bluuebunny/crossref_metadata_2025 huggingface dataset:
Suppression of NANOG Expression Reduces Drug Resistance of Cancer Stem Cells in Glioblastoma
Authors: Smith Jonhoi , Field Melvin , Sugaya Kiminobu
Published: June 2023

Glioblastoma (GBM) is an aggressive and incurable primary brain tumor that harbors therapy-resistant cancer stem cells (CSCs). Due to the limited effectiveness of conventional chemotherapies and radiation treatments against CSCs, there is a critical need for the development of innovative therapeutic approaches. Our previous research revealed the significant expression of embryonic stemness genes, NANOG and OCT4, in CSCs, suggesting their role in enhancing cancer-specific stemness and drug resistance. In our current study, we employed RNA interference (RNAi) to suppress the expression of these genes and observed an increased susceptibility of CSCs to the anticancer drug, temozolomide (TMZ). Suppression of NANOG expression induced cell cycle arrest in CSCs, specifically in the G0 phase, and it concomitantly decreased the expression of PDK1. Since PDK1 activates the PI3K/AKT pathway to promote cell proliferation and survival, our findings suggest that NANOG contributes to chemotherapy resistance in CSCs through PI3K/AKT pathway activation. Therefore, the combination of TMZ treatment with RNAi targeting NANOG holds promise as a therapeutic strategy for GBM.
Single-Molecule Telomere Assay via Optical Mapping (SMTA-OM) Can Potentially Define the ALT Positivity of Cancer
Authors: Raseley Kaitlin , Jinwala Zeal , Zhang Dong , Xiao Ming
Published: June 2023

Telomeres play an essential role in protecting the ends of linear chromosomes and maintaining the integrity of the human genome. One of the key hallmarks of cancers is their replicative immortality. As many as 85–90% of cancers activate the expression of telomerase (TEL+) as the telomere maintenance mechanism (TMM), and 10–15% of cancers utilize the homology-dependent repair (HDR)-based Alternative Lengthening of Telomere (ALT+) pathway. Here, we performed statistical analysis of our previously reported telomere profiling results from Single Molecule Telomere Assay via Optical Mapping (SMTA-OM), which is capable of quantifying individual telomeres from single molecules across all chromosomes. By comparing the telomeric features from SMTA-OM in TEL+ and ALT+ cancer cells, we demonstrated that ALT+ cancer cells display certain unique telomeric profiles, including increased fusions/internal telomere-like sequence (ITS+), fusions/internal telomere-like sequence loss (ITS−), telomere-free ends (TFE), super-long telomeres, and telomere length heterogeneity, compared to TEL+ cancer cells. Therefore, we propose that ALT+ cancer cells can be differentiated from TEL+ cancer cells using the SMTA-OM readouts as biomarkers. In addition, we observed variations in SMTA-OM readouts between different ALT+ cell lines that may potentially be used as biomarkers for discerning subtypes of ALT+ cancer and monitoring the response to cancer therapy.
Sequencing and Characterization of M. morganii Strain UM869: A Comprehensive Comparative Genomic Analysis of Virulence, Antibiotic Resistance, and Functional Pathways
Authors: Behera Dibyajyoti Uttameswar , Dixit Sangita , Gaur Mahendra , Mishra Rukmini , Sahoo Rajesh Kumar , Sahoo Maheswata , Behera Bijay Kumar , Subudhi Bharat Bhusan , Bharat Sutar Suhas , Subudhi Enketeswara
Published: June 2023

Morganella morganii is a Gram-negative opportunistic Enterobacteriaceae pathogen inherently resistant to colistin. This species causes various clinical and community-acquired infections. This study investigated the virulence factors, resistance mechanisms, functional pathways, and comparative genomic analysis of M. morganii strain UM869 with 79 publicly available genomes. The multidrug resistance strain UM869 harbored 65 genes associated with 30 virulence factors, including efflux pump, hemolysin, urease, adherence, toxin, and endotoxin. Additionally, this strain contained 11 genes related to target alteration, antibiotic inactivation, and efflux resistance mechanisms. Further, the comparative genomic study revealed a high genetic relatedness (98.37%) among the genomes, possibly due to the dissemination of genes between adjoining countries. The core proteome of 79 genomes contains the 2692 core, including 2447 single-copy orthologues. Among them, six were associated with resistance to major antibiotic classes manifested through antibiotic target alteration (PBP3, gyrB) and antibiotic efflux (kpnH, rsmA, qacG; rsmA; CRP). Similarly, 47 core orthologues were annotated to 27 virulence factors. Moreover, mostly core orthologues were mapped to transporters (n = 576), two-component systems (n = 148), transcription factors (n = 117), ribosomes (n = 114), and quorum sensing (n = 77). The presence of diversity in serotypes (type 2, 3, 6, 8, and 11) and variation in gene content adds to the pathogenicity, making them more difficult to treat. This study highlights the genetic similarity among the genomes of M. morganii and their restricted emergence, mostly in Asian countries, in addition to their growing pathogenicity and resistance. However, steps must be taken to undertake large-scale molecular surveillance and to direct suitable therapeutic interventions.
Multi-Omics Pipeline and Omics-Integration Approach to Decipher Plant’s Abiotic Stress Tolerance Responses
Authors: Roychowdhury Rajib , Das Soumya Prakash , Gupta Amber , Parihar Parul , Chandrasekhar Kottakota , Sarker Umakanta , Kumar Ajay , Ramrao Devade Pandurang , Sudhakar Chinta
Published: June 2023

The present day’s ongoing global warming and climate change adversely affect plants through imposing environmental (abiotic) stresses and disease pressure. The major abiotic factors such as drought, heat, cold, salinity, etc., hamper a plant’s innate growth and development, resulting in reduced yield and quality, with the possibility of undesired traits. In the 21st century, the advent of high-throughput sequencing tools, state-of-the-art biotechnological techniques and bioinformatic analyzing pipelines led to the easy characterization of plant traits for abiotic stress response and tolerance mechanisms by applying the ‘omics’ toolbox. Panomics pipeline including genomics, transcriptomics, proteomics, metabolomics, epigenomics, proteogenomics, interactomics, ionomics, phenomics, etc., have become very handy nowadays. This is important to produce climate-smart future crops with a proper understanding of the molecular mechanisms of abiotic stress responses by the plant’s genes, transcripts, proteins, epigenome, cellular metabolic circuits and resultant phenotype. Instead of mono-omics, two or more (hence ‘multi-omics’) integrated-omics approaches can decipher the plant’s abiotic stress tolerance response very well. Multi-omics-characterized plants can be used as potent genetic resources to incorporate into the future breeding program. For the practical utility of crop improvement, multi-omics approaches for particular abiotic stress tolerance can be combined with genome-assisted breeding (GAB) by being pyramided with improved crop yield, food quality and associated agronomic traits and can open a new era of omics-assisted breeding. Thus, multi-omics pipelines together are able to decipher molecular processes, biomarkers, targets for genetic engineering, regulatory networks and precision agriculture solutions for a crop’s variable abiotic stress tolerance to ensure food security under changing environmental circumstances.
Detecting and Predicting Archaeological Sites Using Remote Sensing and Machine Learning—Application to the Saruq Al-Hadid Site, Dubai, UAE
Authors: Ben-Romdhane Haïfa , Francis Diana , Cherif Charfeddine , Pavlopoulos Kosmas , Ghedira Hosni , Griffiths Steven
Published: June 2023

In this paper, the feasibility of satellite remote sensing in detecting and predicting locations of buried objects in the archaeological site of Saruq Al-Hadid, United Arab Emirates (UAE) was investigated. Satellite-borne synthetic aperture radar (SAR) is proposed as the main technology for this initial investigation. In fact, SAR is the only satellite-based technology able to detect buried artefacts from space, and it is expected that fine-resolution images of ALOS/PALSAR-2 (L-band SAR) would be able to detect large features (>1 m) that might be buried in the subsurface (<2 m) under optimum conditions, i.e., dry and bare soil. SAR data were complemented with very high-resolution Worldview-3 multispectral images (0.31 m panchromatic, 1.24 m VNIR) to obtain a visual assessment of the study area and its land cover features. An integrated approach, featuring the application of advanced image processing techniques and geospatial analysis using machine learning, was adopted to characterise the site while automating the process and investigating its applicability. Results from SAR feature extraction and geospatial analyses showed detection of the areas on the site that were already under excavation and predicted new, hitherto unexplored archaeological areas. The validation of these results was performed using previous archaeological works as well as geological and geomorphological field surveys. The modelling and prediction accuracies are expected to improve with the insertion of a neural network and backpropagation algorithms based on the performed cluster groups following more recent field surveys. The validated results can provide guidance for future on-site archaeological work. The pilot process developed in this work can therefore be applied to similar arid environments for the detection of archaeological features and guidance of on-site investigations.
Use of Digital Healthcare Communication to Improve Urologists’ Surveillance of Lithiasis Patients Treated with Internal Urinary Drainage Pre- and Post-COVID-19 Period
Authors: Vintilă Mihai , Mischianu Dan , Honțaru Octavia-Sorina , Dobra Mihai , Sterian Alin Gabriel
Published: June 2023

The COVID-19 pandemic has greatly affected lithiasis patients, which has led to an increase in the number of internal stents that have been installed. In this paper, two studies were carried out, a clinical study and a quantitative study. The aim of the first study was to evaluate the incidence and the prevalence of bacterial urinary colonization in patients with obstructive urolithiasis who needed internal stents implanted. In the second study, a multiple linear regression was created to identify the opinion of urologists regarding the importance of using digital technologies to improve the communication process. The result of the clinical study illustrates that the prevalence of urinary colonization in patients with internal stents carried out for obstructive urolithiasis was 35%, with this value being influenced by co-infection with COVID-19. The results of the quantitative study illustrated the fact that urologists are open to using new online technologies to facilitate communication with patients. The results have high importance for both doctors and patients, illustrating the main factors that have the ability to influence the communication process. The hospital managers should take into account the results obtained in this study when they choose to use certain online communication technologies with patients.
“It’s Not Important”—The Social Constructing of Poor Physical Health as ‘Normal’ among People with Schizophrenia: Integrated Findings from an Ethnographic Study
Authors: Lerbæk Birgitte , Jørgensen Rikke , McCloughen Andrea
Published: June 2023

People with schizophrenia have shortened life expectancy partly due to physical ill health. Management of coexisting mental and physical health issues is complex, and knowledge in the field is lacking. This study investigated how physical health was managed among people with schizophrenia, by integrating findings from three separate analyses conducted in an ethnographic study. Qualitative data generation methods were used; 505 h of field work were undertaken among nine participants with schizophrenia and 27 mental healthcare professionals were interviewed using a semi-structured interview approach. Three separate analyses were conducted using thematic and discourse analysis. Progressive focusing was used to integrate findings. Across the mental health care contexts that were part of this research, managing physical health was characterised by a lack of recognition of the seriousness of physical health issues as part of everyday life among people with schizophrenia. Poor physical health was accounted for as being “not of importance” by both mental health care professionals and the participants experiencing physical health issues. The integrated findings offer new insights about the social co-construction of poor physical health as something normal. At the individual level, this shared understanding by people with schizophrenia and healthcare professionals contributed to sustaining inexpedient management strategies of “modifying” behaviour or “retreating” from everyday life when physical health issues were experienced.
A Scoping Review of Economic Evaluations to Inform the Reorientation of Preventive Health Services in Australia
Authors: Taylor Rachael , Sullivan Deborah , Reeves Penny , Kerr Nicola , Sawyer Amy , Schwartzkoff Emma , Bailey Andrew , Williams Christopher , Hure Alexis
Published: June 2023

The Australian National Preventive Health Strategy 2021–2030 recommended the establishment of evidence-based frameworks to enable local public health services to identify strategies and interventions that deliver value for money. This study aimed to review the cost-effectiveness of preventive health strategies to inform the reorientation of local public health services towards preventive health interventions that are financially sustainable. Four electronic databases were searched for reviews published between 2005 and February 2022. Reviews that met the following criteria were included: population: human studies, any age or sex; concept 1: primary and/or secondary prevention interventions; concept 2: full economic evaluation; context: local public health services as the provider of concept 1. The search identified 472 articles; 26 were included. Focus health areas included mental health (n = 3 reviews), obesity (n = 1), type 2 diabetes (n = 3), dental caries (n = 2), public health (n = 4), chronic disease (n = 5), sexual health (n = 1), immunisation (n = 1), smoking cessation (n = 3), reducing alcohol (n = 1), and fractures (n = 2). Interventions that targeted obesity, type 2 diabetes, smoking cessation, and fractures were deemed cost-effective, however, more studies are needed, especially those that consider equity in priority populations.
Inclusion of a Parental Component in a Sports-Based HIV Prevention Program for Dominican Youth
Authors: Gesualdo Chrys , Larsen Helle , Garcia Pilar
Published: June 2023

Background: Underprivileged youth in the Dominican Republic (DR) are at high risk of acquiring the human immunodeficiency virus (HIV). Protective parenting practices may inhibit sexual risk-taking. Objective: We investigated whether parental involvement in a sports-based HIV prevention program increased self-efficacy to prevent HIV and safe sex behavior among Dominican youth. Method: The study had a quasi-experimental design with repeated measures. N = 90 participants between 13 and 24 years of age participated in the program through two different trainings, UNICA and A Ganar, both of which had an experimental (i.e., program with parental component) and a control (i.e., program without parental component) condition. Results: Self-efficacy to prevent HIV significantly increased among participants in the experimental condition of UNICA. Self-efficacy for safe sex increased among sexually active participants in the experimental condition of A Ganar. Implications for Impact: These findings are important to meet the United Nations’ Sustainable Development Goal of good health and wellbeing, as they suggest that parental involvement in sports-based HIV prevention programs can enhance their positive effects for increasing youth’s self-efficacy to practice HIV-preventive behaviors. Randomized control trials and longitudinal studies are needed.
Anticoagulant Treatment in Patients with AF and Very High Thromboembolic Risk in the Era before and after the Introduction of NOAC: Observation at a Polish Reference Centre
Authors: Bielecka Bernadetta , Gorczyca-Głowacka Iwona , Ciba-Stemplewska Agnieszka , Wożakowska-Kapłon Beata
Published: June 2023

Atrial fibrillation (AF) is associated with an increased risk of stroke. Therefore, patients with AF require appropriate management and anticoagulant therapy. To balance therapy risks and benefits, oral anticoagulants (OAC) treatment should be ‘tailored’ in patients at a high risk of stroke and bleeding. However, some studies have demonstrated that certain groups of patients do not receive anticoagulants despite the high risk of stroke or thromboembolism. The study aimed to analyse therapeutic methods of stroke prevention in very high-risk patients (CHA2DS2-VASc score of ≥5 in men and ≥6 in women), identify factors predisposing against the use of OACs and assess the administration of anticoagulants before the introduction of non-vitamin K antagonist OAC (NOAC) in 2004–2011 and beyond (years 2012–2019). The analysis covered 2441 patients with AF at a very high thromboembolic risk who were hospitalised in a reference cardiological centre from 2004 to 2019. Data concerning patients’ sex, age, comorbidities, type of AF, renal and echocardiographic parameters, reasons for hospitalisation and applied treatment were collected from medical records. HAS-BLED, CHADS2, and CHA2DS2-VASc scores were calculated for all patients. The treatment with oral anticoagulants was compared in the entire population over 2004–2011 and 2012–2019. In this study, a fifth of patients were not treated with OAC. Most patients hospitalised in the years 2012–2019 were treated with OAC. The predictors of not using OAC turned out to be: age of >74 years, heart failure, cancer, paroxysmal AF, and acute coronary syndrome (ACS) or elective coronary angiography/percutaneous coronary intervention (PCI) as a reason for hospitalisation. The introduction of NOAC was associated with a decline in the use of VKA (from 62% to 19.1%) and APT (from 29.1% to 1.3%). This study outlines reasons to initiate OAC treatment in very high-risk patients in clinical practice.
Improving the Scope of Child Mental Health Interventions in Our Modern World
Authors: Wright Barry
Published: June 2023

Twenty years ago, an important systematic review showed that the empirical research evidence for interventions available for children and young people with mental health problems were rarely developed with their specific developmental needs in mind [...]
Children’s Transitions to Adulthood and Midlife Parents’ Depressive Symptoms and Activities of Daily Living Conditions in the United States
Authors: Zhang Xing , Hammersmith Anna M.
Published: June 2023

Background: Parents and children are close over the life course. However, these relationships often change as parents age and children enter adulthood. Today, the entrance into adulthood for children has become delayed and increasingly unstable. Such changes may interrupt the child’s acquisition of resources used to support themselves and their midlife parents, having implications for parents’ mental and physical health. The purpose of this study is to examine the role of adult children’s transitions to adulthood on parents’ mental and physical health. Methods: Using data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) and the Add Health Parent Study (AHPS), we investigated how certain transitions to adulthood (e.g., education, marriage, residential independence, employment, parenthood, and incarceration) for children were linked to the mental and physical health of their midlife parents. Results: In sum, we found that children’s educational attainment was linked to fewer activities of daily living (ADL) limitations and depressive symptoms among parents. Children’s marriage and employment were also associated with fewer ADL limitations among parents. Conclusions: Our findings reveal that adult children’s circumstances are associated with the mental and physical health of their midlife parents.
Impact of Advance Care Planning on the Hospitalization-Associated Utilization and Cost of Patients with Alzheimer’s Disease-Related Disorders Receiving Primary Care via Telehealth in a Provider Shortage Area: A Quantitative Pre-Study
Authors: Yoo Ji Won , Reed Peter S. , Shen Jay J. , Carson Jennifer , Kang Mingon , Reeves Jerry , Kim Yonsu , Choe Ian , Kim Pearl , Kim Laurie , Kang Hee-Taik , Tabrizi Maryam
Published: June 2023

Telehealth has been adopted as an alternative to in-person primary care visits. With multiple participants able to join remotely, telehealth can facilitate the discussion and documentation of advance care planning (ACP) for those with Alzheimer’s disease-related disorders (ADRDs). We measured hospitalization-associated utilization outcomes, instances of hospitalization and 90-day re-hospitalizations from payors’ administrative databases and verified the data via electronic health records. We estimated the hospitalization-associated costs using the Nevada State Inpatient Dataset and compared the estimated costs between ADRD patients with and without ACP documentation in the year 2021. Compared to the ADRD patients without ACP documentation, those with ACP documentation were less likely to be hospitalized (mean: 0.74; standard deviation: 0.31; p < 0.01) and were less likely to be readmitted within 90 days of discharge (mean: 0.16; standard deviation: 0.06; p < 0.01). The hospitalization-associated cost estimate for ADRD patients with ACP documentation (mean: USD 149,722; standard deviation: USD 80,850) was less than that of the patients without ACP documentation (mean: USD 200,148; standard deviation: USD 82,061; p < 0.01). Further geriatrics workforce training is called for to enhance ACP competencies for ADRD patients, especially in areas with provider shortages where telehealth plays a comparatively more important role.
Five-Aminolevulinic Acid (5-ALA) Induces Heme Oxygenase-1 and Ameliorates Palmitic Acid-Induced Endoplasmic Reticulum Stress in Renal Tubules
Authors: Hamada Shintaro , Mae Yukari , Takata Tomoaki , Hanada Hinako , Kubo Misaki , Taniguchi Sosuke , Iyama Takuji , Sugihara Takaaki , Isomoto Hajime
Published: June 2023

Steatosis, or ectopic lipid deposition, is the fundamental pathophysiology of non-alcoholic steatohepatitis and chronic kidney disease. Steatosis in the renal tubule causes endoplasmic reticulum (ER) stress, leading to kidney injury. Thus, ER stress could be a therapeutic target in steatonephropathy. Five-aminolevulinic acid (5-ALA) is a natural product that induces heme oxygenase (HO)-1, which acts as an antioxidant. This study aimed to investigate the therapeutic potential of 5-ALA in lipotoxicity-induced ER stress in human primary renal proximal tubule epithelial cells. Cells were stimulated with palmitic acid (PA) to induce ER stress. Cellular apoptotic signals and expression of genes involved in the ER stress cascade and heme biosynthesis pathway were analyzed. The expression of glucose-regulated protein 78 (GRP78), a master regulator of ER stress, increased significantly, followed by increased cellular apoptosis. Administration of 5-ALA induced a remarkable increase in HO-1 expression, thus ameliorating PA-induced GRP78 expression and apoptotic signals. BTB and CNC homology 1 (BACH1), a transcriptional repressor of HO-1, was significantly downregulated by 5-ALA treatment. HO-1 induction attenuates PA-induced renal tubular injury by suppressing ER stress. This study demonstrates the therapeutic potential of 5-ALA against lipotoxicity through redox pathway.
Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0
Authors: Tang Chih-Hsin
Published: June 2023

Arthritis has a high prevalence globally and includes over 100 types, the most common of which are rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA), and inflammatory arthritis [...]
The Changes in Mitochondrial Morphology and Physiology Accompanying Apoptosis in Galleria mellonella (Lepidoptera) Immunocompetent Cells during Conidiobolus coronatus (Entomophthorales) Infection
Authors: Kaczmarek Agata , Wrońska Anna Katarzyna , Boguś Mieczysława Irena
Published: June 2023

Mitochondria have been shown to play an important role in apoptosis using mammalian cell lines. However, their role in insects is not fully understood; thus, more indepth studies of insect cell apoptosis are necessary. The present study investigates mitochondrial involvement during Conidiobolus coronatus-induced apoptosis in Galleria mellonella hemocytes. Previous research has shown that fungal infection could induce apoptosis in insect hemocytes. Our findings indicate that mitochondria undergo several morphological and physiological changes during fungal infection, e.g., loss of mitochondrial membrane potential, megachannel formation, disturbances in intracellular respiration, increased nonrespiratory oxygen consumption in mitochondria, decreased ATP-coupled oxygen consumption and increased non-ATP–coupled oxygen consumption, decreased extracellular and intracellular oxygen consumption, and increased extracellular pH. Our findings confirm that G. mellonella immunocompetent cells demonstrate Ca2+ overload in mitochondria, translocation of cytochrome c-like protein from mitochondrial to cytosol fraction, and higher activation of caspase-9-like protein after C. coronatus infection. Most importantly, several of the changes observed in insect mitochondria are similar to those accompanying apoptosis in mammalian cells, suggesting that the process is evolutionarily conserved.
The Role of IL-23 in the Pathogenesis and Therapy of Inflammatory Bowel Disease
Authors: Korta Aleksandra , Kula Julia , Gomułka Krzysztof
Published: June 2023

Interleukin-23 (IL-23) is a proinflammatory cytokine produced mainly by macrophages and antigen-presenting cells (APCs) after antigenic stimulation. IL-23 plays a significant role as a mediator of tissue damage. Indeed, the irregularities in IL-23 and its receptor signaling have been implicated in inflammatory bowel disease. IL-23 interacts with both the innate and adaptive immune systems, and IL-23/Th17 appears to be involved in the development of chronic intestinal inflammation. The IL-23/Th17 axis may be a critical driver of this chronic inflammation. This review summarizes the main aspects of IL-23’s biological function, cytokines that control cytokine production, effectors of the IL-23 response, and the molecular mechanisms associated with IBD pathogenesis. Although IL-23 modulates and impacts the development, course, and recurrence of the inflammatory response, the etiology and pathophysiology of IBD are not completely understood, but mechanism research shows huge potential for clinical applications as therapeutic targets in IBD treatment.
Metabolic Adaption of Flexor Carpi Radialis to Amplexus Behavior in Asiatic Toads (Bufo gargarizans)
Authors: Yan Chengzhi , Ma Hui , Yang Yuejun , Mi Zhiping
Published: June 2023

Amplexus is a type of mating behavior among toads that is essential for successful external fertilization. Most studies have primarily focused on the behavioral diversity of amplexus, and less is known regarding the metabolic changes occurring in amplectant males. The aim of this study was to compare the metabolic profiles of amplectant Asiatic toad (Bufo gargarizans) males in the breeding period (BP group) and the resting males in the non-breeding period (NP group). A metabolomic analysis was conducted on the flexor carpi radialis (FCR), an essential forelimb muscle responsible for clasping during courtship. A total of 66 differential metabolites were identified between the BP and NP groups, including 18 amino acids, 12 carbohydrates, and 8 lipids, and they were classified into 9 categories. Among these differential metabolites, 13 amino acids, 11 carbohydrates, and 7 lipids were significantly upregulated in the BP group compared to the NP group. In addition, a KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis identified 17 significant metabolic pathways, including ABC transporters, aminoacyl-tRNA biosynthesis, arginine biosynthesis, pantothenate and CoA biosynthesis, and fructose and mannose metabolism. These results suggest that amplectant male toads are metabolically more active than those during the non-breeding period, and this metabolic adaptation increases the likelihood of reproductive success.
New Perspectives in Dried Blood Spot Biomarkers for Lysosomal Storage Diseases
Authors: Spiewak Justyna , Doykov Ivan , Papandreou Apostolos , Hällqvist Jenny , Mills Philippa , Clayton Peter T. , Gissen Paul , Mills Kevin , Heywood Wendy E.
Published: June 2023

Dried blood spots (DBSs) biomarkers are convenient for monitoring for specific lysosomal storage diseases (LSDs), but they could have relevance for other LSDs. To determine the specificity and utility of glycosphingolipidoses biomarkers against other LSDs, we applied a multiplexed lipid liquid chromatography tandem mass spectrometry assay to a DBS cohort of healthy controls (n = 10) and Gaucher (n = 4), Fabry (n = 10), Pompe (n = 2), mucopolysaccharidosis types I–VI (n = 52), and Niemann–Pick disease type C (NPC) (n = 5) patients. We observed no complete disease specificity for any of the markers tested. However, comparison among the different LSDs highlighted new applications and perspectives of the existing biomarkers. We observed elevations in glucosylceramide isoforms in the NPC and Gaucher patients relative to the controls. In NPC, there was a greater proportion of C24 isoforms, giving a specificity of 96–97% for NPC, higher than 92% for the NPC biomarker N-palmitoyl-O-phosphocholineserine ratio to lyso-sphingomyelin. We also observed significantly elevated levels of lyso-dihexosylceramide in Gaucher and Fabry disease as well as elevated lyso-globotriaosylceramide (Lyso-Gb3) in Gaucher disease and the neuronopathic forms of Mucopolysaccharidoses. In conclusion, DBS glucosylceramide isoform profiling has increased the specificity for the detection of NPC, thereby improving diagnostic accuracy. Low levels of lyso-lipids can be observed in other LSDs, which may have implications in their disease pathogenesis.
Identification and Isolation of α-Glucosidase Inhibitors from Siraitia grosvenorii Roots Using Bio-Affinity Ultrafiltration and Comprehensive Chromatography
Authors: Lu Fenglai , Sun Jiayi , Jiang Xiaohua , Song Jingru , Yan Xiaojie , Teng Qinghu , Li Dianpeng
Published: June 2023

The discovery of bioactive compounds from medicinal plants has played a crucial role in drug discovery. In this study, a simple and efficient method utilizing affinity-based ultrafiltration (UF) coupled with high-performance liquid chromatography (HPLC) was developed for the rapid screening and targeted separation of α-glucosidase inhibitors from Siraitia grosvenorii roots. First, an active fraction of S. grosvenorii roots (SGR2) was prepared, and 17 potential α-glucosidase inhibitors were identified based on UF-HPLC analysis. Second, guided by UF-HPLC, a combination of MCI gel CHP-20P column chromatography, high-speed counter-current countercurrent chromatography, and preparative HPLC were conducted to isolate the compounds producing active peaks. Sixteen compounds were successfully isolated from SGR2, including two lignans and fourteen cucurbitane-type triterpenoids. The structures of the novel compounds (4, 6, 7, 8, 9, and 11) were elucidated using spectroscopic methods, including one- and two-dimensional nuclear magnetic resonance spectroscopy and high-resolution electrospray ionization mass spectrometry. Finally, the α-glucosidase inhibitory activities of the isolated compounds were verified via enzyme inhibition assays and molecular docking analysis, all of which were found to exhibit certain inhibitory activity. Compound 14 exhibited the strongest inhibitory activity, with an IC50 value of 430.13 ± 13.33 μM, which was superior to that of acarbose (1332.50 ± 58.53 μM). The relationships between the structures of the compounds and their inhibitory activities were also investigated. Molecular docking showed that the highly active inhibitors interacted with α-glucosidase through hydrogen bonds and hydrophobic interactions. Our results demonstrate the beneficial effects of S. grosvenorii roots and their constituents on α-glucosidase inhibition.
The Brain at High Altitude: From Molecular Signaling to Cognitive Performance
Authors: Aboouf Mostafa A. , Thiersch Markus , Soliz Jorge , Gassmann Max , Schneider Gasser Edith M.
Published: June 2023

The brain requires over one-fifth of the total body oxygen demand for normal functioning. At high altitude (HA), the lower atmospheric oxygen pressure inevitably challenges the brain, affecting voluntary spatial attention, cognitive processing, and attention speed after short-term, long-term, or lifespan exposure. Molecular responses to HA are controlled mainly by hypoxia-inducible factors. This review aims to summarize the cellular, metabolic, and functional alterations in the brain at HA with a focus on the role of hypoxia-inducible factors in controlling the hypoxic ventilatory response, neuronal survival, metabolism, neurogenesis, synaptogenesis, and plasticity.
AIEE-Active Flavones as a Promising Tool for the Real-Time Tracking of Uptake and Distribution in Live Zebrafish
Authors: Wu Yi , He Ying , Luo Huiqing , Jin Tingting , He Feng
Published: June 2023

In recent years, aggregation-induced emission enhancement (AIEE) molecules have shown great potential for applications in the fields of bio-detection, imaging, optoelectronic devices, and chemical sensing. Based on our previous studies, we investigated the fluorescence properties of six flavonoids and confirmed that compounds 1–3 have good aggregation-induced emission enhancement (AIEE) properties through a series of spectroscopic experiments. Compounds with AIEE properties have addressed the limitation imposed by the aggregation-caused quenching (ACQ) of classic organic dyes owing to their strong fluorescence emission and high quantum yield. Based on their excellent fluorescence properties, we evaluated their performance in the cell and we found that they could label mitochondria specifically by comparing their Pearson correlation coefficients (R) with Mito Tracker Red and Lyso-Tracker Red. This suggests their future application in mitochondrial imaging. Furthermore, studies of uptake and distribution characterization in 48 hpf zebrafish larvae revealed their potential for monitoring real-time drug behavior. The uptake of compounds by larvae varies significantly across different time cycles (between uptake and utilization in the tissue). This observation has important implications for the development of visualization techniques for pharmacokinetic processes and can enable real-time feedback. More interestingly, according to the data presented, tested compounds aggregated in the liver and intestine of 168 hpf larvae. This finding suggests that they could potentially be used for monitoring and diagnosing liver and intestinal diseases.
Galanin 2 Receptor: A Novel Target for a Subset of Pancreatic Ductal Adenocarcinoma
Authors: Namsolleck Pawel , Kofler Barbara , Moll Gert N.
Published: June 2023

Galanin is a 30 amino acid peptide that stimulates three subtype receptors (GAL1–3R). M89b is a lanthionine-stabilized, C-terminally truncated galanin analog that specifically stimulates GAL2R. We investigated the potential of M89b as a therapeutic for pancreatic ductal adenocarcinoma (PDAC) and assessed its safety. The anti-tumor activity of subcutaneously injected M89b on the growth of patient-derived xenografts of PDAC (PDAC–PDX) in mice was investigated. In addition, the safety of M89b was assessed in vitro using a multi-target panel to measure the off-target binding and modulation of enzyme activities. In a PDAC–PDX with a high GAL2R expression, M89b completely inhibited the growth of the tumor (p < 0.001), while in two PDAC–PDXs with low GAL2R expression, low or negligeable inhibition of tumor growth was measured, and in the PDX without GAL2R expression no influence on the tumor growth was observed. The M89b treatment of the GAL2R high-PDAC–PDX-bearing mice led to a reduction in the expression of RacGap1 (p < 0.05), PCNA (p < 0.01), and MMP13 (p < 0.05). In vitro studies involving a multi-target panel of pharmacologically relevant targets revealedexcellent safety of M89b. Our data indicated that GAL2R is a safe and valuable target for treating PDACs with high GAL2R expression.
Antiangiogenic Effect of Dopamine and Dopaminergic Agonists as an Adjuvant Therapeutic Option in the Treatment of Cancer, Endometriosis, and Osteoarthritis
Authors: Mendoza-Torreblanca Julieta Griselda , Cárdenas-Rodríguez Noemi , Carro-Rodríguez Jazmín , Contreras-García Itzel Jatziri , Garciadiego-Cázares David , Ortega-Cuellar Daniel , Martínez-López Valentín , Alfaro-Rodríguez Alfonso , Evia-Ramírez Alberto Nayib , Ignacio-Mejía Iván , Vargas-Hernández Marco Antonio , Bandala Cindy
Published: June 2023

Dopamine (DA) and dopamine agonists (DA-Ag) have shown antiangiogenic potential through the vascular endothelial growth factor (VEGF) pathway. They inhibit VEGF and VEGF receptor 2 (VEGFR 2) functions through the dopamine receptor D2 (D2R), preventing important angiogenesis-related processes such as proliferation, migration, and vascular permeability. However, few studies have demonstrated the antiangiogenic mechanism and efficacy of DA and DA-Ag in diseases such as cancer, endometriosis, and osteoarthritis (OA). Therefore, the objective of this review was to describe the mechanisms of the antiangiogenic action of the DA-D2R/VEGF-VEGFR 2 system and to compile related findings from experimental studies and clinical trials on cancer, endometriosis, and OA. Advanced searches were performed in PubMed, Web of Science, SciFinder, ProQuest, EBSCO, Scopus, Science Direct, Google Scholar, PubChem, NCBI Bookshelf, DrugBank, livertox, and Clinical Trials. Articles explaining the antiangiogenic effect of DA and DA-Ag in research articles, meta-analyses, books, reviews, databases, and clinical trials were considered. DA and DA-Ag have an antiangiogenic effect that could reinforce the treatment of diseases that do not yet have a fully curative treatment, such as cancer, endometriosis, and OA. In addition, DA and DA-Ag could present advantages over other angiogenic inhibitors, such as monoclonal antibodies.
Effect of 12-Week BMI-Based Vitamin D3 Supplementation in Parkinson’s Disease with Deep Brain Stimulation on Physical Performance, Inflammation, and Vitamin D Metabolites
Authors: Bytowska Zofia Kinga , Korewo-Labelle Daria , Berezka Paweł , Kowalski Konrad , Przewłócka Katarzyna , Libionka Witold , Kloc Wojciech , Kaczor Jan Jacek
Published: June 2023

Parkinson’s disease (PD) is the second most common neurodegenerative disease. To manage motor symptoms not controlled adequately with medication, deep brain stimulation (DBS) is used. PD patients often manifest vitamin D deficiency, which may be connected with a higher risk of falls. We administered a 12-week vitamin D3 supplementation based on BMI (with higher doses given to patients with higher BMI) to investigate its effects on physical performance and inflammation status in PD patients with DBS. Patients were randomly divided into two groups: treated with vitamin D3 (VitD, n = 13), and supplemented with vegetable oil as the placebo group (PL, n = 16). Patients underwent functional tests to assess their physical performance three times during this study. The serum 25(OH)D3 concentration increased to the recommended level of 30 ng/mL in the VitD group, and a significant elevation in vitamin D metabolites in this group was found. We observed significant improvement in the Up and Go and the 6 MWT in the VitD group. In inflammation status, we noticed a trend toward a decrease in the VitD group. To conclude, achieving the optimal serum 25(OH)D3 concentration is associated with better functional test performance and consequently may have a positive impact on reducing falling risk in PD.
Unveiling the Prognostic Significance of BCL6+/CD10+ Mantle Cell Lymphoma: Meta-Analysis of Individual Patients and Systematic Review
Authors: Castillo Dani Ran , Park Daniel , Jeon Won Jin , Joung Bowon , Lee Jae , Yang Chieh , Pham Bryan , Hino Christopher , Chong Esther , Shields Andrea , Nguyen Anthony , Brothers Joel , Liu Yan , Zhang Ke K. , Cao Huynh
Published: June 2023

Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma (NHL) characterized by a hallmark translocation of t (11; 14). CD10 negativity has been used to differentiate MCL from other NHL types; however, recently, there has been an increase in the number of reported cases of CD10-positive MCL. This warrants further investigation into this rarer immunophenotype and its clinical significance. BCL6, which is a master transcription factor for the regulation of cell proliferation and key oncogene in B cell lymphomagenesis, has been reported to have co-expression with CD10 in MCL. The clinical significance of this aberrant antigen expression remains unknown. We conducted a systematic review by searching four databases and selected five retrospective analyses and five case series. Two survival analyses were conducted to determine if BCL6 positivity conferred a survival difference: 1. BCL6+ vs. BCL6− MCL. 2. BCL6+/CD10+ vs. BCL6−/CD10+ MCL. Correlation analysis was conducted to determine if BCL6 positivity correlated with the Ki67 proliferation index (PI). Overall survival (OS) rates were performed by the Kaplan–Meier method and log-rank test. Our analyses revealed that BCL6+ MCL had significantly shorter overall survival (median OS: 14 months vs. 43 months; p = 0.01), BCL6+/CD10+ MCL had an inferior outcome vs. BCL6+/CD10− MCL (median OS: 20 months vs. 55 months p = 0.1828), BCL6+ MCL had significantly higher percentages of Ki67% (Ki67% difference: 24.29; p = 0.0094), and BCL6 positivity had a positive correlation with CD10+ status with an odds ratio 5.11 (2.49, 10.46; p = 0.0000286). Our analysis showed that BCL6 expression is correlated with CD10 positivity in MCL, and BCL6 expression demonstrated an inferior overall survival. The higher Ki67 PI in BCL6+ MCL compared to BCL6− MCL further supports the idea that the BCL6+ immunophenotype may have prognostic value in MCL. MCL management should consider incorporating prognostic scoring systems adjusted for BCL6 expression. Targeted therapies against BCL6 may offer potential therapeutic options for managing MCL with aberrant immunophenotypes.
Maintaining Genome Integrity: Protein Kinases and Phosphatases Orchestrate the Balancing Act of DNA Double-Strand Breaks Repair in Cancer
Authors: Qin Sisi , Kitty Ichiwa , Hao Yalan , Zhao Fei , Kim Wootae
Published: June 2023

DNA double-strand breaks (DSBs) are the most lethal DNA damages which lead to severe genome instability. Phosphorylation is one of the most important protein post-translation modifications involved in DSBs repair regulation. Kinases and phosphatases play coordinating roles in DSB repair by phosphorylating and dephosphorylating various proteins. Recent research has shed light on the importance of maintaining a balance between kinase and phosphatase activities in DSB repair. The interplay between kinases and phosphatases plays an important role in regulating DNA-repair processes, and alterations in their activity can lead to genomic instability and disease. Therefore, study on the function of kinases and phosphatases in DSBs repair is essential for understanding their roles in cancer development and therapeutics. In this review, we summarize the current knowledge of kinases and phosphatases in DSBs repair regulation and highlight the advancements in the development of cancer therapies targeting kinases or phosphatases in DSBs repair pathways. In conclusion, understanding the balance of kinase and phosphatase activities in DSBs repair provides opportunities for the development of novel cancer therapeutics.
Pharmacokinetics and Tissue Distribution of Bee Venom-Derived Phospholipase A2 Using a Sandwich ELISA after Subcutaneous Injection of New Composition Bee Venom in Rats
Authors: Chae Soon Uk , Jo Seong Jun , Lee Chae Bin , Lee Sangyoung , Park Ji-Hyun , Jung Jin-Su , Park Eui-Suk , Bae Hyunsu , Bae Soo Kyung
Published: June 2023

Bee venom is a traditional drug used to treat the nervous system, musculoskeletal system, and autoimmune diseases. A previous study found that bee venom and one of its components, phospholipase A2, can protect the brain by suppressing neuroinflammation and can also be used to treat Alzheimer’s disease. Thus, new composition bee venom (NCBV), which has an increased phospholipase A2 content of up to 76.2%, was developed as a treatment agent for Alzheimer’s disease by INISTst (Republic of Korea). The aim of this study was to characterize the pharmacokinetic profiles of phospholipase A2 contained in NCBV in rats. Single subcutaneous administration of NCBV at doses ranging from 0.2 mg/kg to 5 mg/kg was conducted, and pharmacokinetic parameters of bee venom-derived phospholipase A2 (bvPLA2) increased in a dose-dependent manner. Additionally, no accumulation was observed following multiple dosings (0.5 mg/kg/week), and other constituents of NCBV did not affect the pharmacokinetic profile of bvPLA2. After subcutaneous injection of NCBV, the tissue-to-plasma ratios of bvPLA2 for the tested nine tissues were all <1.0, indicating a limited distribution of the bvPLA2 within the tissues. The findings of this study may help understand the pharmacokinetic characteristics of bvPLA2 and provide useful information for the clinical application of NCBV.
Correction: Maliszewska et al. On the Photo-Eradication of Methicillin-Resistant Staphylococcus aureus Biofilm Using Methylene Blue. Int. J. Mol. Sci. 2022, 24, 791
Authors: Maliszewska Irena , Zdubek Anna
Published: June 2023

The authors wish to make the following corrections to this paper [...]
Effects of Exercise Preconditioning on Doxorubicin-Induced Liver and Kidney Toxicity in Male and Female Rats
Authors: Boeno Franccesco P. , Patel Jay , Montalvo Ryan N. , Lapierre-Nguyen Stephanie S. , Schreiber Claire M. , Smuder Ashley J.
Published: June 2023

Doxorubicin (DOX) is a highly effective chemotherapy agent prescribed for cancer treatment. However, the clinical use of DOX is limited due to off-target toxicity in healthy tissues. In this regard, hepatic and renal metabolic clearance results in DOX accumulation within these organ systems. Within the liver and kidneys, DOX causes inflammation and oxidative stress, which promotes cytotoxic cellular signaling. While there is currently no standard of care to treat DOX hepatic- and nephrotoxicity, endurance exercise preconditioning may be an effective intervention to prevent elevations in liver alanine transaminase (ALT) and aspartate aminotransferase (AST) and to improve kidney creatinine clearance. To determine whether exercise preconditioning is sufficient to reduce liver and kidney toxicity resulting from acute exposure to DOX chemotherapy treatment, male and female Sprague–Dawley rats remained sedentary or were exercise trained prior to saline or DOX exposure. Our findings demonstrate that DOX treatment elevated AST and AST/ALT in male rats, with no effects of exercise preconditioning to prevent these increases. We also showed increased plasma markers of renin–angiotensin–aldosterone system (RAAS) activation and urine markers of proteinuria and proximal tubule damage, with male rats revealing greater differences compared to females. Exercise preconditioning showed improved urine creatinine clearance and reduced cystatin c in males, while females had reduced plasma angiotensin II (AngII) levels. Our results demonstrate both tissue- and sex-specific responses related to the effects of exercise preconditioning and DOX treatment on markers of liver and kidney toxicity.