bluuebunny/crossref_metadata_2025 huggingface dataset:
Design and Synthesis of P(AAm-co-NaAMPS)-Alginate-Xanthan Hydrogels and the Study of Their Mechanical and Rheological Properties in Artificial Vascular Graft Applications
Authors: Li Zhutong , Giarto Joshua , Zhang Jue , Gim Jinsu , Chen Edward , Enriquez Eduardo , Jafuta Lauren , Mahalingam Esha , Turng Lih-Sheng
Published: May 2024

Cardiovascular diseases (CVDs) are the number one cause of mortality among non-communicable diseases worldwide. Expanded polytetrafluoroethylene (ePTFE) is a widely used material for making artificial vascular grafts to treat CVDs; however, its application in small-diameter vascular grafts is limited by the issues of thrombosis formation and intimal hyperplasia. This paper presents a novel approach that integrates a hydrogel layer on the lumen of ePTFE vascular grafts through mechanical interlocking to efficiently facilitate endothelialization and alleviate thrombosis and restenosis problems. This study investigated how various gel synthesis variables, including N,N’-Methylenebisacrylamide (MBAA), sodium alginate, and calcium sulfate (CaSO4), influence the mechanical and rheological properties of P(AAm-co-NaAMPS)-alginate-xanthan hydrogels intended for vascular graft applications. The findings obtained can provide valuable guidance for crafting hydrogels suitable for artificial vascular graft fabrication. The increased sodium alginate content leads to increased equilibrium swelling ratios, greater viscosity in hydrogel precursor solutions, and reduced transparency. Adding more CaSO4 decreases the swelling ratio of a hydrogel system, which offsets the increased swelling ratio caused by alginate. Increased MBAA in the hydrogel system enhances both the shear modulus and Young’s modulus while reducing the transparency of the hydrogel system and the pore size of freeze-dried samples. Overall, Hydrogel (6A12M) with 2.58 mg/mL CaSO4 was the optimal candidate for ePTFE–hydrogel vascular graft applications due to its smallest pore size, highest shear storage modulus and Young’s modulus, smallest swelling ratio, and a desirable precursor solution viscosity that facilitates fabrication.
Genotype–Phenotype Correlations in Alport Syndrome—A Single-Center Experience
Authors: Lujinschi Ștefan Nicolaie , Sorohan Bogdan Marian , Obrișcă Bogdan , Vrabie Alexandra , Lupușoru Gabriela , Achim Camelia , Andronesi Andreea Gabriella , Covic Andreea , Ismail Gener
Published: May 2024

Background: Alport syndrome (AS) is a common and heterogeneous genetic kidney disease, that often leads to end-stage kidney disease (ESKD). Methods: This is a single-center, retrospective study that included 36 adults with type IV collagen (COL4) mutations. Our main scope was to describe how genetic features influence renal survival. Results: A total of 24 different mutations were identified, of which eight had not been previously described. Mutations affecting each of the type IV collagen α chains were equally prevalent (33.3%). Most of the patients had pathogenic variants (61.1%). Most patients had a family history of kidney disease (71%). The most prevalent clinical picture was nephritic syndrome (64%). One-third of the subjects had extrarenal manifestations, 41.6% of patients had ESKD at referral, and another 8.3% developed ESKD during follow-up. The median renal survival was 42 years (95% CI, 29.98–54.01). The COL4A4 group displayed better renal survival than the COL4A3 group (p = 0.027). Patients with missense variants had higher renal survival (p = 0.023). Hearing loss was associated with lower renal survival (p < 0.001). Conclusions: Patients with COL4A4 variants and those with missense mutations had significantly better renal survival, whereas those with COL4A3 variants and those with hearing loss had worse prognoses.
Allegorical Vision: The Promotion of the Senses and the Vision of the Entendimiento in Calderón’s El cubo de la Almudena
Authors: Levinson Katerina J.
Published: May 2024

The following article examines the role of the sentidos and the entendimiento in Pedro Calderón de la Barca’s auto sacramental, El cubo de la Almudena. While scholarship recognises the pervasiveness of the play on the senses in early modern Spain, scholars often either deny or overemphasise the reliability of the senses as a means of truth acquisition. Moreover, scholarship often attaches too much weight to hearing, thus neglecting the role of the eyes of the entendimiento. Based on a Thomistic framework, Calderón demonstrates that the literal element of allegory relies on the active vehicle of the senses to serve as guides for the entendimiento and an entrance into devotion. Although hearing plays a central role in the play, it serves as a herald for sight, by which the devotee exercises faith. Moreover, where the sentidos prove limited, the entendimiento is an auxiliary support that makes up for their lack, seeing beyond sensual perception through faith. In this way, the medium of the auto sacramental and the theology of the Eucharist train the audience to use the vision of faith through both the senses and the entendimiento to see the allegorical meaning of the play, the divine nature of the Eucharist provided by Mary.
The Impact of Exercise on Interleukin-6 to Counteract Immunosenescence: Methodological Quality and Overview of Systematic Reviews
Authors: Reis Anne Sulivan Lopes da Silva , Furtado Guilherme Eustáquio , Menuchi Marcos Rodrigo Trindade Pinheiro , Borges Grasiely Faccin
Published: May 2024

Objective: This study evaluated the methodological quality of published systematic reviews on randomized and non-randomized clinical trials to synthesize evidence on the association between IL-6, immunosenescence, and aerobic and/or resistance exercise. Method: The Preferred Reporting Items for Overviews of Systematic Reviews (PRIO-harms) guideline was used, with registration number CRD42022346142-PROSPERO. Relevant databases such as Cochrane Library, PubMed, Web of Science, Scopus, and Google Scholar were searched using English Medical Subject Headings terms. Inclusion criteria were systematic reviews analyzing aerobic exercise, resistance exercise, or a combination of both and assessing IL-6 as a biomarker of cellular immunosenescence in humans. The Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2) was employed. Results: Out of 742 identified articles, 18 were eligible, and 13 were selected for analysis. Sample sizes ranged from 249 to 1421 participants, mostly female, with ages ranging from 17 to 95 years. Aerobic exercise was the most studied type (46.15%), followed by combined exercise (38.46%) and resistance exercise (15.38%). Aerobic exercise showed a statistically significant reduction in IL-6, C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α) levels. Among the 13 reviews analyzed using AMSTAR-2, 8 were rated as critically low quality, and 5 were classified as low quality. Conclusion: Aerobic exercise has anti-inflammatory properties and the potential to modulate IL-6, CRP, and TNF-α levels in immunosenescence. However, the limited methodological quality of the analyzed systematic reviews highlights the urgent need for robust, high-quality studies to improve access to information and facilitate evidence-based decision-making in healthcare.
The General Public and Young Adults’ Knowledge and Perception of Palliative Care: A Systematic Review
Authors: Batzler Yann-Nicolas , Schallenburger Manuela , Schwartz Jacqueline , Marazia Chantal , Neukirchen Martin
Published: May 2024

Background: As a result of demographic change, chronic and oncological diseases are gaining importance in the context of public health. Palliative care plays a crucial role in maintaining the quality of life of those affected. International guidelines demand access to palliative care not only for the elderly but also for younger people who face severe illnesses. It can be assumed that palliative care will become increasingly important for them. In order to develop public health strategies which are able to promote palliative care, it is important to assess the knowledge of, and attitude towards, palliative care as found among members of the general public and its specific target groups. In particular, little is known about young adults’ knowledge and perceptions of palliative care. Objectives and design: This work aimed to assess the understanding and viewpoints regarding palliative care among the general population and among young adults aged 18 to 24. We therefore conducted a systematic review, which, for this target population, could be seen as a novel approach. Methods: Exclusion and inclusion criteria were developed using the PICOS process. Literature was researched within MEDLINE (via PubMed), Google Scholar and Web of Science. A search string was developed and refined for all three databases. Grey literature was included. Duplicates were excluded using Mendeley. The literature was independently screened by two researchers. Narrative synthesis was used to answer the main research question. Results: For the general public, palliative care is still associated with death and dying and comforting sick people towards the end of their lives. Multiple social determinants are linked to better knowledge of palliative care: higher education, higher income, female gender, having relatives that received palliative care, and permanent employment. The population’s knowledge of palliative care structures increases, the longer such structures have been established within a country. Young adults are familiar with the term palliative care, yet their understanding lacks nuance. They associate palliative care with death and dying and perceive palliative care to be a medical discipline primarily for the elderly. Nevertheless, young adults demand participation within the planning of interventions to destigmatize palliative care. Conclusions: The general public still lacks a detailed understanding of palliative care. Palliative care faces stigma at multiple levels, which creates barriers for those who set out to implement it. However, addressing young adults as a crucial peer group can help break down barriers and promote access to palliative care.
Eco-Sustainability of Soils in Baby-Leaf Crop Systems under Tunnel through the Application of C-Rich Inputs: Towards Combating Soil Degradation
Authors: Picariello Enrica , Fornasier Flavio , Bilotto Maurizio , Mignoli Emiliana , Baiano Salvatore , Morra Luigi
Published: May 2024

Fresh-cut leafy vegetables are produced in Southern Italy in very intensive crop systems under tunnel greenhouses in which continuous cropping has triggered soil organic carbon (SOC) depletion and the risk of degradation of soil fertility. A two-year trial of soil organic amendment was carried out on a private farm producing baby-leaf crops on a very poor OC soil (<1%). Biowaste compost, two types of olive pomace composts and buffalo manure were compared to evaluate their ability to recover a positive SOC balance and sustain crop growth and yield. The effects on soil health and crop system were studied by measuring different aspects such as SOC stock change and SOC sequestration rate, soil microbial biomass and nine enzyme activities, yields of rocket and concentration of nitrates in leaves. Soil amendments were distributed once a year at doses of 15 and 30 Mg ha−1 as fresh matter without integration of mineral fertilizers. In our study, the SOC stock improved in the amended soils in a range of 4–6 Mg ha−1, except for dose 30 of buffalo manure, with the highest values where biowaste compost was applied. Our data showed an increase in biological parameters in all the amended soils with respect to Control. In soil amended with olive pomace, however, compost mineralization rates likely did not match crops’ nutrient needs so the yields of rocket were lower than with the biowaste compost and buffalo manure. Biowaste compost showed the best results as it balanced the best C conversion efficiency, the higher increment of SOC and yields of rocket.
The Impact of Genotype and Controlled Environment Cultivation Parameters on Tomato-Leaf-Derived Exosome-like Nanoparticle Yield and Properties
Authors: Viršilė Akvilė , Samuolienė Giedrė , Laužikė Kristina , Mikalauskienė Emilija , Balion Zbigniev , Jekabsone Aistė
Published: May 2024

Horticultural plant material offers several advantages for isolating exosomes and other natural plant-derived exosome-like nanoparticles (PDENs) due to the accessibility and affordability of plant material for widespread applications. This study aims to explore the impacts of the tomato genotype (‘Admiro’, ‘Roma’, ‘Brooklyn’, ‘Marmande’ and ‘Betalux’) and the main cultivation parameters in controlled environment agriculture on the yield and properties of their PDENs for pharmaceutical and cosmeceutical applications. The PDEN yield, size distribution, and antioxidative properties of young tomato seedlings were evaluated. The ‘Betalux’ tomato was distinguished by a remarkably higher nanoparticle concentration and a uniform size distribution and was selected for further experiments. The impact of cultivation temperature (18, 22, and 26 °C), nitrogen nutrition (0, 250, and 500 mg L−1), and the lighting photosynthetic photon flux density (PPFD; 150, 250, and 450 µmol m−2 s−1) on nanoparticle properties was investigated. Optimal conditions consisting of a temperature of 22 °C, 250 mg L−1 nitrogen nutrition, and 250 µmol m−2 s−1 lighting PPFD were used as a reference. Optimal temperature, nitrogen nutrition, and lighting intensity resulted in the highest nanoparticle yield, the most uniform particle distribution, and the highest impact of PDEN preparations on keratinocyte metabolic activity. Deviation from optimal cultivation conditions reduced the tomato biomass and the PDEN protein and yield.
Deflamin Attenuated Lung Tissue Damage in an Ozone-Induced COPD Murine Model by Regulating MMP-9 Catalytic Activity
Authors: Baltazar-García Elia Ana , Vargas-Guerrero Belinda , Lima Ana , Boavida Ferreira Ricardo , Mendoza-Magaña María Luisa , Ramírez-Herrera Mario Alberto , Baltazar-Díaz Tonatiuh Abimael , Domínguez-Rosales José Alfredo , Salazar-Montes Adriana María , Gurrola-Díaz Carmen Magdalena
Published: May 2024

Chronic obstructive pulmonary disease (COPD) is comprised of histopathological alterations such as pulmonary emphysema and peribronchial fibrosis. Matrix metalloproteinase 9 (MMP-9) is one of the key enzymes involved in both types of tissue remodeling during the development of lung damage. In recent studies, it was demonstrated that deflamin, a protein component extracted from Lupinus albus, markedly inhibits the catalytic activity of MMP-9 in experimental models of colon adenocarcinoma and ulcerative colitis. Therefore, in the present study, we investigated for the first time the biological effect of deflamin in a murine COPD model induced by chronic exposure to ozone. Ozone exposure was carried out in C57BL/6 mice twice a week for six weeks for 3 h each time, and the treated group was orally administered deflamin (20 mg/kg body weight) after each ozone exposure. The histological results showed that deflamin attenuated pulmonary emphysema and peribronchial fibrosis, as evidenced by H&E and Masson’s trichrome staining. Furthermore, deflamin administration significantly decreased MMP-9 activity, as assessed by fluorogenic substrate assay and gelatin zymography. Interestingly, bioinformatic analysis reveals a plausible interaction between deflamin and MMP-9. Collectively, our findings demonstrate the therapeutic potential of deflamin in a COPD murine model, and suggest that the attenuation of the development of lung tissue damage occurs by deflamin-regulated MMP-9 catalytic activity.
Vitamin Status in Patients with Phenylketonuria: A Systematic Review and Meta-Analysis
Authors: Bokayeva Kamila , Jamka Małgorzata , Walkowiak Dariusz , Duś-Żuchowska Monika , Herzig Karl-Heinz , Walkowiak Jarosław
Published: May 2024

The published data on the vitamin status of patients with phenylketonuria (PKU) is contradictory; therefore, this systematic review and meta-analysis evaluated the vitamin status of PKU patients. A comprehensive search of multiple databases (PubMed, Web of Sciences, Cochrane, and Scopus) was finished in March 2024. The included studies compared vitamin levels between individuals diagnosed with early-treated PKU and healthy controls while excluding pregnant and lactating women, untreated PKU or hyperphenylalaninemia cases, control groups receiving vitamin supplementation, PKU patients receiving tetrahydrobiopterin or pegvaliase, and conference abstracts. The risk of bias in the included studies was assessed by the Newcastle–Ottawa scale. The effect sizes were expressed as standardised mean differences. The calculation of effect sizes with 95% CI using fixed-effects models and random-effects models was performed. A p-value < 0.05 was considered statistically significant. The study protocol was registered in the PROSPERO database (CRD42024519589). Out of the initially identified 11,086 articles, 24 met the criteria. The total number of participants comprised 770 individuals with PKU and 2387 healthy controls. The meta-analyses of cross-sectional and case–control studies were conducted for vitamin B12, D, A, E, B6 and folate levels. PKU patients demonstrated significantly higher folate levels (random-effects model, SMD: 1.378, 95% CI: 0.436, 2.320, p = 0.004) and 1,25-dihydroxyvitamin D concentrations (random-effects model, SMD: 2.059, 95% CI: 0.250, 3.868, p = 0.026) compared to the controls. There were no significant differences in vitamin A, E, B6, B12 or 25-dihydroxyvitamin D levels. The main limitations of the evidence include a limited number of studies and their heterogeneity and variability in patients’ compliance. Our findings suggest that individuals with PKU under nutritional guidance can achieve a vitamin status comparable to that of healthy subjects. Our study provides valuable insights into the nutritional status of PKU patients, but further research is required to confirm these findings and explore additional factors influencing vitamin status in PKU.
Strength Training Protects High-Fat-Fed Ovariectomized Mice against Insulin Resistance and Hepatic Steatosis
Authors: Santos Jessica D. M. , Silva José F. T. , Alves Ester dos S. , Cruz Alessandra G. , Santos Anne R. M. , Camargo Felipe N. , Talarico Carlos H. Z. , Silva Carlos A. A. , Camporez João Paulo
Published: May 2024

Menopause is characterized by a reduction in sex hormones in women and is associated with metabolic changes, including fatty liver and insulin resistance. Lifestyle changes, including a balanced diet and physical exercise, are necessary to prevent these undesirable changes. Strength training (ST) has been widely used because of the muscle and metabolic benefits it provides. Our study aims to evaluate the effects of ST on hepatic steatosis and insulin resistance in ovariectomized mice fed a high-fat diet (HFD) divided into four groups as follows: simulated sedentary surgery (SHAM-SED), trained simulated surgery (SHAM-EXE), sedentary ovariectomy (OVX-SED), and trained ovariectomy (OVX-EXE). They were fed an HFD for 9 weeks. ST was performed thrice a week. ST efficiently reduced body weight and fat percentage and increased lean mass in OVX mice. Furthermore, ST reduced the accumulation of ectopic hepatic lipids, increased AMPK phosphorylation, and inhibited the de novo lipogenesis pathway. OVX-EXE mice also showed a better glycemic profile, associated with greater insulin sensitivity identified by the euglycemic–hyperinsulinemic clamp, and reduced markers of hepatic oxidative stress compared with sedentary animals. Our data support the idea that ST can be indicated as a non-pharmacological treatment approach to mitigate metabolic changes resulting from menopause.
PROTACs in Ovarian Cancer: Current Advancements and Future Perspectives
Authors: Vorderbruggen Makenzie , Velázquez-Martínez Carlos A. , Natarajan Amarnath , Karpf Adam R.
Published: May 2024

Ovarian cancer is the deadliest gynecologic malignancy. The majority of patients diagnosed with advanced ovarian cancer will relapse, at which point additional therapies can be administered but, for the most part, these are not curative. As such, a need exists for the development of novel therapeutic options for ovarian cancer patients. Research in the field of targeted protein degradation (TPD) through the use of proteolysis-targeting chimeras (PROTACs) has significantly increased in recent years. The ability of PROTACs to target proteins of interest (POI) for degradation, overcoming limitations such as the incomplete inhibition of POI function and the development of resistance seen with other inhibitors, is of particular interest in cancer research, including ovarian cancer research. This review provides a synopsis of PROTACs tested in ovarian cancer models and highlights PROTACs characterized in other types of cancers with potential high utility in ovarian cancer. Finally, we discuss methods that will help to enable the selective delivery of PROTACs to ovarian cancer and improve the pharmacodynamic properties of these agents.
The Effect of Orally Administered Multi-Strain Probiotic Formulation (Lactobacillus, Bifidobacterium) on the Phagocytic Activity and Oxidative Metabolism of Peripheral Blood Granulocytes and Monocytes in Lambs
Authors: Wójcik Roman , Małaczewska Joanna , Tobolski Dawid , Miciński Jan , Kaczorek-Łukowska Edyta , Zwierzchowski Grzegorz
Published: May 2024

Probiotic feed additives have attracted considerable research interest in recent years because the effectiveness of probiotics can differ across microbial strains and the supplemented macroorganisms. The present study was conducted on 16 lambs divided equally into two groups (C—control and E—experimental). The examined lambs were aged 11 days at the beginning of the experiment and 40 days at the end of the experiment. The diet of group E lambs was supplemented with a multi-strain probiotic formulation (Lactobacillus plantarum AMT14, Lactobacillus plantarum AMT4, Lactobacillus rhamnosus AMT15, and Bifidobacterium animalis AMT30), whereas group C lambs did not receive the probiotic additive. At the beginning of the experiment (day 0) and on experimental days 15 and 30, blood was sampled from the jugular vein to determine and compare: phagocytic activity (Phagotest) and oxidative metabolism (Phagoburst) of peripheral blood granulocytes and monocytes by flow cytometry. An analysis of the phagocytic activity of granulocytes and monocytes revealed significantly higher levels of phagocytic activity (expressed as the percentage of phagocytic cells and mean fluorescence intensity) in lambs that were administered the multi-strain probiotic formulation compared with lambs in the control group. The probiotic feed additive also exerted a positive effect on the oxidative metabolism of both granulocytes and monocytes (expressed as the percentage of oxidative metabolism and mean fluorescence intensity) after stimulation with Escherichia coli bacteria and with PMA (4-phorbol-12-β-myristate-13-acetate). These findings suggest that the tested probiotic formulation may have a positive effect on the immune status of lambs.
Investigating the Balance between Structural Conservation and Functional Flexibility in Photosystem I
Authors: Nelson Nathan
Published: May 2024

Photosynthesis, as the primary source of energy for all life forms, plays a crucial role in maintaining the global balance of energy, entropy, and enthalpy in living organisms. Among its various building blocks, photosystem I (PSI) is responsible for light-driven electron transfer, crucial for generating cellular reducing power. PSI acts as a light-driven plastocyanin-ferredoxin oxidoreductase and is situated in the thylakoid membranes of cyanobacteria and the chloroplasts of eukaryotic photosynthetic organisms. Comprehending the structure and function of the photosynthetic machinery is essential for understanding its mode of action. New insights are offered into the structure and function of PSI and its associated light-harvesting proteins, with a specific focus on the remarkable structural conservation of the core complex and high plasticity of the peripheral light-harvesting complexes.
Synergy of Oxygen Vacancy and Surface Modulation Endows Hollow Hydrangea-like MnCo2O4.5 with Enhanced Capacitive Performance
Authors: Li Gaofeng , Li Yanyan , Wang Pengfei , Chen Lingling , Li Longfei , Bao Chen , Tu Jianfei , Ruan Dianbo
Published: May 2024

Surface chemistry and bulk structure jointly play crucial roles in achieving high-performance supercapacitors. Here, the synergistic effect of surface chemistry properties (vacancy and phosphorization) and structure-derived properties (hollow hydrangea-like structure) on energy storage is explored by the surface treatment and architecture design of the nanostructures. The theoretical calculations and experiments prove that surface chemistry modulation is capable of improving electronic conductivity and electrolyte wettability. The structural engineering of both hollow and nanosheets produces a high specific surface area and an abundant pore structure, which is favorable in exposing more active sites and shortens the ion diffusion distance. Benefiting from its admirable physicochemical properties, the surface phosphorylated MnCo2O4.5 hollow hydrangea-like structure (P-MnCoO) delivers a high capacitance of 425 F g−1 at 1 A g−1, a superior capability rate of 63.9%, capacitance retention at 10 A g−1, and extremely long cyclic stability (91.1% after 10,000 cycles). The fabricated P-MnCoO/AC asymmetric supercapacitor achieved superior energy and power density. This work opens a new avenue to further improve the electrochemical performance of metal oxides for supercapacitors.
Simultaneous Treatment of 5-Aminosalicylic Acid and Treadmill Exercise More Effectively Improves Ulcerative Colitis in Mice
Authors: Jin Jun-Jang , Ko Il-Gyu , Hwang Lakkyong , Kim Sang-Hoon , Jee Yong-Seok , Jeon Hyeon , Park Su Bee , Jeon Jung Won
Published: May 2024

Ulcerative colitis (UC) is characterized by continuous mucosal ulceration of the colon, starting in the rectum. 5-Aminosalicylic acid (5-ASA) is the main therapy for ulcerative colitis; however, it has side effects. Physical exercise effectively increases the number of anti-inflammatory and anti-immune cells in the body. In the current study, the effects of simultaneous treatment of treadmill exercise and 5-ASA were compared with monotherapy with physical exercise or 5-ASA in UC mice. To induce the UC animal model, the mice consumed 2% dextran sulfate sodium dissolved in drinking water for 7 days. The mice in the exercise groups exercised on a treadmill for 1 h once a day for 14 days after UC induction. The 5-ASA-treated groups received 5-ASA by enema injection using a 200 μL polyethylene catheter once a day for 14 days. Simultaneous treatment improved histological damage and increased body weight, colon weight, and colon length, whereas the disease activity index score and collagen deposition were decreased. Simultaneous treatment with treadmill exercise and 5-ASA suppressed pro-inflammatory cytokines and apoptosis following UC. The benefits of this simultaneous treatment may be due to inhibition on nuclear factor-κB/mitogen-activated protein kinase signaling activation. Based on this study, simultaneous treatment of treadmill exercise and 5-ASA can be considered as a new therapy of UC.
Inhibition of Shikimate Kinase from Methicillin-Resistant Staphylococcus aureus by Benzimidazole Derivatives. Kinetic, Computational, Toxicological, and Biological Activity Studies
Authors: Rios-Soto Lluvia , Hernández-Campos Alicia , Tovar-Escobar David , Castillo Rafael , Sierra-Campos Erick , Valdez-Solana Mónica , Téllez-Valencia Alfredo , Avitia-Domínguez Claudia
Published: May 2024

Antimicrobial resistance (AMR) is one of the biggest threats in modern times. It was estimated that in 2019, 1.27 million deaths occurred around the globe due to AMR. Methicillin-resistant Staphylococcus aureus (MRSA) strains, a pathogen considered of high priority by the World Health Organization, have proven to be resistant to most of the actual antimicrobial treatments. Therefore, new treatments are required to be able to manage this increasing threat. Under this perspective, an important metabolic pathway for MRSA survival, and absent in mammals, is the shikimate pathway, which is involved in the biosynthesis of chorismate, an intermediate for the synthesis of aromatic amino acids, folates, and ubiquinone. Therefore, the enzymes of this route have been considered good targets to design novel antibiotics. The fifth step of the route is performed by shikimate kinase (SK). In this study, an in-house chemical library of 170 benzimidazole derivatives was screened against MRSA shikimate kinase (SaSK). This effort led to the identification of the first SaSK inhibitors, and the two inhibitors with the greatest inhibition activity (C1 and C2) were characterized. Kinetic studies showed that both compounds were competitive inhibitors with respect to ATP and non-competitive for shikimate. Structural analysis through molecular docking and molecular dynamics simulations indicated that both inhibitors interacted with ARG113, an important residue involved in ATP binding, and formed stable complexes during the simulation period. Biological activity evaluation showed that both compounds were able to inhibit the growth of a MRSA strain. Mitochondrial assays showed that both compounds modify the activity of electron transport chain complexes. Finally, ADMETox predictions suggested that, in general, C1 and C2 can be considered as potential drug candidates. Therefore, the benzimidazole derivatives reported here are the first SaSK inhibitors, representing a promising scaffold and a guide to design new drugs against MRSA.
Screening of Small-Molecule Libraries Using SARS-CoV-2-Derived Sequences Identifies Novel Furin Inhibitors
Authors: Jorkesh Alireza , Rothenberger Sylvia , Baldassar Laura , Grybaite Birute , Kavaliauskas Povilas , Mickevicius Vytautas , Dettin Monica , Vascon Filippo , Cendron Laura , Pasquato Antonella
Published: May 2024

SARS-CoV-2 is the pathogen responsible for the most recent global pandemic, which has claimed hundreds of thousands of victims worldwide. Despite remarkable efforts to develop an effective vaccine, concerns have been raised about the actual protection against novel variants. Thus, researchers are eager to identify alternative strategies to fight against this pathogen. Like other opportunistic entities, a key step in the SARS-CoV-2 lifecycle is the maturation of the envelope glycoprotein at the RARR685↓ motif by the cellular enzyme Furin. Inhibition of this cleavage greatly affects viral propagation, thus representing an ideal drug target to contain infection. Importantly, no Furin-escape variants have ever been detected, suggesting that the pathogen cannot replace this protease by any means. Here, we designed a novel fluorogenic SARS-CoV-2-derived substrate to screen commercially available and custom-made libraries of small molecules for the identification of new Furin inhibitors. We found that a peptide substrate mimicking the cleavage site of the envelope glycoprotein of the Omicron variant (QTQTKSHRRAR-AMC) is a superior tool for screening Furin activity when compared to the commercially available Pyr-RTKR-AMC substrate. Using this setting, we identified promising novel compounds able to modulate Furin activity in vitro and suitable for interfering with SARS-CoV-2 maturation. In particular, we showed that 3-((5-((5-bromothiophen-2-yl)methylene)-4-oxo-4,5 dihydrothiazol-2-yl)(3-chloro-4-methylphenyl)amino)propanoic acid (P3, IC50 = 35 μM) may represent an attractive chemical scaffold for the development of more effective antiviral drugs via a mechanism of action that possibly implies the targeting of Furin secondary sites (exosites) rather than its canonical catalytic pocket. Overall, a SARS-CoV-2-derived peptide was investigated as a new substrate for in vitro high-throughput screening (HTS) of Furin inhibitors and allowed the identification of compound P3 as a promising hit with an innovative chemical scaffold. Given the key role of Furin in infection and the lack of any Food and Drug Administration (FDA)-approved Furin inhibitor, P3 represents an interesting antiviral candidate.
Silver Complexes of Miconazole and Metronidazole: Potential Candidates for Melanoma Treatment
Authors: Fabijańska Małgorzata , Rybarczyk-Pirek Agnieszka J. , Dominikowska Justyna , Stryjska Karolina , Żyro Dominik , Markowicz-Piasecka Magdalena , Szynkowska-Jóźwik Małgorzata Iwona , Ochocki Justyn , Sikora Joanna
Published: May 2024

Melanoma, arguably the deadliest form of skin cancer, is responsible for the majority of skin-cancer-related fatalities. Innovative strategies concentrate on new therapies that avoid the undesirable effects of pharmacological or medical treatment. This article discusses the chemical structures of [(MTZ)2AgNO3], [(MTZ)2Ag]2SO4, [Ag(MCZ)2NO3], [Ag(MCZ)2BF4], [Ag(MCZ)2SbF6] and [Ag(MCZ)2ClO4] (MTZ—metronidazole; MCZ—miconazole) silver(I) compounds and the possible relationship between the molecules and their cytostatic activity against melanoma cells. Molecular Hirshfeld surface analysis and computational methods were used to examine the possible association between the structure and anticancer activity of the silver(I) complexes and compare the cytotoxicity of the silver(I) complexes of metronidazole and miconazole with that of silver(I) nitrate, cisplatin, metronidazole and miconazole complexes against A375 and BJ cells. Additionally, these preliminary biological studies found the greatest IC50 values against the A375 line were demonstrated by [Ag(MCZ)2NO3] and [(MTZ)2AgNO3]. The compound [(MTZ)2AgNO3] was three-fold more toxic to the A375 cells than the reference (cisplatin) and 15 times more cytotoxic against the A375 cells than the normal BJ cells. Complexes of metronidazole with Ag(I) are considered biocompatible at a concentration below 50 µmol/L.
About a Possible Impact of Endodontic Infections by Fusobacterium nucleatum or Porphyromonas gingivalis on Oral Carcinogenesis: A Literature Overview
Authors: Ciani Luca , Libonati Antonio , Dri Maria , Pomella Silvia , Campanella Vincenzo , Barillari Giovanni
Published: May 2024

Periodontitis is linked to the onset and progression of oral squamous cell carcinoma (OSCC), an epidemiologically frequent and clinically aggressive malignancy. In this context, Fusobacterium (F.) nucleatum and Porphyromonas (P.) gingivalis, two bacteria that cause periodontitis, are found in OSCC tissues as well as in oral premalignant lesions, where they exert pro-tumorigenic activities. Since the two bacteria are present also in endodontic diseases, playing a role in their pathogenesis, here we analyze the literature searching for information on the impact that endodontic infection by P. gingivalis or F. nucleatum could have on cellular and molecular events involved in oral carcinogenesis. Results from the reviewed papers indicate that infection by P. gingivalis and/or F. nucleatum triggers the production of inflammatory cytokines and growth factors in dental pulp cells or periodontal cells, affecting the survival, proliferation, invasion, and differentiation of OSCC cells. In addition, the two bacteria and the cytokines they induce halt the differentiation and stimulate the proliferation and invasion of stem cells populating the dental pulp or the periodontium. Although most of the literature confutes the possibility that bacteria-induced endodontic inflammatory diseases could impact on oral carcinogenesis, the papers we have analyzed and discussed herein recommend further investigations on this topic.
Restoration of Lactobacillus johnsonii and Enterococcus faecalis Caused the Elimination of Tritrichomonas sp. in a Model of Antibiotic-Induced Dysbiosis
Authors: Makusheva Yulia , Goncharova Elena , Bets Victoria , Korel Anastasya , Arzhanova Elena , Litvinova Ekaterina
Published: May 2024

Inflammatory bowel disease (IBD) is a multifactorial disease involving the interaction of the gut microbiota, genes, host immunity, and environmental factors. Dysbiosis in IBD is associated with pathobiont proliferation, so targeted antibiotic therapy is a rational strategy. When restoring the microbiota with probiotics, it is necessary to take into account the mutual influence of co-cultivated microorganisms, as the microbiota is a dynamic community of species that mediates homeostasis and physiological processes in the intestine. The aim of our study was to investigate the recovery efficacy of two potential probiotic bacteria, L. johnsonii and E. faecalis, in Muc2−/− mice with impaired mucosal layer. Two approaches were used to determine the efficacy of probiotic supplementation in mice with dysbiosis caused by mucin-2 deficiency: bacterial seeding on selective media and real-time PCR analysis. The recovery time and the type of probiotic bacteria relocated affected only the number of E. faecalis. A significant positive correlation was found between colony-forming unit (CFU) and the amount of E. faecalis DNA in the group that was replanted with probiotic E. faecalis. As for L. johnsonii, it could be restored to its original level even without any additional bacteria supplementation after two weeks. Interestingly, the treatment of mice with L. johnsonii caused a decrease in the amount of E. faecalis. Furthermore, either L. johnsonii or E. faecalis treatment eliminated protozoan overgrowth caused by antibiotic administration.
Real-Time PCR Method as Diagnostic Tool for Detection of Periodontal Pathogens in Patients with Periodontitis
Authors: Kuret Sendi , Kalajzic Nina , Ruzdjak Matija , Grahovac Blaženka , Jezina Buselic Marina Adriana , Sardelić Sanda , Delic Anja , Susak Lana , Sutlovic Davorka
Published: May 2024

The most common type of periodontal disease is chronic periodontitis, an inflammatory condition caused by pathogenic bacteria in subgingival plaque. The aim of our study was the development of a real-time PCR test as a diagnostic tool for the detection and differentiation of five periodontopathogenic bacteria, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Prevotella intermedia, and Treponema denticola, in patients with periodontitis. We compared the results of our in-house method with the micro-IDent® semiquantitative commercially available test based on the PCR hybridization method. DNA was isolated from subgingival plaque samples taken from 50 patients and then analyzed by both methods. Comparing the results of the two methods, they show a specificity of 100% for all bacteria. The sensitivity for A. actinomycetemcomitans was 97.5%, for P. gingivalis 96.88%, and for P. intermedia 95.24%. The sensitivity for Tannerella forsythia and T. denticola was 100%. The Spearman correlation factor of two different measurements was 0.976 for A. actinomycetemcomitans, 0.967 for P. gingivalis, 0.949 for P. intermedia, 0.966 for Tannerella forsythia, and 0.917 for T. denticola. In conclusion, the in-house real-time PCR method developed in our laboratory can provide information about relative amount of five bacterial species present in subgingival plaque in patients with periodontitis. It is likely that such a test could be used in dental diagnostics in assessing the efficacy of any treatment to reduce the bacterial burden.
RNA-Seq Reveals That Multiple Pathways Are Involved in Tuber Expansion in Tiger Nuts (Cyperus esculentus L.)
Authors: Hou Guangshan , Wu Guojiang , Jiang Huawu , Bai Xue , Chen Yaping
Published: May 2024

The tiger nut (Cyperus esculentus L.) is a usable tuber and edible oil plant. The size of the tubers is a key trait that determines the yield and the mechanical harvesting of tiger nut tubers. However, little is known about the anatomical and molecular mechanisms of tuber expansion in tiger nut plants. This study conducted anatomical and comprehensive transcriptomics analyses of tiger nut tubers at the following days after sowing: 40 d (S1); 50 d (S2); 60 d (S3); 70 d (S4); 90 d (S5); and 110 d (S6). The results showed that, at the initiation stage of a tiger nut tuber (S1), the primary thickening meristem (PTM) surrounded the periphery of the stele and was initially responsible for the proliferation of parenchyma cells of the cortex (before S1) and then the stele (S2–S3). The increase in cell size of the parenchyma cells occurred mainly from S1 to S3 in the cortex and from S3 to S4 in the stele. A total of 12,472 differentially expressed genes (DEGs) were expressed to a greater extent in the S1–S3 phase than in S4–S6 phase. DEGs related to tuber expansion were involved in cell wall modification, vesicle transport, cell membrane components, cell division, the regulation of plant hormone levels, signal transduction, and metabolism. DEGs involved in the biosynthesis and the signaling of indole-3-acetic acid (IAA) and jasmonic acid (JA) were expressed highly in S1–S3. The endogenous changes in IAA and JAs during tuber development showed that the highest concentrations were found at S1 and S1–S3, respectively. In addition, several DEGs were related to brassinosteroid (BR) signaling and the G-protein, MAPK, and ubiquitin–proteasome pathways, suggesting that these signaling pathways have roles in the tuber expansion of tiger nut. Finally, we come to the conclusion that the cortex development preceding stele development in tiger nut tubers. The auxin signaling pathway promotes the division of cortical cells, while the jasmonic acid pathway, brassinosteroid signaling, G-protein pathway, MAPK pathway, and ubiquitin protein pathway regulate cell division and the expansion of the tuber cortex and stele. This finding will facilitate searches for genes that influence tuber expansion and the regulatory networks in developing tubers.
Detection of Korean Phishing Messages Using Biased Discriminant Analysis under Extreme Class Imbalance Problem
Authors: Kim Siyoon , Park Jeongmin , Ahn Hyun , Lee Yonggeol
Published: May 2024

In South Korea, the rapid proliferation of smartphones has led to an uptick in messenger phishing attacks associated with electronic communication financial scams. In response to this, various phishing detection algorithms have been proposed. However, collecting messenger phishing data poses challenges due to concerns about its potential use in criminal activities. Consequently, a Korean phishing dataset can be composed of imbalanced data, where the number of general messages might outnumber the phishing ones. This class imbalance problem and data scarcity can lead to overfitting issues, making it difficult to achieve high performance. To solve this problem, this paper proposes a phishing messages classification method using Biased Discriminant Analysis without resorting to data augmentation techniques. In this paper, by optimizing the parameters for BDA, we achieved exceptionally high performances in the phishing messages classification experiment, with 95.45% for Recall and 96.85% for the BA metric. Moreover, when compared with other algorithms, the proposed method demonstrated robustness against overfitting due to the class imbalance problem and exhibited minimal performance disparity between training and testing datasets.
Temperature Effect on the Growth and Development of Habrobracon hebetor Say (Hymenoptera: Braconidae) Reared on Ephestia elutella (Hübner) (Lepidoptera: Pyralidae) Larvae
Authors: Huang Yong , Liu Wenjing , Lü Jianhua , Wang Wenkai , Guo Yafei
Published: May 2024

Augmentative release of parasitoids has been an important component of integrated insect management for stored product protection. Understanding the effect of different temperatures on the growth and development of parasitoids is in favor of mass rearing of parasitoids. Habrobracon hebetor Say (Hymenoptera: Braconidae) is a highly cosmopolitan, gregarious ecto-parasitoid of a variety of Lepidopterous larvae. Thus, the growth and development of H. hebetor reared on Ephestia elutella (Hübner) (Lepidoptera: Pyralidae) larvae were investigated at 15, 20, 25, 30, and 35 °C. Habrobracon hebetor could complete growth and development, and the developmental duration decreased with increasing temperature at 15, 20, 25, 30, and 35 °C. The development threshold temperatures of H. hebetor eggs, larvae, pupae, and egg-to-adult stages were 13.89, 6.39, 9.24, and 9.29 °C, and the effective accumulated temperatures were 23.33, 46.40, 142.68, and 240.31 °C·d, respectively. The total number of eggs laid by H. hebetor, the hatching rate of H. hebetor eggs, and the percentage of female offspring reached the maximum of 192.39, 83.89%, and 74.04% at 30 °C, respectively. There was no significant difference in pupal survival rate in the temperature range of 15 °C to 35 °C. At 30 °C, the pre-oviposition duration of H. hebetor was the shortest (0.87 d). Therefore, the optimal rearing temperature of H. hebetor was 30 °C. The present results are useful for the large-scale rearing of H. hebetor using E. elutella larvae as hosts and effectively implementing the biological control of stored-product insects.
Outcome of Pulmonary Embolism with and without Ischemic Stroke
Authors: Keller Karsten , Schmitt Volker H. , Hahad Omar , Hobohm Lukas
Published: May 2024

Background: Ischemic stroke is the second, and pulmonary embolism (PE) is the third most common cardiovascular cause of death after myocardial infarction. Data regarding risk factors for ischemic stroke in patients with acute PE are limited. Methods: Patients were selected by screening the German nationwide in-patient sample for PE (ICD-code I26) and were stratified by ischemic stroke (ICD code I63) and compared. Results: The nationwide in-patient sample comprised 346,586 hospitalized PE patients (53.3% females) in Germany from 2011 to 2014; among these, 6704 (1.9%) patients had additionally an ischemic stroke. PE patients with ischemic stroke had a higher in-hospital mortality rate than those without (28.9% vs. 14.5%, p < 0.001). Ischemic stroke was independently associated with in-hospital death (OR 2.424, 95%CI 2.278–2.579, p < 0.001). Deep venous thrombosis and/or thrombophlebitis (DVT) combined with heart septal defect (OR 24.714 [95%CI 20.693–29.517], p < 0.001) as well as atrial fibrillation/flutter (OR 2.060 [95%CI 1.943–2.183], p < 0.001) were independent risk factors for stroke in PE patients. Systemic thrombolysis was associated with a better survival in PE patients with ischemic thrombolysis who underwent cardio-pulmonary resuscitation (CPR, OR 0.55 [95%CI 0.36–0.84], p = 0.006). Conclusions: Ischemic stroke did negatively affect the survival of PE. Combination of DVT and heart septal defect and atrial fibrillation/flutter were strong and independent risk factors for ischemic stroke in PE patients. In PE patients with ischemic stroke, who had to underwent CPR, systemic thrombolysis was associated with improved survival.