bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the Diagnostic Utility of Selected Serum Adipokines and Cytokines in Subjects with MASLD—A Pilot Study
Authors: Zyśk Beata , Ostrowska Lucyna , Smarkusz-Zarzecka Joanna , Orywal Karolina , Mroczko Barbara , Cwalina Urszula
Published: May 2024

Excess adipose tissue, particularly of the visceral type, triggering chronic low-grade inflammation and altering its secretory profile, is a contributing factor to the initiation and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to compare the levels of selected adipokines and cytokines in individuals with normal weight and obesity, assessing their potential for diagnosing MASLD and establishing a cutoff point for body fat content associated with hepatic steatosis development. The research involved 99 participants categorized by body mass index and MASLD presence, undergoing body composition analysis, liver elastography, biochemical tests, and evaluation of adipokines and cytokines in serum. The results indicated elevated IL-6 (interleukin 6) serum levels in individuals with obesity with MASLD compared to the normal-weight group without MASLD. The multivariate regression analysis demonstrated a connection between hepatic steatosis and total adipose tissue content, VAT (visceral adipose tissue), VAT/SAT (subcutaneous adipose tissue) ratio, HOMA-IR (homeostasis model assessment of insulin resistance), IL-6, Il-1β (interleukin 1β), and MMP-2 (matrix metalloproteinase 2). Among the adipokines and cytokines examined in this study, interleukin 6 was the strongest predictor of MASLD regardless of gender. In addition, an association between the development of hepatic steatosis and higher serum IL-1β levels and higher adipose tissue was observed in women. However, further studies on a larger group of patients are needed to consider the use of these cytokines as markers of MASLD. The HOMA-IR index demonstrated potential diagnostic utility in identifying hepatic steatosis.
Ecdysterone and Turkesterone—Compounds with Prominent Potential in Sport and Healthy Nutrition
Authors: Todorova Velislava , Ivanova Stanislava , Chakarov Dzhevdet , Kraev Krasimir , Ivanov Kalin
Published: May 2024

The naturally occurring compounds ecdysterone and turkesterone, which are present in plants, including Rhaponticum carthamoides Willd. (Iljin), Spinacia oleracea L., Chenopodium quinoa Willd., and Ajuga turkestanica (Regel) Briq, are widely recognized due to their possible advantages for both general health and athletic performance. The current review investigates the beneficial biological effects of ecdysterone and turkesterone in nutrition, highlighting their roles not only in enhancing athletic performance but also in the management of various health problems. Plant-based diets, associated with various health benefits and environmental sustainability, often include sources rich in phytoecdysteroids. However, the therapeutic potential of phytoecdysteroid-rich extracts extends beyond sports nutrition, with promising applications in treating chronic fatigue, cardiovascular diseases, and neurodegenerative disorders.
Effects of Dietary Carbohydrate Concentration and Glycemic Index on Blood Glucose Variability and Free Fatty Acids in Individuals with Type 1 Diabetes
Authors: Seckiner Selda , Bas Murat , Simsir Ilgin Yildirim , Ozgur Su , Akcay Yasemin , Aslan Cigdem Gozde , Kucukerdonmez Ozge , Cetinkalp Sevki
Published: May 2024

Monitoring glycemic control status is the cornerstone of diabetes management. This study aimed to reveal whether moderate-carbohydrate (CHO) diets increase the risk of free fatty acid (FFA) levels, and it presents the short-term effects of four different diet models on blood sugar, glycemic variability (GV), and FFA levels. This crossover study included 17 patients with type 1 diabetes mellitus to identify the effects of four diets with different CHO contents and glycemic index (GI) on GV and plasma FFA levels. Diet 1 (D1) contained 40% CHO with a low GI, diet 2 (D2) contained 40% CHO with a high GI, diet 3 (D3) contained 60% CHO with a low GI, and diet 4 (D4) contained 60% CHO with a high GI. Interventions were performed with sensor monitoring in four-day periods and completed in four weeks. No statistical difference was observed among the groups in terms of blood glucose area under the curve (p = 0.78), mean blood glucose levels (p = 0.28), GV (p = 0.59), and time in range (p = 0.567). FFA and total triglyceride levels were higher in the D1 group (p < 0.014 and p = 0.002, respectively). Different diets may increase the risk of cardiovascular diseases by affecting GI, FFA, and blood glucose levels.
An Explanatory Model of Vascular Access Care Quality: Results of a Cross-Sectional Observational Study
Authors: Casanova-Vivas Sonia , Ballestar-Tarín María Luisa , García-Molina Pablo , Lorente-Pomar Ana Belén , Palau Gomar Ana , Hevilla Cucarella Enrique Bdo. , Blasco José-María , Gomis-Baldoví Sonia
Published: May 2024

The management of nursing care regarding patients’ vascular access is a priority. This study determines the contribution of the variables involved in the quality of care and maintenance of vascular access (VA) devices in admitted patients in the Valencian Community. Methods: Using the STROBE statement, an observational, cross-sectional study was conducted on 1576 VA devices. Data were collected using the INCATIV Questionnaire. We performed a multivariate analysis of the questionnaire variables. Results: In total, 50% had a good or very good assessment of the VA condition. This was positively correlated with anatomical location, dressing type, dressing date record, use of needle-free connectors (NFCs), date of last dressing change, presence of phlebitis, visibility of the insertion site and characteristics of the dressing’s condition (p < 0.001). The model indicated that the presence of phlebitis was the clearest predictor of a poor VA care assessment (OR = 20.579), followed by no visibility of the insertion site (OR = 14.209). Results also indicated that uncovered VA lumens or no NFCs used were related to a negative quality assessment. Conclusion: By managing and controlling these variables, the likelihood of providing optimal care is ensured. This enables the establishment of a standardised care approach for all nursing professionals and the building of a new quality indicator.
When Infections Are Found: A Qualitative Study Characterizing Best Management Practices for Central Line-Associated Bloodstream Infection and Catheter-Associated Urinary Tract Infection Performance Monitoring and Feedback
Authors: Gaughan Alice A. , MacEwan Sarah R. , Gregory Megan E. , Eramo Jennifer L. , Rush Laura J. , Hebert Courtney L. , McAlearney Ann Scheck
Published: May 2024

Healthcare-associated infections (HAIs) remain a significant patient safety problem that can lead to illness and death, despite the implementation of clinical bundles to prevent HAIs. Management practices can support HAI prevention, but their role in HAI performance monitoring and feedback is not well understood. To address this knowledge gap, we previously conducted semi-structured interviews with staff at 18 hospitals to examine the role of management practices around the prevention of central line-associated bloodstream infections (CLABSIs) and catheter-associated urinary tract infections (CAUTIs). Interview transcripts were analyzed to identify themes related to HAI performance monitoring and feedback. The current analysis focuses on 10 higher-performing hospitals that were successful in preventing CLABSIs and CAUTIs. These institutions had robust practices including timely event analysis, leadership engagement, and multidisciplinary participation in HAI reviews. Across these sites, we found common goals including investigating HAIs without blame and identifying opportunities for improvement. Management practices such as timely analysis of HAIs, collaboration between facility leadership and multidisciplinary team members, and a focus on identifying the failure of a procedure or protocol, rather than the failure of staff members, are all approaches that can support infection prevention efforts. These management practices may be especially important as hospitals attempt to address increases in CLABSI and CAUTI rates that may have occurred during the coronavirus pandemic.
Analysis of Knowledge and Satisfaction in Virtual Clinical Simulation among Nursing Students: A Mixed Study
Authors: Medel Daniel , Reguant Mercedes , Cemeli Tània , Jiménez Herrera María , Campoy Carme , Bonet Aida , Sanromà-Ortíz Montserrat , Roca Judith
Published: May 2024

Virtual simulation offers a powerful educational tool with considerable, albeit underexplored potential. This technology immerses students in lifelike digital scenarios, fostering the acquisition of knowledge and skills necessary for their future careers. This study aimed to assess knowledge acquisition and satisfaction outcomes among students using a virtual simulation teaching approach. The specific objectives were (1) to compare pre-and posttest knowledge acquisition, (2) to investigate the influence of prior professional experience on knowledge, and (3) to explore satisfaction levels with virtual simulation. One hundred and fifty-nine nursing students participated in a virtual simulation-based clinical intervention, entailing the resolution of a virtual adult patient hospitalized with respiratory pathology. Sociodemographic data and prior professional experience were collected, and knowledge was evaluated through pre-to-post tests. Satisfaction levels were assessed using open-ended questions. Quantitative data were analyzed using descriptive statistics, Wilcoxon, Mann–Whitney U, and Cohen’s tests, while qualitative data underwent keyword-in-context analysis. Significant differences were noted between pre- and posttest knowledge levels, with prior experience showing no significant impact on knowledge acquisition. Participants reported high levels of satisfaction. Lexicometric analysis identified four clusters of words related to the key terms “simulation”, “learn”, “activity”, and “knowledge”. Virtual clinical simulation effectively enhances knowledge acquisition and fosters satisfaction, with students recognizing the positive impact of this approach on their learning. Consequently, virtual simulation contributes to the training of competent health professionals.
Can Music Reduce Stress and Anxiety in the Operating Room Team? Insights from a Cross-Sectional Study in Northern Italy Healthcare Services
Authors: Rubbi Ivan , Roveri Anna , Pasquinelli Gianandrea , Cadas Claudia , Carvello Maicol , Lupo Roberto , Vitale Elsa , Di Lorenzo Petia , Sangiorgi Nicola , Conte Luana , Cremonini Valeria
Published: May 2024

Background. Music evokes positive emotions and reduces stress and anxiety. Operating room (OR) staff face various challenges which can lead to high levels of stress. The aim of the study is to assess whether listening to music during intraoperative phases improves the work environment by reducing anxiety and stress in the entire surgical team. Methods. A prospective observational study was conducted from February to September 2023, involving medical personnel, nursing staff, and nursing students. They were divided into two groups: Group 1 with music during surgical procedures, and Group 2 without music. Participants were administered two validated instruments: the Zung Anxiety Self-Assessment Scale (SAS) to measure anxiety, and the Positive and Negative Affect Schedule to assess emotions generating stress. Additional items were included for demographics, job satisfaction, and the organization method. Results. Music did not impact anxiety, but increased positive emotions while reducing negative ones. Music had an ancillary effect, highlighting the need for significant organizational interventions aimed at increasing operator satisfaction, including offering voluntary instead of mandatory assignments to nursing staff. Conclusions. Music appears to reduce stress in the intraoperative team when supported by a positive work environment in which assigned operators have chosen to work in the OR.
Primary Health Care Case-Management Nurses during the COVID-19 Pandemic: A Qualitative Study
Authors: Molina-Gil María José , Guerra-Martín María Dolores , Diego-Cordero Rocío De
Published: May 2024

The COVID-19 has caused high morbidity and mortality in vulnerable people, such as those affected by chronic diseases, and case-management nurses (CMNs) are reference professionals for their health care and management. The objective of this study is to better understand the discourse, experiences, and feelings about the professional performance of CMNs during the pandemic. A qualitative study was conducted by conducting semi-structured interviews with CMNs (n = 31) from the province of Seville (Spain) and performing a narrative discourse analysis. The Atlas Ti 6.2 software program was used. Two categories were defined: 1. CMNs’ competencies (76 verbatim testimonies); and 2. Consequences of the COVID-19 pandemic (61 verbatim testimonies). This study was granted due permission by the Research Ethics Committee belonging to the University of Seville, under protocol code: 1139-N-22. The pandemic caused an increase in CMNs’ workload, and they had to assume their usual care tasks for vulnerable populations in addition to simultaneously prioritizing assistance in nursing homes. We can highlight CMNs’ adaptation to the pandemic situation and to these new requirements in the context of their significant social commitment to the advanced practice of the profession, a commitment that is closely related to leadership. We should also indicate that interpersonal relationships were improved, and that there was technological progress. Some CMNs mentioned an increase in their workload and reported experiencing burnout syndrome. We conclude that CMNs’ management of health care during the pandemic has been extraordinary, especially in regard to the most vulnerable populations of patients, including individuals with chronic diseases and institutionalized older adults, a fact that has been valued by the institutions and by society in general.
Impact of Artificial Intelligence on Nursing Students’ Attitudes toward Older Adults: A Pre/Post-Study
Authors: White Anne , Maguire Mary Beth , Brown Austin , Keen Diane
Published: May 2024

As the global population ages, nurses with a positive attitude toward caring for older adults is crucial. However, studies indicate that nursing students often exhibit negative attitudes toward older adults. This study aimed to determine if a three-phased educational intervention significantly improved nursing students’ attitudes toward older adults. A pre/post-test study design was used to measure the change in nursing students’ attitudes toward older adults, as measured by the UCLA Geriatrics Attitudes Survey, after participating in an Artificial Intelligence in Education learning event (n = 151). Results indicate that post-intervention scores (M = 35.07, SD = 5.34) increased from pre-intervention scores (M = 34.50, SD = 4.86). This difference was statistically significant at the 0.10 significance level (t = 1.88, p = 0.06). Incorporating artificial intelligence technology in a learning event is an effective educational strategy due to its convenience, repetition, and measurable learning outcomes. Improved attitudes toward older adults are foundational for delivering competent care to a rapidly growing aging population. This study was prospectively registered with the university’s Institutional Review Board (IRB) on 30 July 2021 with the registration number IRB-FY22-3.
Comparative Analysis of Dental Health Outcomes from Two Outreach Camps in Zanzibar, Tanzania: 2019 and 2023
Authors: Al Harthy Nutayla , Al Ismaili Mohammed , Qutieshat Abubaker
Published: May 2024

Background: In low- and middle-income countries, oral health is frequently marginalized due to limited dental care access. This cross-sectional study assesses the outcomes of dental outreach camps in Zanzibar, Tanzania, organized in 2019 and 2023, to understand their impact on addressing local oral health needs over a four-year span. Methods: The study involved a thorough examination and analysis of clinical dental health data from both outreach camps. In 2019, 224 patients were examined, and in 2023, the number increased to 354. The assessment covered various dental health parameters, including dental caries, DMFT/dmft indices, enamel fluorosis, dental trauma, oral mucosa lesions, and non-carious tooth surface loss. Results: The analysis demonstrated a significant reduction in dental caries among adolescents and teens, decreasing from 62.5% in 2019 to 35.59% in 2023 (p < 0.0001). Similarly, the prevalence of teeth missing due to caries showed marked reductions from 40.2% to 9.04% in adolescents and teens (p < 0.0001) and from 25.89% to 11.86% among preschool and school-aged children (p = 0.004). Moreover, a significant change was observed in the Basic Erosive Wear Examination (BEWE) scores, with cases showing no erosive tooth wear (BEWE = 0) decreasing from 49.1% to 33.3% (p = 0.016), and cases with initial loss of enamel surface texture (BEWE = 1) increasing from 47.3% to 61% (p = 0.044). Conclusions: The outreach camps conducted in 2019 and 2023 showed tangible improvements in certain dental health metrics, particularly a reduction in dental caries and missing teeth due to caries among adolescents and teens. However, the uptick in non-carious tooth surface loss points to emerging dental health concerns. These results underline the importance of sustained and targeted dental health interventions to improve oral health outcomes in underserved communities such as Zanzibar.
Seroprevalence of Toxoplasma gondii among HIV Positive Patients under Surveillance in Greek Infectious Disease Units: A Screening Study with Comparative Evaluation of Serological Methods
Authors: Voyiatzaki Chrysa , Zare Chormizi Apollon Dareios , Tsoumani Maria E. , Efstathiou Antonia , Konstantinidis Konstantinos , Chaniotis Dimitrios , Chrysos Georgios , Argyraki Aikaterini , Papastamopoulos Vasileios , Kotsianopoulou Marika
Published: May 2024

This study aims to screen for IgG antibodies against Toxoplasma gondii (T. gondii) in the sera of 155 newly diagnosed Human Immunodeficiency Virus (HIV) positive patients under surveillance in Greek Infectious Disease Units. Additionally, risk factors based on patient demographics were examined, and a comparative evaluation of commercially available serological methods was conducted. Three methods were employed to detect IgG antibodies against T. gondii: Enzyme-Linked Immunosorbent Assay (ELISA), Indirect Immunofluorescence Antibody Test (IFAT), and Western Blot (WB), which was used as a reference here. Forty-nine sera samples were true-positive for IgG antibodies against T. gondii, resulting in a 31.61% positivity rate, and the immunoassay test statistical reliability analysis resulted in higher IFAT accuracy (90.97%) compared to ELISA (76.26%). Furthermore, statistical analysis of demographic and immunological data included in the study placed female and foreign/non-Greek individuals at 2.24 (p = 0.0009) and 2.34 (p = 0.0006) times higher risk of positive T. gondii IgG testing compared to their male and Greek counterparts, respectively. Our findings on positivity rates and comparative serology underscore the importance of early and suitable screening measures for newly diagnosed HIV+ patients to mitigate the life-threatening outcomes that may arise from a potential subsequent T. gondii activation.
Involvement of Inflammatory Cytokines, Renal NaPi-IIa Cotransporter, and TRAIL Induced-Apoptosis in Experimental Malaria-Associated Acute Kidney Injury
Authors: Simião Gustavo Martins , Parreira Kleber Simônio , Klein Sandra Gabriela , Ferreira Flávia Batista , Freitas Fernanda de Souza , Silva Eduardo Ferreira da , Silva Neide Maria , Silva Murilo Vieira da , Lima Wânia Rezende
Published: May 2024

The murine model of experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA was used to investigate the relationship among pro-inflammatory cytokines, alterations in renal function biomarkers, and the induction of the TRAIL apoptosis pathway during malaria-associated acute kidney injury (AKI). Renal function was evaluated through the measurement of plasma creatinine and blood urea nitrogen (BUN). The mRNA expression of several cytokines and NaPi-IIa was quantified. Kidney sections were examined and cytokine levels were assessed using cytometric bead array (CBA) assays. The presence of glomerular IgG deposits and apoptosis-related proteins were investigated using in situ immunofluorescence assays and quantitative real-time PCR, respectively. NaPi-IIa downregulation in the kidneys provided novel insights into the pathogenesis of hypophosphatemia during CM. Histopathological analysis revealed characteristic features of severe malaria-associated nephritis, including glomerular collapse and tubular alterations. Pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, were upregulated. The TRAIL apoptosis pathway was significantly activated, implicating its role in renal apoptosis. The observed alterations in renal biomarkers and the downregulation of NaPi-IIa shed light on potential mechanisms contributing to renal dysfunction in ECM. The intricate balance between pro- and anti-inflammatory cytokines, along with the activation of the TRAIL apoptosis pathway, highlights the complexity of malaria-associated AKI and provides new therapeutic targets.
Polio Surge Capacity Support Program Contributions to Building Country Capacities in Support of Polio Outbreak Preparedness and Response: Lessons Learned and Remaining Challenges
Authors: Abebe Fikru , Eboh Victor Anochieboh , Weldetsadik Mesfin Belew , Kone Ibrahima , Kebede Tessema Assegid , Harries Paul Thomas , Diomande Veh Kesse Fabien
Published: May 2024

Despite coordinated efforts at global level, through the Global Polio Eradication Initiative (GPEI), poliomyelitis disease (Polio) is still a major public health issue. The wild poliovirus type-1 (WPV1) is still endemic in Afghanistan and Pakistan, and new circulations of the WPV1 were confirmed in southeast Africa in 2021, in Malawi and Mozambique. The circulating vaccine derived polioviruses (cVDPV) are also causing outbreaks worldwide. The Task Force for Global Health (TFGH)’s Polio Surge Capacity Support Program, established in 2019, is an effort to reinforce the existing partnership with the GPEI to strengthen countries’ capacities for polio outbreak preparedness and response. In four years, its coordinated efforts with GPEI partners have resulted in a remarkable improvement in the early detection of poliovirus circulation and reducing the missed children gaps in many countries. However, these encouraging results cannot hide an increasingly complex programmatic environment with numerous funding and operational challenges.
Post-Conization HPV Vaccination and Its Impact on Viral Status: A Retrospective Cohort Study in Troms and Finnmark, 2022
Authors: Rykkelid Marie , Wennberg Helga Marie , Richardsen Elin , Sørbye Sveinung Wergeland
Published: May 2024

Human papillomavirus (HPV) is associated with cellular changes in the cervix leading to cancer, which highlights the importance of vaccination in preventing HPV infections and subsequent cellular changes. Women undergoing the loop electrosurgical excision procedure (LEEP), a treatment for high-grade cervical intraepithelial neoplasia (CIN2+), remain at risk of recurrence. This study assessed the effect of post-conization HPV vaccination on the viral status of women at six months post-conization, aiming to evaluate the vaccine’s effectiveness in preventing recurrence of CIN2+. A retrospective cohort study was conducted among women in Troms and Finnmark who underwent conization in 2022. Using the SymPathy database and the national vaccination register (SYSVAK), we analyzed the vaccination statuses and HPV test results of women born before 1991, who had not received the HPV vaccine prior to conization. Out of 419 women undergoing conization, 243 met the inclusion criteria. A significant association was found between post-conization HPV vaccination and a negative HPV test at six months of follow-up (ARR = 12.1%, p = 0.039). Post-conization HPV vaccination significantly reduced the risk of a positive HPV test at the first follow-up, suggesting its potential in preventing the recurrence of high-grade cellular changes. However, the retrospective design and the insufficient control of confounding variables in this study underscore the need for further studies to confirm these findings.
Structural Modification and Optimisation of Hyperoside Oriented to Inhibit TGF-β-Induced EMT Activity in Alveolar Epithelial Cells
Authors: Gao Ziye , Xu Mengzhen , Liu Chuanguo , Gong Kai , Yu Xin , Lu Kaihui , Zhu Jiang , Guan Haixing , Zhu Qingjun
Published: May 2024

Pulmonary fibrosis (PF) is a disease characterised by diffuse nonspecific alveolar inflammation with interstitial fibrosis, which clinically manifests as dyspnoea and a significant decline in lung function. Many studies have shown that the epithelial–mesenchymal transition (EMT) plays a pivotal role in the pathogenesis of pulmonary fibrosis. Based on our previous findings, hypericin (Hyp) can effectively inhibit the process of the EMT to attenuate lung fibrosis. Therefore, a series of hyperoside derivatives were synthesised via modifying the structure of hyperoside, and subsequently evaluated for A549 cytotoxicity. Among these, the pre-screening of eight derivatives inhibits the EMT. In this study, we evaluated the efficacy of Z6, the most promising hyperoside derivative, in reversing TGF-β1-induced EMTs and inhibiting the EMT-associated migration of A549 cells. After the treatment of A549 cells with Z6 for 48 h, RT-qPCR and Western blot results showed that Z6 inhibited TGF-β1-induced EMTs in epithelial cells by supressing morphological changes in A549 cells, up-regulating E-cadherin (p < 0.01, p < 0.001), and down-regulating Vimentin (p < 0.01, p < 0.001). This treatment significantly reduced the mobility of transforming growth factor β1 (TGF-β1)-stimulated cells (p < 0.001) as assessed by wound closure, while increasing the adhesion rate of A549 cells (p < 0.001). In conclusion, our results suggest that hyperoside derivatives, especially compound Z6, are promising as potential lead compounds for treating pulmonary fibrosis, and therefore deserve further investigation.
Hydrogen Sulfide Delivery to Enhance Bone Tissue Engineering Cell Survival
Authors: Ali Akbari Ghavimi Soheila , Faulkner Trent J. , Tata Rama Rao , Hemmerla August J. , Huddleston Samantha E. , Rezaei Farnoushsadat , Lungren Ethan S. , Zhang Rui , Bumann Erin E. , Ulery Bret D.
Published: May 2024

Though crucial for natural bone healing, local calcium ion (Ca2+) and phosphate ion (Pi) concentrations can exceed the cytotoxic limit leading to mitochondrial overload, oxidative stress, and cell death. For bone tissue engineering applications, H2S can be employed as a cytoprotective molecule to enhance mesenchymal stem cell (MSC) tolerance to cytotoxic Ca2+/Pi concentrations. Varied concentrations of sodium hydrogen sulfide (NaSH), a fast-releasing H2S donor, were applied to assess the influence of H2S on MSC proliferation. The results suggested a toxicity limit of 4 mM for NaSH and that 1 mM of NaSH could improve cell proliferation and differentiation in the presence of cytotoxic levels of Ca2+ (32 mM) and/or Pi (16 mM). To controllably deliver H2S over time, a novel donor molecule (thioglutamic acid—GluSH) was synthesized and evaluated for its H2S release profile. Excitingly, GluSH successfully maintained cytoprotective level of H2S over 7 days. Furthermore, MSCs exposed to cytotoxic Ca2+/Pi concentrations in the presence of GluSH were able to thrive and differentiate into osteoblasts. These findings suggest that the incorporation of a sustained H2S donor such as GluSH into CaP-based bone graft substitutes can facilitate considerable cytoprotection, making it an attractive option for complex bone regenerative engineering applications.
Distinguishing Molecular Properties of OAT, OATP, and MRP Drug Substrates by Machine Learning
Authors: Nigam Anisha K. , Momper Jeremiah D. , Ojha Anupam Anand , Nigam Sanjay K.
Published: May 2024

The movement of organic anionic drugs across cell membranes is partly governed by interactions with SLC and ABC transporters in the intestine, liver, kidney, blood–brain barrier, placenta, breast, and other tissues. Major transporters involved include organic anion transporters (OATs, SLC22 family), organic anion transporting polypeptides (OATPs, SLCO family), and multidrug resistance proteins (MRPs, ABCC family). However, the sets of molecular properties of drugs that are necessary for interactions with OATs (OAT1, OAT3) vs. OATPs (OATP1B1, OATP1B3) vs. MRPs (MRP2, MRP4) are not well-understood. Defining these molecular properties is necessary for a better understanding of drug and metabolite handling across the gut–liver–kidney axis, gut–brain axis, and other multi-organ axes. It is also useful for tissue targeting of small molecule drugs and predicting drug–drug interactions and drug–metabolite interactions. Here, we curated a database of drugs shown to interact with these transporters in vitro and used chemoinformatic approaches to describe their molecular properties. We then sought to define sets of molecular properties that distinguish drugs interacting with OATs, OATPs, and MRPs in binary classifications using machine learning and artificial intelligence approaches. We identified sets of key molecular properties (e.g., rotatable bond count, lipophilicity, number of ringed structures) for classifying OATs vs. MRPs and OATs vs. OATPs. However, sets of molecular properties differentiating OATP vs. MRP substrates were less evident, as drugs interacting with MRP2 and MRP4 do not form a tight group owing to differing hydrophobicity and molecular complexity for interactions with the two transporters. If the results also hold for endogenous metabolites, they may deepen our knowledge of organ crosstalk, as described in the Remote Sensing and Signaling Theory. The results also provide a molecular basis for understanding how small organic molecules differentially interact with OATs, OATPs, and MRPs.
Targeted Thrombolysis with Magnetic Nanotherapeutics: A Translational Assessment
Authors: Lin Ming-Lu , Wu Siao-Yun , Chen Jyh-Ping , Lu Yi-Ching , Jung Shih-Ming , Wey Shiaw-Pyng , Wu Tony , Ma Yunn-Hwa
Published: May 2024

Plasminogen activators, such as recombinant tissue-type plasminogen activators (rtPAs), while effective in treating thromboembolic diseases, often induce hemorrhagic complications due to non-specific enzyme activities in the systemic circulation. This study evaluated the targeting efficiency, efficacy, biodistribution, and potential toxicity of a rtPA covalently attached to chitosan-coated magnetic nanoparticles (chitosan-MNP-rtPA). The thrombolytic activity of a chitosan-MNP-rtPA was preserved by protection from an endogenous plasminogen activator inhibitor-1 (PAI-1) in whole blood and after circulation in vivo, as examined by thromboelastometry. Single-photon emission computed tomography (SPECT) demonstrated real-time retention of a 99mTc-MNP-rtPA induced by magnet application in a rat embolic model; an 80% reduction in rtPA dosage for a chitosan-MNP-rtPA with magnetic guidance was shown to restore blood flow. After treatment, iron deposition was observed in the reticuloendothelial systems, with portal edema and neutrophil infiltration in the liver at a ten-fold higher dose but not the regular dose. Nevertheless, no liver or renal toxicity was observed at this higher dose. In conclusion, the liver may still be the major deposit site of rtPA nanocomposites after targeted delivery; chitosan-coated MNPs are potentially amenable to target therapeutics with parenteral administration.
Linseed Oil-Based Oleogel Vehicles for Hydrophobic Drug Delivery—Physicochemical and Applicative Properties
Authors: Kudłacik-Kramarczyk Sonia , Drabczyk Anna , Przybyłowicz Alicja , Krzan Marcel
Published: May 2024

In this study, a methodology for synthesizing oleogels based on linseed oil and emulsifiers, such as beeswax and Tween 20 and Tween 80, was developed. Linseed oil served as the main oil phase, while beeswax acted as a gelling and emulsifying agent. Tween compounds are non-ionic surfactants composed of hydrophobic and hydrophilic parts, allowing for the formation of a stable system with promising properties. Surface wetting analysis of the obtained oleogels, FT-IR spectroscopy, and determination of relative and absolute humidity over time, as well as optical microscope analysis and rheological analysis of the obtained oleogels, were conducted as part of the research. The results indicate that increasing the amount of Tween 20 decreases the hydrophilicity of the oleogel, while Tween 80 exhibits the opposite effect. Surface energy analysis suggests that a higher content of Tween 20 may lead to a reduction in the surface energy of the oleogels, which may indicate greater material stability. Changes in relative humidity and FT-IR spectral analysis confirm the influence of emulsifiers on the presence of characteristic functional groups in the structure of the oleogels. Additionally, microscopic analysis suggests that an emulsifier with a longer hydrophobic tail leads to a denser material structure.
Enhanced In Vitro Antiviral Activity of Ivermectin-Loaded Nanostructured Lipid Carriers against Porcine Epidemic Diarrhea Virus via Improved Intracellular Delivery
Authors: Xu Xiaolin , Gao Shasha , Zuo Qindan , Gong Jiahao , Song Xinhao , Liu Yongshi , Xiao Jing , Zhai Xiaofeng , Sun Haifeng , Zhang Mingzhi , Gao Xiuge , Guo Dawei
Published: May 2024

Porcine epidemic diarrhea virus (PEDV) is an acute enteric coronavirus, inducing watery diarrhea and high mortality in piglets, leading to huge economic losses in global pig industry. Ivermectin (IVM), an FDA-approved antiparasitic agent, is characterized by high efficacy and wide applicability. However, the poor bioavailability limits its application. Since the virus is parasitized inside the host cells, increasing the intracellular drug uptake can improve antiviral efficacy. Hence, we aimed to develop nanostructured lipid carriers (NLCs) to enhance the antiviral efficacy of IVM. The findings first revealed the capacity of IVM to inhibit the infectivity of PEDV by reducing viral replication with a certain direct inactivation effect. The as-prepared IVM-NLCs possessed hydrodynamic diameter of 153.5 nm with a zeta potential of −31.5 mV and high encapsulation efficiency (95.72%) and drug loading (11.17%). IVM interacted with lipids and was enveloped in lipid carriers with an amorphous state. Furthermore, its encapsulation in NLCs could enhance drug internalization. Meanwhile, IVM-NLCs inhibited PEDV proliferation by up to three orders of magnitude in terms of viral RNA copies, impeding the accumulation of reactive oxygen species and mitigating the mitochondrial dysfunction caused by PEDV infection. Moreover, IVM-NLCs markedly decreased the apoptosis rate of PEDV-induced Vero cells. Hence, IVM-NLCs showed superior inhibitory effect against PEDV compared to free IVM. Together, these results implied that NLCs is an efficient delivery system for IVM to improve its antiviral efficacy against PEDV via enhanced intracellular uptake.
A Sensitive Assay for Unbound Docetaxel Using Ultrafiltration plus HPLC-MS and Its Application to a Clinical Study
Authors: Wang David , Hughes-Medlicott Natalie , Klingler Lilian , Wang Yi , Hung Noelyn , Duffull Stephen , Hung Tak , Glue Paul , Qin Albert , Kwan Rudolf , Chan Wing-Kai , Jackson Christopher
Published: May 2024

Introduction: Docetaxel, a taxane used in the treatment of solid tumours, exerts pharmacological activity when in its unbound form. We report a sensitive assay to quantify unbound docetaxel after oral administration of docetaxel plus encequidar (oDox+E). Unbound drug quantification is important due to its direct correlation with drug-related toxicity and therapeutic efficacy. We improve on the sensitivity of current assay methods and demonstrate the utility of the assay on a novel formulation of oral docetaxel. Methods: Ultrafiltration followed by high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS) was utilized. Long-term stability, precision, accuracy, and recovery experiments were conducted to validate the assay. Additionally, patient samples from a Phase I dose-escalation pharmacokinetic study were analyzed using the developed assay. Results: The assay method exhibited long-term stability with an observed change between 0.8 and 6.9% after 131 days of storage at −60 °C. Precision and accuracy quality controls met the FDA acceptance criteria. An average recovery of 88% was obtained. Patient sample analysis demonstrated successful implementation of the assay. Conclusion: A validated sensitive assay was developed with an LLOQ of 0.084 ng/mL using 485 µL of human plasma. The sensitivity of the assay allowed quantification of unbound docetaxel concentrations in an early-phase oDox+E clinical study to compare it against IV docetaxel using pharmacokinetic modelling. Successful development of oDox+E represents an opportunity to replace the current IV docetaxel regimen with an oral regimen with lower cost, decreased side effects, and improve patient quality of life and experience.
Again and Again—Survival of Candida albicans in Urine Containing Antifungals
Authors: Facchini Nevio , Wernli Lukas , Rieken Malte , Bonkat Gernot , Wirz Dieter , Braissant Olivier
Published: May 2024

Background: Relapse of Candida albicans urinary tract infection (UTI) is frequent despite appropriate treatment, as commonly used antifungals such fluconazole and flucytosine are only fungistatics. To improve treatment of Candida UTI and decrease relapses, understanding the long-term metabolic activity and survival of C. albicans in urine containing antifungals at minimal inhibitory concentration (MIC) is needed. Methods: we monitored the survival, metabolic activity and consumption of glucose and proteins by C. albicans using conventional methods and isothermal microcalorimetry (IMC). We also investigated the influence of dead Candida cells on the growth of their living counterparts. Results: For 33 days, weak activity was observed in samples containing antifungals in which C. albicans growth rate was reduced by 48%, 60% and 88%, and the lag increased to 172 h, 168 h and 6 h for amphotericin, flucytosine and fluconazole, respectively. The metabolic activity peaks corresponded to the plate counts but were delayed compared to the exhaustion of resources. The presence of dead cells promoted growth in artificial urine, increasing growth rate and reducing lag in similar proportions. Conclusions: Even with antifungal treatment, C. albicans relapses are possible. The low metabolic activity of surviving cells leading to regrowth and chlamydospore formation possibly supported by autophagy are likely important factors in relapses.
Valorisation of Raspberry Seeds in Cosmetic Industry-Green Solutions
Authors: Ćirić Ivanka , Dabić Zagorac Dragana , Sredojević Milica , Fotirić Akšić Milica , Rabrenović Biljana , Blagojević Stevan , Natić Maja
Published: May 2024

The fruit processing industry generates large quantities of by-products well known to be rich in bioactive compounds with numerous nutritional properties and beneficial effects for human health. We developed a strategy to valorise raspberry seeds and obtain valuable ingredients with potential application in cosmetic skincare formulas. Cold press extraction technology was applied to extract oil, and the remaining defatted raspberry seed cake was treated with three proline based deep eutectic solvents (DES) to extract polyphenols. The most potent was proline/citric acid extract, with free and total ellagic acid content (52.4 mg/L and 86.4 mg/L), total phenolic content (TPC, 550.1 mg GAE/L) and radical scavenging activity (RSA, 4742.7 mmol TE/L). After the direct mixing of the extract and after encapsulation with starch as a carrier, the skincare emulsion and microemulsion were characterised by irritation potential (Zein test), transepidermal water loss (TEWL), red blood cell (RBC), and DPPH antioxidant test. The resulting preparations were of improved quality in comparison to the control hand cream, with a low skin irritation effect, lower TEWL, and higher antioxidant potential. This work complies with circular economy principles and green technology standards, and represents the efficient model on how to reuse natural resources through waste minimization.
In Vitro Human Liver Model for Toxicity Assessment with Clinical and Preclinical Instrumentation
Authors: Madorran Eneko , Kocbek Šaherl Lidija , Rakuša Mateja , Munda Miha
Published: May 2024

The existing in vitro toxicological models lack translational potential, which makes difficult the application of gathered information to clinical usage. To tackle this issue, we built a model with four different types of primary liver cells: hepatic sinusoidal endothelial cells, hepatic stellate cells, Kupffer cells and hepatocytes. We cultured them in different combinations of composition and volumes of cell medium, hepatocyte proportions of total cells and additions of extracellular matrixes. We added rifampicin (RIF), ibuprofen (IBU) and 5-fluorouracil (5-FU) to this model and observed the microanatomy and physiology changes for a week with preclinical and clinical instruments. Among the different model configurations, we selected the feature combination of the in vitro model that had similar biomarker values to those measured in clinical diagnostics. When we exposed the selected model configuration to RIF, IBU and 5-FU, we observed similar glucose, triglyceride and albumin dynamics as in vivo (from clinical data). Therefore, we have built an in vitro liver model that resembles the liver microenvironment, and we have analysed it with clinical instrumentation to facilitate data translation. Furthermore, during these observations, we found that Kupffer and LSEC cells are suitable candidates for the search for clinical diagnostic markers of liver function.
Biological Response Following the Systemic Injection of PEG–PAMAM–Rhodamine Conjugates in Zebrafish
Authors: Custódio Beatriz , Carneiro Patrícia , Marques Joana , Leiro Victoria , Valentim Ana M. , Sousa Mafalda , Santos Sofia D. , Bessa José , Pêgo Ana P.
Published: May 2024

Numerous therapeutic and diagnostic approaches used within a clinical setting depend on the administration of compounds via systemic delivery. Biomaterials at the nanometer scale, as dendrimers, act as delivery systems by improving cargo bioavailability, circulation time, and the targeting of specific tissues. Although evaluating the efficacy of pharmacological agents based on nanobiomaterials is crucial, conducting toxicological assessments of biomaterials is essential for advancing clinical translation. Here, a zebrafish larvae model was explored to assess the biocompatibility of poly(amido amine) (PAMAM), one of the most exploited dendrimers for drug delivery. We report the impact of a systemic injection of polyethylene glycol (PEG)-modified G4 PAMAM conjugated with rhodamine (Rho) as a mimetic drug (PEG–PAMAM–Rho) on survival, animal development, inflammation, and neurotoxicity. A concentration- and time-dependent effect was observed on mortality, developmental morphology, and innate immune system activation (macrophages). Significant effects in toxicological indicators were reported in the highest tested concentration (50 mg/mL PEG–PAMAM–Rho) as early as 48 h post-injection. Additionally, a lower concentration of PEG–PAMAM–Rho (5 mg/mL) was found to be safe and subsequently tested for neurotoxicity through behavioral assays. In accordance, no significative signs of toxicity were detected. In conclusion, the dose response of the animal was assessed, and the safe dosage for future use in theragnostics was defined. Additionally, new methodologies were established that can be adapted to further studies in toxicology using other nanosystems for systemic delivery.
Antibacterial Effect of Ozone on Cariogenic Bacteria and Its Potential Prejudicial Effect on Dentin Bond Strength—An In Vitro Study
Authors: Santos Marta , Leandro Flávia , Barroso Helena , Delgado António H. S. , Proença Luís , Polido Mário , Vasconcelos e Cruz Joana
Published: May 2024

Ozone is increasingly utilized in dental caries treatment due to its antibacterial properties. In a context of limited studies and no consensus on protocols, this research aims to assess ozone’s antibacterial efficacy on cariogenic bacteria and its potential adverse impact on dentin bond strength. Streptococcus mutans, Streptococcus sobrinus, Lactobacillus casei, and Actinomyces naeslundii suspensions were exposed to 40 μg/mL of ozone gas and 60 μg/mL of ozonated water (80 s) via a medical ozone generator. Negative and positive control groups (chlorhexidine 2%) were included, and UFC/mL counts were recorded. To examine microtensile bond strength (µTBS), 20 human molars were divided into four groups, and class I cavities were created. After ozone application, samples were restored using an etch-and-rinse and resin composite, then sectioned for testing. The SPSS v. 28 program was used with a significance level of 5%. The µTBS results were evaluated using one-way ANOVA, Tukey HSD, and Games-Howell. Bacterial counts reduced from 106 to 101, but dentin µTBS was significantly impacted by ozone (ANOVA, p < 0.001). Despite ozone’s attractive antibacterial activity, this study emphasizes its detrimental effect on dentin adhesion, cautioning against its use before restorative treatments.
Organ-on-a-Chip: Ubi sumus? Fundamentals and Design Aspects
Authors: Morais Ana Sofia , Mendes Maria , Cordeiro Marta Agostinho , Sousa João J. , Pais Alberto Canelas , Mihăilă Silvia M. , Vitorino Carla
Published: May 2024

This review outlines the evolutionary journey from traditional two-dimensional (2D) cell culture to the revolutionary field of organ-on-a-chip technology. Organ-on-a-chip technology integrates microfluidic systems to mimic the complex physiological environments of human organs, surpassing the limitations of conventional 2D cultures. This evolution has opened new possibilities for understanding cell–cell interactions, cellular responses, drug screening, and disease modeling. However, the design and manufacture of microchips significantly influence their functionality, reliability, and applicability to different biomedical applications. Therefore, it is important to carefully consider design parameters, including the number of channels (single, double, or multi-channels), the channel shape, and the biological context. Simultaneously, the selection of appropriate materials compatible with the cells and fabrication methods optimize the chips’ capabilities for specific applications, mitigating some disadvantages associated with these systems. Furthermore, the success of organ-on-a-chip platforms greatly depends on the careful selection and utilization of cell resources. Advances in stem cell technology and tissue engineering have contributed to the availability of diverse cell sources, facilitating the development of more accurate and reliable organ-on-a-chip models. In conclusion, a holistic perspective of in vitro cellular modeling is provided, highlighting the integration of microfluidic technology and meticulous chip design, which play a pivotal role in replicating organ-specific microenvironments. At the same time, the sensible use of cell resources ensures the fidelity and applicability of these innovative platforms in several biomedical applications.
Contemporary Natural Philosophy and Philosophies—Part 3
Authors: Dodig-Crnkovic Gordana , Schroeder Marcin J.
Published: May 2024

In 2018, we initiated a series of three Special Issues dedicated to contemporary natural philosophy in the spirit of the goals of the journal Philosophies (See Appendix A and Appendix B) [...]