilic contacts, etc. Non-covalent interactions play an important role in materials science, catalysis, and medicinal chemistry. The aim of this Special Issue of International Journal of Molecular Sciences, entitled “Non-Covalent Interactions in Coordination and Organometallic Chemistry”, is to cover the most recent progress in the rapidly growing field of non-covalent interactions in coordination and organometallic chemistry. Both experimental and theoretical studies, fundamental and applied research and any types of manuscripts are welcome for consideration.
New Insights into Dose-Dependent Effects of Curcumin on ARPE-19 Cells
Authors: Carozza Giulia , Tisi Annamaria , Capozzo Annamaria , Cinque Benedetta , Giovannelli Aldo , Feligioni Marco , Flati Vincenzo , Maccarone Rita
Published: November 2022

Opposing dose-dependent effects of curcumin (Cur) have been documented in Retinal Pigment Epithelium (RPE); therefore, to shed the light on the mechanisms of action is crucial for ophthalmic applications. On this basis we explored new insights about the dose-dependent mechanisms triggered by Cur in human retinal pigment epithelial cells (ARPE-19). Three concentrations (0.01 mM; 0.05 mM; 0.1 mM) of Cur were tested, followed by morphological, molecular, and functional analysis of the cells. Cur 0.01 mM promotes a significant increase in cell proliferation, not affecting cell cycle progression and apoptosis; by contrast, Cur 0.05 mM and 0.1 mM block cellular proliferation and trigger S-phase cell cycle arrest without inducing apoptosis. The observation of neuronal-like morphological changes in Cur 0.05 mM and 0.1 mM were not associated with neuronal differentiation, as observed by the quantification of Neurofilament-200 and by the analysis of voltage-dependent currents by patch clamp. Evaluation of autophagic markers LC3BII and p62 revealed significant modulations, suggesting an important activation of autophagy in ARPE-19 cells treated with Cur 0.05 mM and Cur 0.1 mM; conversely, Cur 0.01 mM did not affect autophagy. Altogether, our findings show new dose-dependent mechanisms of action of Cur that suggest a wide therapeutic application in ocular diseases with different pathogenesis (i.e., proliferative vitreoretinopathy or Age-Related Macular Degeneration).
Clinical and Molecular Insights into Gastrointestinal Dysfunction in Myotonic Dystrophy Types 1 & 2
Authors: Peterson Janel A. M. , Cooper Thomas A.
Published: November 2022

Myotonic dystrophy (DM) is a highly variable, multisystemic disorder that clinically affects one in 8000 individuals. While research has predominantly focused on the symptoms and pathological mechanisms affecting striated muscle and brain, DM patient surveys have identified a high prevalence for gastrointestinal (GI) symptoms amongst affected individuals. Clinical studies have identified chronic and progressive dysfunction of the esophagus, stomach, liver and gallbladder, small and large intestine, and rectum and anal sphincters. Despite the high incidence of GI dysmotility in DM, little is known regarding the pathological mechanisms leading to GI dysfunction. In this review, we summarize results from clinical and molecular analyses of GI dysfunction in both genetic forms of DM, DM type 1 (DM1) and DM type 2 (DM2). Based on current knowledge of DM primary pathological mechanisms in other affected tissues and GI tissue studies, we suggest that misregulation of alternative splicing in smooth muscle resulting from the dysregulation of RNA binding proteins muscleblind-like and CUGBP-elav-like is likely to contribute to GI dysfunction in DM. We propose that a combinatorial approach using clinical and molecular analysis of DM GI tissues and model organisms that recapitulate DM GI manifestations will provide important insight into defects impacting DM GI motility.
Enzymatically Modified Isoquercitrin: Production, Metabolism, Bioavailability, Toxicity, Pharmacology, and Related Molecular Mechanisms
Authors: Owczarek-Januszkiewicz Aleksandra , Magiera Anna , Olszewska Monika Anna
Published: November 2022

Quercetin and its glycosides, such as isoquercitrin or rutin, are among the most ubiquitous flavonoids present in plants. They possess numerous health-promoting properties, whose applicability is, however, limited by poor water solubility and absorption issues. Enzymatically modified isoquercitrin (EMIQ) is an isoquercitrin derivative obtained from rutin via enzymatic transformations that greatly enhance its bioavailability. Due to advantageous reports on its safety and bioactivity, EMIQ is currently gaining importance as a food additive and a constituent of dietary supplements. This review summarizes the thus-far-conducted investigations into the metabolism, toxicity, biological properties, and molecular mechanisms of EMIQ and presents a comprehensive characterization of this valuable substance, which might represent the future of flavonoid supplementation.
Effect of Cross-Linking Cations on In Vitro Biocompatibility of Apple Pectin Gel Beads
Authors: Popov Sergey , Paderin Nikita , Chistiakova Elizaveta , Ptashkin Dmitry , Markov Pavel A.
Published: November 2022

The study aimed to compare the in vitro biocompatibility of pectin gels formed by different cross-linking cations. Hydrogel beads named CaPG, ZnPG, FePG, and AlPG were prepared from 4% solutions of apple pectin using ionotropic gelling with CaCl2, ZnCl2, FeCl3, and AlCl3, respectively. Cations influenced the gel strength of the wet gel beads in the following order (least strong) Ca2+ < Zn2+ < Fe3+~Al3+ (most strong). The swelling degree of the CaPG beads after 24 h of incubation in the RPMI-1640 medium was 104%, whereas the ZnPG, FePG, and AlPG beads swelled by 76, 108, and 134%, respectively. The strength of the pectin gel decreased significantly after incubation in the RPMI-1640 medium for 24 h, regardless of the cross-linking cation, although the FePG beads remained the strongest. All the pectin beads adsorbed serum proteins to a low degree, however the serum protein adsorption by the ZnPG and FePG beads (1.46 ± 0.87 and 1.35 ± 0.19 µg/mm2) was more than the CaPG and AlPG beads (0.31 ± 0.36 and 0.44 ± 0.25 µg/mm2). All the pectin beads reduced the production of TNF-α and IL-10 by hPBMCs in response to LPS stimulation. The IL-1β response of cells to LPS was significantly reduced by the CaPG, ZnPG, and FePG beads, whereas the AlPG beads enhanced it twofold. The CaPG, FePG, and AlPG beads had no cytotoxicity. The viability of hPBMCs and human fibroblasts incubated with ZnPG beads was 5.3 and 7.2%, respectively. Thus, the use of different cross-linking cations changed the properties of the pectin gel, which is important for biocompatibility.
EGFR-Targeted Cellular Delivery of Therapeutic Nucleic Acids Mediated by Boron Clusters
Authors: Kaniowski Damian , Suwara Justyna , Ebenryter-Olbińska Katarzyna , Jakóbik-Kolon Agata , Nawrot Barbara
Published: November 2022

New boron carriers with high boron content and targeted cancer-cell delivery are considered the first choice for boron neutron capture therapy (BNCT) for cancer treatment. Previously, we have shown that composites of antisense oligonucleotide and boron clusters are functional nanoparticles for the downregulation of expression of epidermal growth factor receptor (EGFR) and can be loaded into EGFR-overexpressing cancer cells without a transfection factor. In this study, we hypothesize that free cellular uptake is mediated by binding and activation of the EGFR by boron clusters. Proteomic analysis of proteins pulled-down from various EGFR-overexpressing cancer cells using short oligonucleotide probes, conjugated to 1,2-dicarba-closo-dodecaborane (1,2-DCDDB, [C2B10H12]) and [(3,3′-Iron-1,2,1′,2′-dicarbollide)−] (FESAN, [Fe(C2B9H11)2]−), evidenced that boron cage binds to EGFR subdomains. Moreover, inductively coupled plasma mass spectrometry (ICP MS) and fluorescence microscopy analyses confirmed that FESANs-highly decorated B-ASOs were efficiently delivered and internalized by EGFR-overexpressing cells. Antisense reduction of EGFR in A431 and U87-MG cells resulted in decreased boron accumulation compared to control cells, indicating that cellular uptake of B-ASOs is related to EGFR-dependent internalization. The data obtained suggest that EGFR-mediated cellular uptake of B-ASO represents a novel strategy for cellular delivery of therapeutic nucleic acids (and possibly other medicines) conjugated to boron clusters.
Anti-Cancer Effects of a New Herbal Medicine PSY by Inhibiting the STAT3 Signaling Pathway in Colorectal Cancer Cells and Its Phytochemical Analysis
Authors: Han Sanghee , Kim Hail , Lee Min Young , Lee Junhee , Ahn Kwang Seok , Ha In Jin , Lee Seok-Geun
Published: November 2022

Colorectal cancer (CRC) is an inflammation-associated common cancer worldwide. Paejang-san and Mori Cortex Radicis have been traditionally used for treating intestinal inflammatory diseases in Korea and China. In the present study, we developed a new herbal formula as an alternative to CRC treatments, which is composed of two main components of Paejangsan (Patriniae Radix (Paejang in Korean) and Coix Seed (Yiyiin in Korean)), and Mori Cortex Radicis (Sangbekpi in Korean) based on the addition and subtraction theory in traditional medicine, hence the name PSY, and explored the potential therapeutic effects of the new formula PSY in human CRC cells by analyzing viability, cell cycle and apoptosis. We found that PSY ethanol extract (EtOH-Ex), but not water extract, significantly suppressed the viability of human CRC cells, and synergistically decreased the cell proliferation compared to each treatment of Patriniae Radix and Coix Seed extract (PY) or Mori Cortex Radicis extract (S), suggesting the combination of PY and S in a 10-to-3 ratio for the formula PSY. PSY EtOH-Ex in the combination ratio reduced cell viability but induced cell cycle arrest at the G2/M and sub-G1 phases as well as apoptosis in CRC cells. In addition, the experimental results of Western blotting, immunofluorescence staining and reporter assays showed that PSY also inhibited STAT3 by reducing its phosphorylation and nuclear localization, which resulted in lowering STAT3-mediated transcriptional activation. In addition, PSY regulated upstream signaling molecules of STAT3 by inactivating JAK2 and Src and increasing SHP1. Moreover, the chemical profiles of PSY from UPLC-ESI-QTOF MS/MS analysis revealed 38 phytochemicals, including seven organic acids, eight iridoids, two lignans, twelve prenylflavonoids, eight fatty acids, and one carbohydrate. Furthermore, 21 potentially bioactive compounds were highly enriched in the PSY EtOH-Ex compared to the water extract. Together, these results indicate that PSY suppresses the proliferation of CRC cells by inhibiting the STAT3 signaling pathway, suggesting PSY as a potential therapeutic agent for treating CRC and 21 EtOH-Ex-enriched phytochemicals as anti-cancer drug candidates which may act by inhibiting STAT3.
Enhanced Acetaminophen Electrochemical Sensing Based on Nitrogen-Doped Graphene
Authors: Magerusan Lidia , Pogacean Florina , Pruneanu Stela
Published: November 2022

Because of the widespread acetaminophen usage and the danger of harmful overdosing effects, developing appropriate procedures for its quantitative and qualitative assay has always been an intriguing and fascinating problem. A quick, inexpensive, and environmentally friendly approach based on direct voltage anodic graphite rod exfoliation in the presence of inorganic salt aqueous solution ((NH4)2SO4–0.3 M) has been established for the preparation of nitrogen-doped graphene (exf-NGr). The XRD analysis shows that the working material appears as a mixture of few (76.43%) and multi-layers (23.57%) of N-doped graphenes. From XPS, the C/O ratio was calculated to be 0.39, indicating a significant number of structural defects and the existence of multiple oxygen-containing groups at the surface of graphene sheets caused by heteroatom doping. Furthermore, the electrochemical performances of glassy carbon electrodes (GCEs) modified with exf-NGr for acetaminophen (AMP) detection and quantification have been assessed. The exf-NGr/GCE-modified electrode shows excellent reproducibility, stability, and anti-interfering characteristics with improved electrocatalytic activity over a wide detection range (0.1–100 µM), with a low limit for AMP detection (LOD = 3.03 nM). In addition, the developed sensor has been successfully applied in real sample analysis for the AMP quantification from different commercially available pharmaceutical formulations.
OSCA Genes in Bread Wheat: Molecular Characterization, Expression Profiling, and Interaction Analyses Indicated Their Diverse Roles during Development and Stress Response
Authors: Kaur Amandeep , Sharma Alok , Madhu  , Dixit Sameer , Singh Kashmir , Upadhyay Santosh Kumar
Published: November 2022

The hyperosmolality-gated calcium-permeable channels (OSCA) are pore-forming transmembrane proteins that function as osmosensors during various plant developmental processes and stress responses. In our analysis, through in silico approaches, a total of 42 OSCA genes are identified in the Triticum aestivum genome. A phylogenetic analysis reveals the close clustering of the OSCA proteins of Arabidopsis thaliana, Oryza sativa, and T. aestivum in all the clades, suggesting their origin before the divergence of dicots and monocots. Furthermore, evolutionary analyses suggest the role of segmental and tandem duplication events (Des) and purifying selection pressure in the expansion of the OSCA gene family in T. aestivum. Expression profiling in various tissue developmental stages and under abiotic and biotic stress treatments reveals the probable functioning of OSCA genes in plant development and the stress response in T. aestivum. In addition, protein–protein and protein–chemical interactions reveal that OSCA proteins might play a putative role in Ca2+-mediated developmental processes and adaptive responses. The miRNA interaction analysis strengthens the evidence for their functioning in various biological processes and stress-induced signaling cascades. The current study could provide a foundation for the functional characterization of TaOSCA genes in future studies.