bluuebunny/crossref_metadata_2025 huggingface dataset:
BAP31-Mediated miR-206/133b Cluster Promotes Transendothelial Migration and Metastasis of Colorectal Cancer
Authors: Zhang Qi , Wang Changli , Wu Yufei , Liu Jingjing , Wang Tianyi , Wang Bing
Published: November 2023

Dysregulated B cell receptor-associated protein 31 (BAP31) plays a crucial role in tumor progression. This study aimed to investigate the functions and molecular mechanism of BAP31 on the miR-206/133b cluster in colorectal cancer (CRC). qPCR was conducted to detect miRNA and mRNA levels in tissues and cells. Western blot assays were used to assess the levels of biomarkers and targets, as well as the levels of BAP31 and HOXD10. Wound healing, coculture and transwell assays were conducted to assess the transendothelial migration abilities of CRC cells. A luciferase assay was employed to assess miRNA binding effects on targets, as well as the initiating transcription effect of genomic fragments. Tumor growth and lung metastatic models were established through an in vivo animal study. BAP31 overexpression in CRC cells led to a reduction in the expression of the miR-206/133b cluster. The expression of the miR-206/133b cluster was correlated with the transendothelial migration capability of CRC cells. The miR-206/133b cluster was found to directly regulate cell division cycle 42 (CDC42) and actin-related protein 2/3 complex subunit 5 (ARPC5) in the tight junction pathway (hsa04530). Moreover, a potential transcription regulator of the miR-206/133b cluster was also found to be Homeobox D10 (HOXD10). We further elucidated the molecular mechanisms and functional mechanisms of BAP31’s regulatory role in the expression levels of the miR-206/133b cluster by inhibiting HOXD10 translocation from the cytoplasm to the nucleus. In conclusion, this study provides valuable insights into how BAP31 regulates the transcription of the miR-206/133b cluster and how BAP31-related lung metastases arise in CRC.
Enhancement of Growth and Secondary Metabolites by the Combined Treatment of Trace Elements and Hydrogen Water in Wheat Sprouts
Authors: Kousar Muniba , Kim Yu Rim , Kim Ji Yeon , Park Joonho
Published: November 2023

This study aimed to evaluate the response of Triticum aestivum to hydrogen water (HW) and trace elements treated with HW. A pot experiment was conducted to assess the growth indices, secondary metabolites, and antioxidant levels. The response surface methodology (RSM) approach was used to ascertain the concentrations and significant interaction between treatments. The outcomes demonstrated that the combined treatment of Se acid and Mo oxide exhibited a notable positive effect on the growth and secondary metabolites, when treated with HW as compared to distilled water (DW). Notably, the interaction between these two treatments is significant, and the higher response was observed at the optimal concentration of 0.000005% for Se acid and 0.06% for Mo oxide. Additionally, an in vitro experiment revealed that the mixture treatment inhibits the accumulation of lipids in HepG2 hepatocytes cells. Moreover, metabolic analysis revealed that upregulated metabolites are linked to the inhibition of lipid accumulation. In addition, the analysis emphasizes that the continued benefits of higher plants as a renewable supply for chemicals compounds, especially therapeutic agents, are being expanded and amplified by these state-of-the-art technologies.
Red Flags in Primary Mitochondrial Diseases: What Should We Recognize?
Authors: Conti Federica , Di Martino Serena , Drago Filippo , Bucolo Claudio , Micale Vincenzo , Montano Vincenzo , Siciliano Gabriele , Mancuso Michelangelo , Lopriore Piervito
Published: November 2023

Primary mitochondrial diseases (PMDs) are complex group of metabolic disorders caused by genetically determined impairment of the mitochondrial oxidative phosphorylation (OXPHOS). The unique features of mitochondrial genetics and the pivotal role of mitochondria in cell biology explain the phenotypical heterogeneity of primary mitochondrial diseases and the resulting diagnostic challenges that follow. Some peculiar features (“red flags”) may indicate a primary mitochondrial disease, helping the physician to orient in this diagnostic maze. In this narrative review, we aimed to outline the features of the most common mitochondrial red flags offering a general overview on the topic that could help physicians to untangle mitochondrial medicine complexity.
Osteogenic Potential of Human Dental Pulp Stem Cells (hDPSCs) Growing on Poly L-Lactide-Co-Caprolactone and Hyaluronic Acid (HYAFF-11TM) Scaffolds
Authors: Bar Julia K. , Lis-Nawara Anna , Kowalczyk Tomasz , Grelewski Piotr G. , Stamnitz Sandra , Gerber Hanna , Klimczak Aleksandra
Published: November 2023

Bone tissue engineering using different scaffolds is a new therapeutic approach in regenerative medicine. This study explored the osteogenic potential of human dental pulp stem cells (hDPSCs) grown on a hydrolytically modified poly(L-lactide-co-caprolactone) (PLCL) electrospun scaffold and a non-woven hyaluronic acid (HYAFF-11™) mesh. The adhesion, immunophenotype, and osteogenic differentiation of hDPSCs seeded on PLCL and HYAFF-11™ scaffolds were analyzed. The results showed that PLCL and HYAFF-11™ scaffolds significantly supported hDPSCs adhesion; however, hDPSCs’ adhesion rate was significantly higher on PLCL than on HYAFF-11™. SEM analysis confirmed good adhesion of hDPSCs on both scaffolds before and after osteogenesis. Alizarin red S staining showed mineral deposits on both scaffolds after hDPSCs osteogenesis. The mRNA levels of runt-related transcription factor 2 (Runx2), collagen type I (Coll-I), osterix (Osx), osteocalcin (Ocn), osteopontin (Opn), bone sialoprotein (Bsp), and dentin sialophosphoprotein (Dspp) gene expression and their proteins were higher in hDPSCs after osteogenic differentiation on both scaffolds compared to undifferentiated hDPSCs on PLCL and HYAFF-11™. These results showed that PLCL scaffolds provide a better environment that supports hDPSCs attachment and osteogenic differentiation than HYAFF-11™. The high mRNA of early osteogenic gene expression and mineral deposits observed after hDPSCs osteogenesis on a PLCL mat indicated its better impact on hDPSCs’ osteogenic potential than that of HYAFF-11™, and hDPSC/PLCL constructs might be considered in the future as an innovative approach to bone defect repair.
Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs
Authors: Kontoghiorghes George J.
Published: November 2023

The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols could ideally be designed in all diseases including for millions of patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well as many variations and limitations. EID is an adverse prognostic factor for all diseases and especially for millions of chronically red-blood-cell-transfused patients. Differences in iron chelation therapy posology cause disappointing results in neurodegenerative diseases at low doses, but lifesaving outcomes in thalassemia major (TM) when using higher doses. In particular, the transformation of TM from a fatal to a chronic disease has been achieved using effective doses of oral deferiprone (L1), which improved compliance and cleared excess toxic iron from the heart associated with increased mortality in TM. Furthermore, effective L1 and L1/deferoxamine combination posology resulted in the complete elimination of EID and the maintenance of normal iron store levels in TM. The selection of effective chelation protocols has been monitored by MRI T2* diagnosis for EID levels in different organs. Millions of other iron-loaded patients with sickle cell anemia, myelodysplasia and haemopoietic stem cell transplantation, or non-iron-loaded categories with EID in different organs could also benefit from such chelation therapy advances. Drawbacks of chelation therapy include drug toxicity in some patients and also the wide use of suboptimal chelation protocols, resulting in ineffective therapies. Drug metabolic effects, and interactions with other metals, drugs and dietary molecules also affected iron chelation therapy. Drug selection and the identification of effective or optimal dose protocols are essential for positive therapeutic outcomes in the use of chelating drugs in TM and other iron-loaded and non-iron-loaded conditions, as well as general iron toxicity.
Antitumor Effect of Poplar Propolis on Human Cutaneous Squamous Cell Carcinoma A431 Cells
Authors: Zhang Chuang , Tian Yuanyuan , Yang Ao , Tan Weihua , Liu Xiaoqing , Yang Wenchao
Published: November 2023

Propolis is a gelatinous substance processed by western worker bees from the resin of plant buds and mixed with the secretions of the maxillary glands and beeswax. Propolis has extensive biological activities and antitumor effects. There have been few reports about the antitumor effect of propolis against human cutaneous squamous cell carcinoma (CSCC) A431 cells and its potential mechanism. CCK-8 assays, label-free proteomics, RT–PCR, and a xenograft tumor model were employed to explore this possibility. The results showed that the inhibition rate of A431 cell proliferation by the ethanol extract of propolis (EEP) was dose-dependent, with an IC50 of 39.17 μg/mL. There were 193 differentially expressed proteins in the EEP group compared with the control group (p < 0.05), of which 103 proteins (53.37%) were upregulated, and 90 proteins (46.63%) were downregulated. The main three activated and suppressed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were extracellular matrix (ECM)-receptor interaction, amoebiasis, cell adhesion molecules (CAMs), nonalcoholic fatty liver disease (NAFLD), retrograde endocannabinoid signaling, and Alzheimer’s disease. The tumor volume of the 100 mg/kg EEP group was significantly different from that of the control group (p < 0.05). These results provide a theoretical basis for the potential treatment of human CSCC A431 cell tumors using propolis.
Cellular Responses to Extracellular Vesicles as Potential Markers of Colorectal Cancer Progression
Authors: Guarnerio Sonia , Tempest Robert , Maani Rawan , Hunt Stuart , Cole Laura M. , Le Maitre Christine L. , Chapple Keith , Peake Nicholas
Published: November 2023

The development of novel screening tests aims to support early asymptomatic diagnosis and subtyping patients according to similar traits in the heterogeneous cancer cohort. Extracellular vesicles (EVs) are promising candidates for the detection of disease markers from bodily fluids, but limitations in the standardisation of isolation methods and the intrinsic EV heterogeneity obtained from liquid biopsies are currently obstacles to clinical adoption. Here, cellular responses to cancer EVs were initially explored as potential complementary biomarkers for stage separation using colorectal cancer (CRC) SW480 and SW620 cell line models. A pilot study on a small cohort of CRC patients and controls was then developed by performing a multivariate analysis of cellular responses to plasma-derived EVs. Several cell activities and markers involved in tumour microenvironment pathways were influenced by the treatment of cell line EVs in a stage-dependent manner. The multivariate analysis combining plasma EV markers and cellular responses to plasma EVs was able to separate patients according to disease stage. This preliminary study offers the potential of considering cellular responses to EVs in combination with EV biomarkers in the development of screening methods.
Transcriptomic and Metabolomic Analyses Reveal the Importance of Lipid Metabolism and Photosynthesis Regulation in High Salinity Tolerance in Barley (Hordeum vulgare L.) Leaves Derived from Mutagenesis Combined with Microspore Culture
Authors: Xu Hongwei , Halford Nigel G. , Guo Guimei , Chen Zhiwei , Li Yingbo , Zhou Longhua , Liu Chenghong , Xu Rugen
Published: November 2023

Barley is the most salt-tolerant cereal crop. However, little attention has been paid to the salt-tolerant doubled haploids of barley derived from mutagenesis combined with isolated microspore culture. In the present study, barley doubled haploid (DH) line 20, which was produced by mutagenesis combined with isolated microspore culture, showed stably and heritably better salt tolerance than the wild type H30 in terms of fresh shoot weight, dry shoot weight, K+/Na+ ratio and photosynthetic characteristics. Transcriptome and metabolome analyses were performed to compare the changes in gene expression and metabolites between DH20 and H30. A total of 462 differentially expressed genes (DEGs) and 152 differentially accumulated metabolites (DAMs) were identified in DH20 compared to H30 under salt stress. Among the DAMs, fatty acids were the most accumulated in DH20 under salt stress. The integration of transcriptome and metabolome analyses revealed that nine key biomarkers, including two metabolites and seven genes, could distinguish DH20 and H30 when exposed to high salt. The pathways of linoleic acid metabolism, alpha-linolenic acid metabolism, glycerolipid metabolism, photosynthesis, and alanine, aspartate and glutamate metabolism were significantly enriched in DH20 with DEGs and DAMs in response to salt stress. These results suggest that DH20 may enhance resilience by promoting lipid metabolism, maintaining energy metabolism and decreasing amino acids metabolism. The study provided novel insights for the rapid generation of homozygous mutant plants by mutagenesis combined with microspore culture technology and also identified candidate genes and metabolites that may enable the mutant plants to cope with salt stress.
Hearing and Hearing Loss Progression in Patients with GJB2 Gene Mutations: A Long-Term Follow-Up
Authors: Sakata Aki , Kashio Akinori , Koyama Misaki , Urata Shinji , Koyama Hajime , Yamasoba Tatsuya
Published: November 2023

We aimed to investigate whether the degree of hearing loss with GJB2 mutations could be predicted by distinguishing between truncating and non-truncating mutations and whether the genotype could predict the hearing loss level. Additionally, we examined the progression of hearing loss in individuals monitored for over 2 years for an average of 6.9 years. The proportion of truncating mutations was higher in patients with profound and severe hearing loss, but it was not accurate enough to predict the degree of hearing loss. Via genotype analysis, mutations of the p.Arg143Trp variants were associated with profound hearing loss, while mutations of the p.Leu79Cysfs*3 allele exhibited a wide range of hearing loss, suggesting that specific genotypes can predict the hearing loss level. Notably, there were only three cases of progression in four ears, all of which involved the p.Leu79Cysfs*3 mutation. Over the long-term follow-up, 4000 Hz was significant, and there was a trend of progression at 250 Hz, suggesting that close monitoring at these frequencies during follow-up may be crucial to confirm progression. The progression of hearing loss was observed in moderate or severe hearing loss cases at the time of the initial diagnosis, emphasizing that children with this level of hearing loss need regular follow-ups.
Diversity and Classification of Genetic Variations in Autism Spectrum Disorder
Authors: Kereszturi Éva
Published: November 2023

Autism spectrum disorder (ASD) is a neurodevelopmental condition with symptoms that affect the whole personality and all aspects of life. Although there is a high degree of heterogeneity in both its etiology and its characteristic behavioral patterns, the disorder is well-captured along the autistic triad. Currently, ASD status can be confirmed following an assessment of behavioral features, but there is a growing emphasis on conceptualizing autism as a spectrum, which allows for establishing a diagnosis based on the level of support need, free of discrete categories. Since ASD has a high genetic predominance, the number of genetic variations identified in the background of the condition is increasing exponentially as genetic testing methods are rapidly evolving. However, due to the huge amount of data to be analyzed, grouping the different DNA variations is still challenging. Therefore, in the present review, a multidimensional classification scheme was developed to accommodate most of the currently known genetic variants associated with autism. Genetic variations have been grouped according to six criteria (extent, time of onset, information content, frequency, number of genes involved, inheritance pattern), which are themselves not discrete categories, but form a coherent continuum in line with the autism spectrum approach.
Early Castration in Horses Does Not Impact Osteoarticular Metabolism
Authors: Rouge Marion , Legendre Florence , Elkhatib Razan , Delalande Christelle , Cognié Juliette , Reigner Fabrice , Barrière Philippe , Deleuze Stefan , Hanoux Vincent , Galéra Philippe , Bouraïma-Lelong Hélène
Published: November 2023

The castration of stallions is traditionally performed after puberty, at around the age of 2 years old. No studies have focused on the effects of early castration on osteoarticular metabolism. Thus, we aimed to compare early castration (3 days after birth) with traditional castration (18 months of age) in horses. Testosterone and estradiol levels were monitored from birth to 33 months in both groups. We quantified the levels of biomarkers of cartilage and bone anabolism (CPII and N-MID) and catabolism (CTX-I and CTX-II), as well as of osteoarthritis (HA and COMP) and inflammation (IL-6 and PGE2). We observed a lack of parallelism between testosterone and estradiol synthesis after birth and during puberty in both groups. The extra-gonadal synthesis of steroids was observed around the 28-month mark, regardless of the castration age. We found the expression of estrogen receptor (ESR1) in cartilage and bone, whereas androgen receptor (AR) expression appeared to be restricted to bone. Nevertheless, with respect to osteoarticular metabolism, steroid hormone deprivation resulting from early castration had no discernable impact on the levels of biomarkers related to bone and cartilage metabolism, nor on those associated with OA and inflammation. Consequently, our research demonstrated that early castration does not disrupt bone and cartilage homeostasis.
Changes in Diversity and Composition of Rhizosphere Bacterial and Fungal Community between Resistant and Susceptible Pakchoi under Plasmodiophora brassicae
Authors: Xi Dan-Dan , Gao Lu , Miao Li-Ming , Ge Li-Ao , Zhang Ding-Yu , Zhang Zhao-Hui , Li Xiao-Feng , Zhu Yu-Ying , Shen Hai-Bin , Zhu Hong-Fang
Published: November 2023

Plasmodiophora brassicae (P. brassicae) is a soil-born pathogen worldwide and can infect most cruciferous plants, which causes great yield decline and economic losses. It is not well known how microbial diversity and community composition change during P. brassicae infecting plant roots. Here, we employed a resistant and a susceptible pakchoi cultivar with and without inoculation with P. brassicae to analyze bacterial and fungal diversity using 16S rRNA V3-V4 and ITS_V1 regions, respectively. 16S rRNA V3-V4 and ITS_V1 regions were amplified and sequenced separately. Results revealed that both fungal and bacterial diversity increased, and composition was changed in the rhizosphere soil of the susceptible pakchoi compared with the resistant cultivar. In the four groups of R_mock, S_mock, R_10d, and S_10d, the most relatively abundant bacterium and fungus was Proteobacteria, accounting for 61.92%, 58.17%, 48.64%, and 50.00%, respectively, and Ascomycota, accounting for 75.11%, 63.69%, 72.10%, and 90.31%, respectively. A total of 9488 and 11,914 bacteria were observed uniquely in the rhizosphere soil of resistant and susceptible pakchoi, respectively, while only 80 and 103 fungi were observed uniquely in the correlated soil. LefSe analysis showed that 107 and 49 differentially abundant taxa were observed in bacteria and fungi. Overall, we concluded that different pakchoi cultivars affect microbial diversity and community composition, and microorganisms prefer to gather around the rhizosphere of susceptible pakchoi. These findings provide a new insight into plant–microorganism interactions.
5-Aza-2′-Deoxycytidine Alters the Methylation Profile of Bortezomib-Resistant U266 Multiple Myeloma Cells and Affects Their Proliferative Potential
Authors: Łuczkowska Karolina , Kulig Piotr , Rusińska Klaudia , Baumert Bartłomiej , Machaliński Bogusław
Published: November 2023

Multiple myeloma (MM) is a plasma cell malignancy that accounts for 1% of all cancers and is the second-most-common hematological neoplasm. Bortezomib (BTZ) is a proteasome inhibitor widely implemented in the treatment of MM alone or in combination with other agents. The development of resistance to chemotherapy is one of the greatest challenges of modern oncology. Therefore, it is crucial to discover and implement new adjuvant therapies that can bypass therapeutic resistance. In this paper, we investigated the in vitro effect of methylation inhibitor 5-Aza-2′-deoxycytidine on the proliferative potential of MM cells and the development of resistance to BTZ. We demonstrate that alterations in the DNA methylation profile are associated with BTZ resistance. Moreover, the addition of methylation inhibitor 5-Aza-2′-deoxycytidine to BTZ-resistant MM cells led to a reduction in the proliferation of the BTZ-resistant phenotype, resulting in the restoration of sensitivity to BTZ. However, further in vitro and ex vivo studies are required before adjuvant therapy can be incorporated into existing treatment regimens.
Calpain and Cardiometabolic Diseases
Authors: Miyazaki Takuro
Published: November 2023

Calpain is defined as a member of the superfamily of cysteine proteases possessing the CysPC motif within the gene. Calpain-1 and -2, which are categorized as conventional isozymes, execute limited proteolysis in a calcium-dependent fashion. Accordingly, the calpain system participates in physiological and pathological phenomena, including cell migration, apoptosis, and synaptic plasticity. Recent investigations have unveiled the contributions of both conventional and unconventional calpains to the pathogenesis of cardiometabolic disorders. In the context of atherosclerosis, overactivation of conventional calpain attenuates the barrier function of vascular endothelial cells and decreases the immunosuppressive effects attributed to lymphatic endothelial cells. In addition, calpain-6 induces aberrant mRNA splicing in macrophages, conferring atheroprone properties. In terms of diabetes, polymorphisms of the calpain-10 gene can modify insulin secretion and glucose disposal. Moreover, conventional calpain reportedly participates in amino acid production from vascular endothelial cells to induce alteration of amino acid composition in the liver microenvironment, thereby facilitating steatohepatitis. Such multifaceted functionality of calpain underscores its potential as a promising candidate for pharmaceutical targets for the treatment of cardiometabolic diseases. Consequently, the present review highlights the pivotal role of calpains in the complications of cardiometabolic diseases and embarks upon a characterization of calpains as molecular targets.
Post-Implantation Inflammatory Responses to Xenogeneic Tissue-Engineered Cartilage Implanted in Rabbit Trachea: The Role of Cultured Chondrocytes in the Modification of Inflammation
Authors: Klabukov Ilya , Atiakshin Dmitri , Kogan Evgenia , Ignatyuk Michael , Krasheninnikov Mikhail , Zharkov Nickolay , Yakimova Anna , Grinevich Vyacheslav , Pryanikov Pavel , Parshin Vladimir , Sosin Dmitry , Kostin Andrey A. , Shegay Peter , Kaprin Andrey D. , Baranovskii Denis
Published: November 2023

Immune responses to tissue-engineered grafts made of xenogeneic materials remain poorly studied. The scope of current investigations is limited by the lack of information on orthotopically implanted grafts. A deeper understanding of these processes is of great importance since innovative surgical approaches include the implantation of xenogeneic decellularized scaffolds seeded by cells. The purpose of our work is to study the immunological features of tracheal repair during the implantation of tissue-engineered constructs based on human xenogeneic scaffolds modified via laser radiation in rabbits. The samples were stained with hematoxylin and Safranin O, and they were immunostained with antibodies against tryptase, collagen II, vimentin, and CD34. Immunological and inflammatory responses were studied by counting immune cells and evaluating blood vessels and collagen. Leukocyte-based inflammation prevailed during the implantation of decellularized unseeded scaffolds; meanwhile, plasma cells were significantly more abundant in tissue-engineered constructs. Mast cells were insignificantly more abundant in tissue-engineered construct samples. Conclusions: The seeding of decellularized xenogeneic cartilage with chondrocytes resulted in a change in immunological reactions upon implantation, and it was associated with plasma cell infiltration. Tissue-engineered grafts widely differed in design, including the type of used cells. The question of immunological response depending on the tissue-engineered graft composition requires further investigation.
From Molecular Insights to Clinical Perspectives in Drug-Associated Bullous Pemphigoid
Authors: de Nicolas-Ruanes Belen , Ballester-Martinez Asuncion , Garcia-Mouronte Emilio , Berna-Rico Emilio , Azcarraga-Llobet Carlos , Fernandez-Guarino Montserrat
Published: November 2023

Bullous pemphigoid (BP), the most common autoimmune blistering disease, is characterized by the presence of autoantibodies targeting BP180 and BP230 in the basement membrane zone. This leads to the activation of complement-dependent and independent pathways, resulting in proteolytic cleavage at the dermoepidermal junction and an eosinophilic inflammatory response. While numerous drugs have been associated with BP in the literature, causality and pathogenic mechanisms remain elusive in most cases. Dipeptidyl peptidase 4 inhibitors (DPP4i), in particular, are the most frequently reported drugs related to BP and, therefore, have been extensively investigated. They can potentially trigger BP through the impaired proteolytic degradation of BP180, combined with immune dysregulation. DPP4i-associated BP can be categorized into true drug-induced BP and drug-triggered BP, with the latter resembling classic BP. Antineoplastic immunotherapy is increasingly associated with BP, with both B and T cells involved. Other drugs, including biologics, diuretics and cardiovascular and neuropsychiatric agents, present weaker evidence and poorly understood pathogenic mechanisms. Further research is needed due to the growing incidence of BP and the increasing identification of new potential triggers.
Virus Engineering and Applications
Authors: Menotti Laura
Published: November 2023

This Special Issue highlights multiple facets of virus engineering, ranging from the dissection of the biological properties of individual viral functions in the context of safe genomic backbones, virus genetic modification for applications in gene therapy, oncolytic virotherapy and vaccine production, to the hurdles presented by quality control and the delivery of viruses for their final applications and finally to the simulation, prediction and validation of virus evolution [...]
Oxidative Stress and Antioxidant Defense Mechanisms in Acute Ischemic Stroke Patients with Concurrent COVID-19 Infection
Authors: Pinoșanu Elena Anca , Surugiu Roxana , Burada Emilia , Pîrșcoveanu Denisa , Stănciulescu Camelia Elena , Sandu Raluca Elena , Pisoschi Cătălina , Albu Carmen Valeria
Published: November 2023

Stroke remains a debilitating cerebrovascular condition associated with oxidative stress, while COVID-19 has emerged as a global health crisis with multifaceted systemic implications. This study investigates the hypothesis that patients experiencing acute ischemic stroke alongside COVID-19 exhibit elevated oxidative stress markers and altered antioxidant defense mechanisms compared to those with acute ischemic stroke. We conducted a single-center prospective cross-sectional study to investigate oxidative stress balance through oxidative damage markers: TBARS (thiobarbituric acid reactive substances level) and PCARB (protein carbonyls); antioxidant defense mechanisms: TAC (total antioxidant capacity), GPx (glutathione peroxidase), GSH (reduced glutathione), CAT (catalase), and SOD (superoxide dismutase); as well as inflammatory response markers: NLR (neutrophil-to-lymphocyte ratio), CRP (C-reactive protein), and ESR (erythrocyte sedimentation rate). Statistical analyses and correlation models were employed to elucidate potential associations and predictive factors. Our results revealed increased oxidative stress, predominantly indicated by elevated levels of TBARS in individuals experiencing ischemic stroke alongside a concurrent COVID-19 infection (p < 0.0001). The Stroke-COVID group displayed notably elevated levels of GSH (p = 0.0139 *), GPx (p < 0.0001 ****), SOD (p = 0.0363 *), and CAT (p = 0.0237 *) activities. Multivariate analysis found a significant association for TBARS (p < 0.0001 ****), PCARB (p = 0.0259 *), and GPx activity (p < 0.0001 ****), together with NLR (p = 0.0220 *) and CRP (p = 0.0008 ***). Notably, the interplay between stroke and COVID-19 infection appears to amplify oxidative damage, potentially contributing to exacerbated neurological deficits and poorer outcomes. This study highlights the intricate relationship between oxidative stress, inflammation, and concurrent health conditions. Understanding these interactions may open avenues for novel therapeutic strategies aimed at ameliorating oxidative damage in patients with acute ischemic stroke and COVID-19, ultimately improving their prognosis and quality of life.
Genetic Correlation of miRNA Polymorphisms and STAT3 Signaling Pathway with Recurrent Implantation Failure in the Korean Population
Authors: Lee Jung Hun , Ahn Eun Hee , Kwon Min Jung , Ryu Chang Su , Ha Yong Hyun , Ko Eun Ju , Lee Jeong Yong , Hwang Ji Young , Kim Ji Hyang , Kim Young Ran , Kim Nam Keun
Published: November 2023

The growing prevalence of in vitro fertilization-embryo transfer procedures has resulted in an increased incidence of recurrent implantation failure (RIF), necessitating focused research in this area. STAT3, a key factor in maternal endometrial remodeling and stromal proliferation, is crucial for successful embryo implantation. While the relationship between STAT3 and RIF has been studied, the impact of single nucleotide polymorphisms (SNPs) in miRNAs, well-characterized gene expression modulators, on STAT3 in RIF cases remains uncharacterized. Here, we investigated 161 RIF patients and 268 healthy control subjects in the Korean population, analyzing the statistical association between miRNA genetic variants and RIF risk. We aimed to determine whether SNPs in specific miRNAs, namely miR-218-2 rs11134527 G>A, miR-34a rs2666433 G>A, miR-34a rs6577555 C>A, and miR-130a rs731384 G>A, were significantly associated with RIF risk. We identified a significant association between miR-34a rs6577555 C>A and RIF prevalence (implantation failure [IF] ≥ 2: adjusted odds ratio [AOR] = 2.264, 95% CI = 1.007–5.092, p = 0.048). These findings suggest that miR-34a rs6577555 C>A may contribute to an increased susceptibility to RIF. However, further investigations are necessary to elucidate the precise mechanisms underlying the role of miR-34a rs6577555 C>A in RIF. This study sheds light on the genetic and molecular factors underlying RIF, offering new avenues for research and potential advancements in the diagnosis and treatment of this complex condition.
The Functional Significance of McMafF_G_K in Molluscs: Implications for Nrf2-Mediated Oxidative Stress Response
Authors: Yao Ronghui , Qiu Longmei , Zhu Li , Chen Xinglu , Zhai Jiaying , Wang Weifeng , Qi Pengzhi , Liao Zhi , Buttino Isabella , Yan Xiaojun , Guo Baoying
Published: November 2023

The nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal regulator of antioxidant gene expression in mammals, forming heterodimer complexes with small Maf proteins through its BZip domain. However, the underlying mechanism of Nrf2 action in molluscs remains poorly understood. The thick shell mussel, Mytilus coruscus, represents a model organism for the marine environment and molluscs interaction research. In this study, we used in silico cloning to obtain a small Maf homologue called McMafF_G_K from M. coruscus. McMafF_G_K possesses a typical BZip domain, suggesting its affiliation with the traditional small Maf family and its potential involvement in the Nrf2 signaling pathway. Transcriptional analysis revealed that McMafF_G_K exhibited a robust response to benzo[a]pyrene (Bap) in the digestive glands. However, this response was down-regulated upon interference with McMafF_G_K-siRNA. Interestingly, the expression levels of Nrf2, NAD(P)H: quinone oxidoreductase (NQO-1), and Glutathione Peroxidase (GPx), which are key players in oxidative stress response, showed a positive correlation with McMafF_G_K in digested adenocytes of M. coruscus. Furthermore, in vitro analysis of antioxidant capacity in digestive gland cells demonstrated that Bap exposure led to an increase in reactive oxygen species (ROS) levels, accompanied by an elevation in total antioxidant capacity (T-AOC), potentially counterbalancing the excessive ROS. Strikingly, transfection of McMafF_G_K siRNA resulted in a significant rise in ROS level and a down-regulation of T-AOC level. To validate the functional relevance of McMafF_G_K, a glutathione S-transferase (GST) pull-down assay confirmed its interaction with McNrf2, providing compelling evidence of their protein interaction. This study significantly contributes to our understanding of the functional role of McMafF_G_K in the Nrf2 signaling pathway and sheds light on its potential as a target for further research in oxidative stress response.
Alteration in Melanin Content in Retinal Pigment Epithelial Cells upon Hydroquinone Exposure
Authors: Nishiyama Takeyuki , Tsujinaka Hiroki , Ueda Tetsuo , Ogata Nahoko
Published: November 2023

Abnormal pigmentation or depigmentation of the retinal pigment epithelium (RPE) is a precursor to neovascular age-related macular degeneration (nAMD). In this study, we evaluated the effects of hydroquinone (HQ), the most potent reductant in cigarette smoke, on the melanin production in RPE cells. Induced pluripotent stem cell (iPS)-derived RPE and adult retinal pigment epithelial (ARPE-19) cells were cultured with HQ. Real-time reverse transcription polymerase chain reaction revealed that the expression of melanin-related genes decreased due to the addition of HQ for 1 day. Enzyme-linked immunosorbent immunoassay showed that the concentration of melanin significantly decreased due to the addition of HQ for 24 h. A suspension of RPE cells with HQ for 24 h was prepared, and the absorbance was measured. The absorbance decreased particularly under blue light, suggesting that blue light may reach the choroid and cause choroidal inflammation. Additionally, melanin levels significantly decreased due to the addition of HQ for 1 week. After blue light irradiation on the RPE with HQ for 1 week, the vascular endothelial growth factor in the medium was significantly higher in the HQ group than in the control group. HQ-induced changes in melanin production may be responsible for the uneven pigmentation of the RPE, and these changes may cause nAMD.
Oxidative Mechanisms and Cardiovascular Abnormalities of Cirrhosis and Portal Hypertension
Authors: Liu Hongqun , Nguyen Henry H. , Hwang Sang Youn , Lee Samuel S.
Published: November 2023

In patients with portal hypertension, there are many complications including cardiovascular abnormalities, hepatorenal syndrome, ascites, variceal bleeding, and hepatic encephalopathy. The underlying mechanisms are not yet completely clarified. It is well known that portal hypertension causes mesenteric congestion which produces reactive oxygen species (ROS). ROS has been associated with intestinal mucosal injury, increased intestinal permeability, enhanced gut bacterial overgrowth, and translocation; all these changes result in increased endotoxin and inflammation. Portal hypertension also results in the development of collateral circulation and reduces liver mass resulting in an overall increase in endotoxin/bacteria bypassing detoxication and immune clearance in the liver. Endotoxemia can in turn aggravate oxidative stress and inflammation, leading to a cycle of gut barrier dysfunction → endotoxemia → organ injury. The phenotype of cardiovascular abnormalities includes hyperdynamic circulation and cirrhotic cardiomyopathy. Oxidative stress is often accompanied by inflammation; thus, blocking oxidative stress can minimize the systemic inflammatory response and alleviate the severity of cardiovascular diseases. The present review aims to elucidate the role of oxidative stress in cirrhosis-associated cardiovascular abnormalities and discusses possible therapeutic effects of antioxidants on cardiovascular complications of cirrhosis including hyperdynamic circulation, cirrhotic cardiomyopathy, and hepatorenal syndrome.
Identification of Flavanone 3-Hydroxylase Gene Family in Strawberry and Expression Analysis of Fruit at Different Coloring Stages
Authors: Zhang Yanqi , Feng Yongqing , Yang Shangwen , Qiao Huilan , Wu Aiyuan , Yang Jinghua , Ma Zonghuan
Published: November 2023

The color of strawberry fruit is an important appearance quality index that affects the marketability of fruit, and the content and type of anthocyanin are two of the main reasons for the formation of fruit color. At present, the research on anthocyanin synthesis mainly focuses on the phenylpropane metabolic pathway, and the F3H gene family is an important member of this metabolic pathway. Therefore, in order to clarify the role of flavanone 3-hydroxylase (F3H) in regulating anthocyanin accumulation in strawberry, we identified F3H gene family members in strawberry and analyzed their bioinformatics and expression at different fruit color stages. The results showed that the strawberry F3H family contains 126 members, which are distributed on seven chromosomes and can be divided into six subgroups. The promoter region of strawberry F3H gene family contains light response elements, abiotic stress response elements and hormone response elements. Intraspecic collinearity analysis showed that there were six pairs of collinearity of the F3H gene. Interspecific collinearity analysis showed that there were more collinearity relationships between strawberry and apple, grape and Arabidopsis, but less collinearity between strawberry and rice. Via tissue-specific expression analysis, we found that the expression levels of FvF3H48, FvF3H120 and FvF3H74 were higher in the stages of germination, growth, flowering and fruit setting. The expression levels of FvF3H42 and FvF3H16 were higher in seeds. The expression levels of FvF3H16 and FvF3H11 were higher in the ovary wall of stage 1, stage 2, stage 3 and stage 5. FvF3H15 and FvF3H48 were highly expressed in the pericardium, anther, receptacle and anther. Real-time fluorescence quantitative PCR showed the expression changes in F3H in the fruit coloring process. The results indicate that the expression levels of most members were higher during the S3 stage, such as FvF3H7, FvF3H16, FvF3H32, FvF3H82, FvF3H89, FvF3H92 and FvF3H112. FvF3H63 and FvF3H104 exhibited particularly high expression levels during the S1 stage, with some genes also showing elevated expression during the S4 stage, including FvF3H13, FvF3H27, FvF3H66 and FvF3H103. FvF3H58, FvF3H69, FvF3H79 and FvF3H80 showed higher expression levels during the S2 stage. These findings lay the groundwork for elucidating the biological functions of the strawberry F3H gene family and the selection of related genes.
Reduced Levels of Lacrimal Glial Cell Line-Derived Neurotrophic Factor (GDNF) in Patients with Focal Epilepsy and Focal Epilepsy with Comorbid Depression: A Biomarker Candidate
Authors: Shpak Alexander A. , Rider Flora K. , Druzhkova Tatiana A. , Zhanina Marina Y. , Popova Sofya B. , Guekht Alla B. , Gulyaeva Natalia V.
Published: November 2023

Our previous studies showed that in patients with brain diseases, neurotrophic factors in lacrimal fluid (LF) may change more prominently than in blood serum (BS). Since glial cell line-derived neurotrophic factor (GDNF) is involved in the control of neuronal networks in an epileptic brain, we aimed to assess the GDNF levels in LF and BS as well as the BDNF and the hypothalamic–pituitary–adrenocortical and inflammation indices in BS of patients with focal epilepsy (FE) and epilepsy and comorbid depression (FE + MDD) and to compare them with those of patients with major depressive disorder (MDD) and healthy controls (HC). GDNF levels in BS were similar in patients and HC and higher in FE taking valproates. GDNF levels in LF were significantly lower in all patient groups compared to controls, and independent of drugs used. GDNF concentrations in LF and BS positively correlated in HC, but not in patient groups. BDNF level was lower in BS of patients compared with HC and higher in FE + MDD taking valproates. A reduction in the GDNF level in LF might be an important biomarker of FE. Logistic regression models demonstrated that the probability of FE can be evaluated using GDNF in LF and BDNF in BS; that of MDD using GDNF in LF and cortisol and TNF-α in BS; and that of epilepsy with MDD using GDNF in LF and TNF-α and BDNF in BS.
Mmp2 Deficiency Leads to Defective Parturition and High Dystocia Rates in Mice
Authors: Kalev-Altman Rotem , Becker Gal , Levy Tamar , Penn Svetlana , Shpigel Nahum Y. , Monsonego-Ornan Efrat , Sela-Donenfeld Dalit
Published: November 2023

Parturition is the final and essential step for mammalian reproduction. While the uterus is quiescent during pregnancy, fundamental changes arise in the myometrial contractility, inducing fetal expulsion. Extracellular matrix (ECM) remodeling is fundamental for these events. The gelatinases subgroup of matrix metalloproteinases (MMPs), MMP2 and MMP9, participate in uterine ECM remodeling throughout pregnancy and parturition. However, their loss-of-function effect is unknown. Here, we determined the result of eliminating Mmp2 and/or Mmp9 on parturition in vivo, using single- and double-knockout (dKO) mice. The dystocia rates were measured in each genotype, and uterine tissue was collected from nulliparous synchronized females at the ages of 2, 4, 9 and 12 months. Very high percentages of dystocia (40–55%) were found in the Mmp2−/− and dKO females, contrary to the Mmp9−/− and wild-type females. The histological analysis of the uterus and cervix revealed that Mmp2−/− tissues undergo marked structural alterations, including highly enlarged myometrial, endometrial and luminal cavity. Increased collagen deposition was also demonstrated, suggesting a mechanism of extensive fibrosis in the Mmp2−/− myometrium, which may result in dystocia. Overall, this study describes a new role for MMP2 in myometrium remodeling during mammalian parturition process, highlighting a novel cause for dystocia due to a loss in MMP2 activity in the uterine tissue.
Gas-Phase vs. Grain-Surface Formation of Interstellar Complex Organic Molecules: A Comprehensive Quantum-Chemical Study
Authors: Martínez-Bachs Berta , Rimola Albert
Published: November 2023

Several organic chemical compounds (the so-called interstellar complex organic molecules, iCOMs) have been identified in the interstellar medium (ISM). Examples of iCOMs are formamide (HCONH2), acetaldehyde (CH3CHO), methyl formate (CH3OCHO), or formic acid (HCOOH). iCOMs can serve as precursors of other organic molecules of enhanced complexity, and hence they are key species in chemical evolution in the ISM. The formation of iCOMs is still a subject of a vivid debate, in which gas-phase or grain-surface syntheses have been postulated. In this study, we investigate the grain-surface-formation pathways for the four above-mentioned iCOMs by transferring their primary gas-phase synthetic routes onto water ice surfaces. Our objective is twofold: (i) to identify potential grain-surface-reaction mechanisms leading to the formation of these iCOMs, and (ii) to decipher either parallelisms or disparities between the gas-phase and the grain-surface reactions. Results obtained indicate that the presence of the icy surface modifies the energetic features of the reactions compared to the gas-phase scenario, by increasing some of the energy barriers. Therefore, the investigated gas-phase mechanisms seem unlikely to occur on the icy grains, highlighting the distinctiveness between the gas-phase and the grain-surface chemistry.
Exploration of the Conformational Scenario for α-, β-, and γ-Cyclodextrins in Dry and Wet Conditions, from Monomers to Crystal Structures: A Quantum-Mechanical Study
Authors: Pantaleone Stefano , Gho Cecilia Irene , Ferrero Riccardo , Brunella Valentina , Corno Marta
Published: November 2023

Cyclodextrins (CDs) constitute a class of cyclic oligosaccharides that are well recognized and largely applied in the drug delivery field, thanks to their biocompatibility, low cost, and the possibility to be derivatized in order to tune and optimize the complexation/release of the specific drug. The conformational flexibility of these systems is one of their key properties and requires a cost-effective methodology to be studied by combining the accuracy of results with the possibility of exploring a large set of conformations. In the present paper, we have explored the conformational potential energy surface of the monomers and dimers of α-, β-, and γ-cyclodextrins (i.e., 6, 7, and 8 monomeric units, respectively) by means of fast but accurate semiempirical methods, which are then refined by state-of-the-art DFT functionals. Moreover, the crystal structure is considered for a more suitable comparison with the IR spectrum experimentally recorded. Calculations are carried out in the gas phase and in water environments, applying both implicit and explicit treatments. We show that the conformation of the studied molecules changes from the gas phase to the water, even if treated implicitly, thus modifying their complexation capability.
Identification and Functions of JHE 6 Specifically Expressed in Bombyx mori Silk Gland
Authors: Zhang Xia , Zhang Jikailang , Wu Keli , Yang Hongguo , Cheng Tingcai , Liu Chun
Published: November 2023

Juvenile hormone esterase (JHE) is the specific enzyme that degrades juvenile hormone (JH) and regulates the JH titer in insects. JH also regulates the development of the silk gland and the synthesis and secretion of silk proteins in Bombyx mori. Here, we identified nine possible JHE family members, Bmjhe1–9. Notably, Bmjhe6 is specifically expressed in the silk gland. Using semi-quantitative, quantitative real-time RT-PCR and Western blot, it was confirmed that Bmjhe6 was specifically expressed in the middle silk gland (MSG) with high levels in the anterior region of the MSG (A-MSG). The immunofluorescence localization analysis revealed that Bmjhe6 is produced within cells, secreted into the gland lumen, and co-transported with silk proteins into the anterior silk gland (ASG). In vitro hormone induction experiments demonstrated that Bmjhe6 responds to a JH analog, increasing its expression after 12–24 h, whereas 20-hydroxyecdysone inhibited it. In addition, Bmjhe6 knockdown using dsBmjhe6 injections accelerated larval development, resulting in increased larval body and silk gland weight. This induced disordered sericin genes (Ser2, Ser3) expression, and key genes in the JH synthesis pathway (BmKr-h1 and BmMet1) were significantly upregulated along with the transcription factors (SGF-1 and Sage). These results indicate that Bmjhe6 plays an important role in silk gland growth and silk protein synthesis by modulating JH signal.