bluuebunny/crossref_metadata_2025 huggingface dataset:
Increasing Fruit and Vegetable Intake of Primary School Children in a Quasi-Randomized Trial: Evaluation of the Three-Year School-Based Multicomponent Intervention
Authors: Ilić Ana , Rumbak Ivana , Brečić Ružica , Barić Irena Colić , Bituh Martina
Published: October 2022

Insufficient consumption of fruit and vegetables was found in primary school children. To address this problem, a three-year school-based multicomponent intervention was conducted in 14 primary schools in the City of Zagreb. The aim of the study was therefore to evaluate one of the primary goals of the intervention—the increase in fruit and vegetable intake among primary school children. A total of 681 children were allocated to the intervention (n = 300 in the control group and n = 381 in the intervention group). The intervention included 23 interactive classroom workshops, 10 cross-curricular activities, 13 homework challenges, visual exposure with educational posters in classrooms, parent education via the website, and the implementation of new dishes into the school food system. Fruit and vegetable intake was assessed using a semi-quantitative food frequency questionnaire at baseline and after the intervention. Data were analyzed by per-protocol analysis. The study involved 259 children (50.2% girls; age 7.7 ± 0.4 years; n = 116 in the control group and n = 143 in the intervention group) who completed a food intake frequency questionnaire at both time points. Children in the intervention group showed a significant increase (p < 0.001) in total daily fruit and vegetable intake (before: 332.1 ± 164.9 g; after: 430.1 ± 186.7 g) compared to the control group (before: 350.2 ± 187.5; after: 382.6 ± 196.8) after the intervention. The increase in fruit and vegetable intake was achieved in 89% of children, while 25% more children reached the daily recommendation of 400 g. The use of the multicomponent intervention showed potential to increase fruit and vegetable intake in primary school children.
Identification of a Hydroxygallic Acid Derivative, Zingibroside R1 and a Sterol Lipid as Potential Active Ingredients of Cuscuta chinensis Extract That Has Neuroprotective and Antioxidant Effects in Aged Caenorhabditis elegans
Authors: Sayed Shimaa M. A. , Alseekh Saleh , Siems Karsten , Fernie Alisdair R. , Luyten Walter , Schmitz-Linneweber Christian , Saul Nadine
Published: October 2022

We examined the effects of the extracts from two traditional Chinese medicine plants, Cuscuta chinensis and Eucommia ulmoides, on the healthspan of the model organism Caenorhabditis elegans. C. chinensis increased the short-term memory and the mechanosensory response of aged C. elegans. Furthermore, both extracts improved the resistance towards oxidative stress, and decreased the intracellular level of reactive oxygen species. Chemical analyses of the extracts revealed the presence of several bioactive compounds such as chlorogenic acid, cinnamic acid, and quercetin. A fraction from the C. chinensis extract enriched in zingibroside R1 improved the lifespan, the survival after heat stress, and the locomotion in a manner similar to the full C. chinensis extract. Thus, zingibroside R1 could be (partly) responsible for the observed health benefits of C. chinensis. Furthermore, a hydroxygallic acid derivative and the sterol lipid 4-alpha-formyl-stigmasta-7,24(241)-dien-3-beta-ol are abundantly present in the C. chinensis extract and its most bioactive fraction, but hardly in E. ulmoides, making them good candidates to explain the overall healthspan benefits of C. chinensis compared to the specific positive effects on stress resistance by E. ulmoides. Our findings highlight the overall anti-aging effects of C. chinensis in C. elegans and provide first hints about the components responsible for these effects.
FTO Common Obesity SNPs Interact with Actionable Environmental Factors: Physical Activity, Sugar-Sweetened Beverages and Wine Consumption
Authors: Chermon Danyel , Birk Ruth
Published: October 2022

Genetic background is estimated to play >50% in common obesity etiology. FTO single nucleotide polymorphisms (SNPs) are strongly associated with BMI, typically in European cohorts. We investigated the interaction of common FTO SNPs with actionable environmental factors, namely physical activity, sugar-sweetened beverages (SSB) and wine consumption, and verified FTO common SNPs predisposition to obesity in the Israeli population. Adults’ (>18 years old, n = 1720) FTO common SNPs data and lifestyle and nutrition habits questionnaires were analyzed using binary logistic regression models, adjusted for confounding variables (age, sex) assuming dominant, recessive and additive genetic models. Eighteen FTO SNPs were associated with significant increased obesity risk and interacted with physical activity (p < 0.001), wine consumption (p < 0.014) and SSB consumption (p < 0.01). Inactive rs9939609 risk-allele carriers had significantly higher obesity risk compared to their active counterparts (OR = 2.54, 95% CI 1.91–3.39 and OR = 3.77, 95% CI 2.47–5.75; p < 0.001 with 3.1 and 3.5 BMI increment for heterozygotes and homozygotes, respectively). SSB consumption (≥1 serving/day) significantly raised obesity risk and wine consumption (1–3 drinks/weekly) significantly lowered obesity risk for rs9939609 risk-allele carriers (OR = 1.54, 95% CI 1.05–2.27; p = 0.028 and OR = 0.61, 95% CI 0.47–0.79; p < 0.001, respectively). Our findings demonstrate that actionable lifestyle factors modify the common FTO obesity risk in predisposed carriers, and they have personal and public health implications.
Docosapentaenoic Acid (DPA, 22:5n-3) Alleviates Ulcerative Colitis via Modification of Gut Microbiota and Their Metabolism
Authors: Dong Ye , Huang Cheng , Yang Jiacheng , Zheng Zhenxiao , Dai Zhiyuan
Published: October 2022

N-3 polyunsaturated fatty acids (n-3PUFA) are regarded as viable alternatives to aid the treatment of ulcerative colitis (UC). Most research focuses on eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA); little information is available about the effect of docosapentaenoic acid (DPA) on the gut microbiota and their metabolism in UC mice. In this study, the changes in gut microbiota and their metabolism in UC mice were studied through the 16S rRNA sequencing method and untargeted metabolomics. Moreover, the differential bacterial genus and differential metabolites in responding to DPA supplementation were screened through permutation test after orthogonal partial least squares discriminant analysis (OPLS-DA). The results indicated that DPA supplementation increased the diversity and altered the composition of the gut microbiota in UC mice; Akkermansia, Alistipes, Butyricicoccus, and Lactobacillus were selected as the differential bacterial genus. Supplementation of DPA also altered the fecal metabolite profile in the UC mice. Moreover, butyrate, N-carbamylglutamate (NCG), and histamine were screened as the differential metabolites. In conclusion, the regulation effect of DPA on the gut microbiota and their metabolism might be involved in the intervention mechanism of DPA in UC. More research needs to be carried out to elucidate the mechanism systematically.
Geraniol Treatment for Irritable Bowel Syndrome: A Double-Blind Randomized Clinical Trial
Authors: Ricci Chiara , Rizzello Fernando , Valerii Maria Chiara , Spisni Enzo , Gionchetti Paolo , Turroni Silvia , Candela Marco , D’Amico Federica , Spigarelli Renato , Bellocchio Irene , Marasco Giovanni , Barbara Giovanni
Published: October 2022

Geraniol is an acyclic monoterpene alcohol with well-known anti-inflammatory and antimicrobial properties which has shown eubiotic activity towards gut microbiota (GM) in patients with irritable bowel syndrome (IBS). Methods: Fifty-six IBS patients diagnosed according to Rome III criteria were enrolled in an interventional, prospective, multicentric, randomized, double-blinded, placebo-controlled trial. In the treatment arm, patients received a low-absorbable geraniol food supplement (LAGS) once daily for four weeks. Results: Patients treated with LAGS showed a significant reduction in their IBS symptoms severity score (IBS-SSS) compared to the placebo (195 vs. 265, p = 0.001). The rate of responders according to IBS-SSS (reduction ≥ 50 points) was significantly higher in the geraniol vs placebo group (52.0% vs. 16.7%, p = 0.009) mainly due to the IBS mixed subtype. There were notable differences in the microbiota composition after geraniol administration, particularly a significant decrease in a genus of Ruminococcaceae, Oscillospira (p = 0.01), a decreasing trend for the Erysipelotrichaceae and Clostridiaceae families (p = 0.1), and an increasing trend for other Ruminococcaceae taxa, specifically Faecalibacterium (p = 0.09). The main circulating proinflammatory cytokines showed no differences between placebo and geraniol arms. Conclusion: LAGS was effective in treating overall IBS symptoms, together with an improvement in the gut microbiota profile, especially for the IBS mixed subtype.
Stressor Factors for Spanish Nursing Students in a Pandemic Context: An Observational Pilot Survey
Authors: Reverté-Villarroya Silvia , Gil-Mateu Elsa , Sauras-Colón Esther , Barceló-Prats Josep , Albacar-Riobóo Núria , Ortega Laura
Published: October 2022

Background: The context of the pandemic in Spain meant a high demand for care. The purpose of this pilot work was to determine the stress factors, conducted on final-year nursing students at a Spanish university, who volunteered to carry out healthcare tasks, in pandemic and post-pandemic contexts. Methods: An observational prospective cohort pilot survey was conducted with an intentional sampling of the forty-seven students. We collected sociodemographic and stressor data using the validated KEZKAK questionnaire. The STROBE checklist was used to evaluate the study. Results: The median scores obtained from nursing students incorporated as auxiliary health workers are lower than those who were not incorporated, and statistically significant differences were found: lack of skills and abilities (p = 0.016); relationship with tutors and colleagues (p = 0.004); impotence and uncertainty (p = 0.011); inability to manage the relationship with the patient (p = 0.009); emotional involvement (p = 0.032); distress caused by the relationship with patients and item overload (p = 0.039); and overload items (p = 0.011). The post-pandemic only maintained “lack of skill and abilities” (p = 0.048), from nursing students incorporated as auxiliary health workers. Conclusion: This pilot study showed that nursing students who joined as auxiliary health personnel presented less perceived stress than non-incorporated nursing students. Still, more prospectively designed clinical research is needed.
Trained Immunity Provides Long-Term Protection against Bacterial Infections in Channel Catfish
Authors: Petrie-Hanson Lora , Peterman Ann E. (Beth)
Published: October 2022

Beta glucan exposure induced trained immunity in channel catfish that conferred long-term protection against Edwardsiella ictaluri and Edwardsiella piscicida infections one month post exposure. Flow cytometric analyses demonstrated that isolated macrophages and neutrophils phagocytosed higher amounts of E. ictaluri and E. piscicida. Beta glucan induced changes in the distribution of histone modifications in the monomethylation and trimethylation of H3K4 and modifications in the acetylation and trimethylation of H3K27. KEGG pathway analyses revealed that these modifications affected expressions of genes controlling phagocytosis, phagosome functions and enhanced immune cell signaling. These analyses correlate the histone modifications with gene functions and to the observed enhanced phagocytosis and to the increased survival following bacterial challenge in channel catfish. These data suggest the chromatin reconfiguration that directs trained immunity as demonstrated in mammals also occurs in channel catfish. Understanding the mechanisms underlying trained immunity can help us design prophylactic and non-antibiotic based therapies and develop broad-based vaccines to limit bacterial disease outbreaks in catfish production.
Quantitative Trait Locus Mapping for Fusarium Wilt Race 4 Resistance in a Recombinant Inbred Line Population of Pima Cotton (Gossypium Barbadense)
Authors: Abdelraheem Abdelraheem , Zhu Yi , Zhang Jinfa
Published: October 2022

Fusarium oxysporum f. sp. vasinfectum (FOV) race 4 (FOV4) causes seedling death immediately after emergence, in addition to leaf chlorosis and necrosis, vascular discoloration, plant wilting, defoliation, and plant death at late stages. Breeding for FOV4 resistance is the most cost effective management method. In this study, 163 recombinant inbred lines (RILs) of FOV4-resistant Pima S-6 × susceptible 89590, together with the two parents (Gossypium barbadense), were artificially inoculated with FOV4 and assayed for resistance based on foliar disease severity ratings (DSR) at 30 days post inoculation (dpi) in two replicated tests in the greenhouse or controlled conditions. Significant genotypic variations were detected for FOV4 resistance in a combined analysis of variance. Although a significant genotype × test interaction was detected for DSR, the 10 most resistant RILs had significantly and consistently lower DSR than the susceptible parent in both tests. The heritability estimate for DSR was 0.65, indicating that two-thirds of the phenotypic variation for FOV4 resistance in this Pima RIL population was due to genetic factors. Based on 404 polymorphic SSR markers, five and four quantitative trait loci (QTL) on six chromosomes (c14, c17, c19, c21, c24, and c25) were detected in Tests 1 and 2, respectively, and each explained 15 to 29% of the phenotypic variation. Three QTL on c17, c24, and c25 were in common between the two tests, accounting for 60% and 75% of the QTL detected in Tests 1 and 2, respectively. The three QTL were also reported in previous studies and will be useful for marker-assisted selection for FOV4 resistance in Pima cotton.
Resistance and Susceptibility Immune Factors at Play during Mycobacterium tuberculosis Infection of Macrophages
Authors: Simper Jan D. , Perez Esteban , Schlesinger Larry S. , Azad Abul K.
Published: October 2022

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M.tb), is responsible for >1.5 million deaths worldwide annually. Innate immune cells, especially macrophages, are the first to encounter M.tb, and their response dictates the course of infection. During infection, macrophages exert a variety of immune factors involved in either controlling or promoting the growth of M.tb. Research on this topic has been performed in both in vitro and in vivo animal models with discrepant results in some cases based on the model of study. Herein, we review macrophage resistance and susceptibility immune factors, focusing primarily on recent advances in the field. We include macrophage cellular pathways, bioeffector proteins and molecules, cytokines and chemokines, associated microbiological factors and bacterial strains, and host genetic factors in innate immune genes. Recent advances in mechanisms underlying macrophage resistance and susceptibility factors will aid in the successful development of host-directed therapeutics, a topic emphasized throughout this review.
Genetic Diversity of Venturia inaequalis in Latvia Revealed by Microsatellite Markers
Authors: Sokolova Olga , Moročko-Bičevska Inga , Lācis Gunārs
Published: October 2022

Apple scab caused by the ascomycete Venturia inaequalis is an economically significant disease worldwide. The annual sexual reproduction of V. inaequalis leads to high variation, changes in the population’s genetic structure and adaptations to the changing environment, including overcoming the host’s resistance. The objective of this study is to characterise and assess the genetic diversity of V. inaequalis populations in two main apple-growing regions in Latvia. In total, 143 V. inaequalis isolates were collected from Latvia, six reference strains with known virulence were obtained from other countries, and all strains were genotyped by 12 SSR markers. The SSR markers were highly variable and informative, identifying 158 alleles that ranged from two to 29 per locus. The Bayesian clustering identified three genetic lineages among the Latvian isolates that did not correlate to the geographic origin, host genotype, organ (leaves or fruits) from which the pathogen was isolated, time of collection, and type of isolation (single conidium or ascospore). The possible relatedness to virulence was detected when reference strains with known virulence were included in the analysis. Our findings correspond with previous studies demonstrating that V. inaequalis in Europe has a high genetic diversity within populations, but low diversity among the populations.
Biocompatible, Multi-Mode, Fluorescent, T2 MRI Contrast Magnetoelectric-Silica Nanoparticles (MagSiNs), for On-Demand Doxorubicin Delivery to Metastatic Cancer Cells
Authors: Waters Margo , Hopf Juliane , Tam Emma , Wallace Stephanie , Chang Jordan , Bennett Zach , Aquino Hadrian , Roeder Ryan , Helquist Paul , Stack M. , Nallathamby Prakash
Published: October 2022

There is a need to improve current cancer treatment regimens to reduce systemic toxicity, to positively impact the quality-of-life post-treatment. We hypothesized the negation of off-target toxicity of anthracyclines (e.g., Doxorubicin) by delivering Doxorubicin on magneto-electric silica nanoparticles (Dox-MagSiNs) to cancer cells. Dox-MagSiNs were completely biocompatible with all cell types and are therapeutically inert till the release of Doxorubicin from the MagSiNs at the cancer cells location. The MagSiNs themselves are comprised of biocompatible components with a magnetostrictive cobalt ferrite core (4–6 nm) surrounded by a piezoelectric fused silica shell of 1.5 nm to 2 nm thickness. The MagSiNs possess T2-MRI contrast properties on par with RESOVIST™ due to their cobalt ferrite core. Additionally, the silica shell surrounding the core was volume loaded with green or red fluorophores to fluorescently track the MagSiNs in vitro. This makes the MagSiNs a suitable candidate for trackable, drug nanocarriers. We used metastatic triple-negative breast cancer cells (MDAMB231), ovarian cancer cells (A2780), and prostate cancer cells (PC3) as our model cancer cell lines. Human umbilical vein endothelial cells (HUVEC) were used as control cell lines to represent blood-vessel cells that suffer from the systemic toxicity of Doxorubicin. In the presence of an external magnetic field that is 300× times lower than an MRI field, we successfully nanoporated the cancer cells, then triggered the release of 500 nM of doxorubicin from Dox-MagSiNs to successfully kill >50% PC3, >50% A2780 cells, and killed 125% more MDAMB231 cells than free Dox.HCl. In control HUVECs, the Dox-MagSiNs did not nanoporate into the HUVECS and did not exhibited any cytotoxicity at all when there was no triggered release of Dox.HCl. Currently, the major advantages of our approach are, (i) the MagSiNs are biocompatible in vitro and in vivo; (ii) the label-free nanoporation of Dox-MagSiNs into cancer cells and not the model blood vessel cell line; (iii) the complete cancellation of the cytotoxicity of Doxorubicin in the Dox-MagSiNs form; (iv) the clinical impact of such a nanocarrier will be that it will be possible to increase the current upper limit for cumulative-dosages of anthracyclines through multiple dosing, which in turn will improve the anti-cancer efficacy of anthracyclines.
Moringa concanensis L. Alleviates DNCB-Induced Atopic Dermatitis-like Symptoms by Inhibiting NLRP3 Inflammasome-Mediated IL-1β in BALB/c Mice
Authors: Kim Kyeong-Min , Kim So-Yeon , Mony Tamanna Jahan , Bae Ho Jung , Choi Seung-Hyuk , Choi Yu-Yeong , An Ju-Yeon , Kim Hyun-Jeong , Cho Ye Eun , Sowndhararajan Kandhasamy , Park Se Jin
Published: October 2022

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus, dry skin and redness on the face and inside elbows or knees. Most patients with AD are children and youths, but it can also develop in adults. In the therapeutic aspect, treatment with corticosteroids for AD has several side effects, such as weight loss, atrophy and acne. In the current study, we examined the anti-inflammatory effect of Moringa concanensis leaves on HaCaT keratinocytes and 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis-like symptoms in BALB/c mice. We observed that M. concanensis treatment exhibited significant inhibition in the production of inflammatory mediators and proinflammatory cytokines, such as IL-1β, in LPS-induced HaCaT keratinocytes by downregulating the NLRP3 inflammasome activation. Moreover, M. concanensis inhibited the activation of JNK, AP-1 and p65, which resulted in the deformation of NLRP3 in LPS-stimulated HaCaT cells. In mice with DNCB-induced AD-like skin lesions, the administration of M. concanensis ameliorated the clinical symptoms, such as the dermatitis score, thickness of lesional ear skin and TEWL. Furthermore, M. concanensis could attenuate the activation of the immune system, such as reducing the spleen index, concentration of the IgE levels and expression of the NLRP3 inflammasome in ear tissues. Therefore, our results suggest that M. concanensis exerts anti-atopic dermatitis effects by inhibiting the NLRP3 inflammasome-mediated IL-1β.
Novel Aporphine- and Proaporphine–Clerodane Hybrids Identified from the Barks of Taiwanese Polyalthia longifolia (Sonn.) Thwaites var. pendula with Strong Anti-DENV2 Activity
Authors: Lo I-Wen , Liao Geng-You , Lee Jin-Ching , Chang Chi-I , Wu Yang-Chang , Chen Yen-Yu , Liu Shang-Pin , Su Huey-Jen , Liu Chih-I , Kuo Chia-Yi , Lin Zheng-Yu , Li Tsung-Lin , Lin Yun-Sheng , Liaw Chia-Ching
Published: October 2022

Hybrid natural products produced via mixed biosynthetic pathways are unique and often surprise one with unexpected medicinal properties in addition to their fascinating structural complexity/diversity. In view of chemical structures, hybridization is a way of diversifying natural products usually through dimerization of two similar or dissimilar subcomponents through a C–C or N–C covalent linkage. Here, we report four structurally attractive diterpene–alkaloid conjugates polyalongarins A–D (1–4), clerodane-containing aporphine and proaporphine alkaloids, the first of its kind from the barks of Taiwanese Polyalthia longifolia (Sonn.) Thwaites var. pendula. In addition to conventional spectroscopic analysis, single crystal X-ray crystallography was employed to determine the chemical structures and stereo-configurations of 1. Compounds 1–4 were subsequently subjected to in vitro antiviral examination against DENV2 by evaluating the expression level of the NS2B protein in DENV2-infected Huh-7 cells. These compounds display encouraging anti-DENV2 activity with superb EC50 (2.8–6.4 μM) and CC50 values (50.4–200 μM). The inhibitory mechanism of 1–4 on NS2B was further explored drawing on in-silico molecular docking analysis. Based on calculated binding affinities and predicted interactions between the functional groups of 1–4 and the allosteric-site residues of the DENV2 NS2B-NS3 protease, our analysis concludes that the clerodane–aporphine/proaporphine-type hybrids are novel and effective DENV NS2B-NS3 protease inhibitors.
Design, Synthesis and Biological Evaluation of Biscarbamates as Potential Selective Butyrylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease
Authors: Matošević Ana , Knežević Anamarija , Zandona Antonio , Maraković Nikola , Kovarik Zrinka , Bosak Anita
Published: October 2022

As butyrylcholinesterase (BChE) plays a role in the progression of symptoms and pathophysiology of Alzheimer’s disease (AD), selective inhibition of BChE over acetylcholinesterase (AChE) can represent a promising pathway in treating AD. The carbamate group was chosen as a pharmacophore because the carbamates currently or previously in use for the treatment of AD displayed significant positive effects on cognitive symptoms. Eighteen biscarbamates with different substituents at the carbamoyl and hydroxyaminoethyl chain were synthesized, and their inhibitory potential toward both cholinesterases and inhibition selectivity were determined. The ability of carbamates to cross the blood–brain barrier (BBB) by passive transport, their cytotoxic profile and their ability to chelate biometals were also evaluated. All biscarbamates displayed a time-dependent inhibition with inhibition rate constants within 10−3–10−6 M−1 min−1 range for both cholinesterases, with generally higher preference to BChE. For two biscarbamates, it was determined that they should be able to pass the BBB by passive transport, while for five biscarbamates, this ability was slightly limited. Fourteen biscarbamates did not exhibit a cytotoxic effect toward liver, kidney and neuronal cells. In conclusion, considering their high BChE selectivity, non-toxicity, ability to chelate biometals and pass the BBB, compounds 2 and 16 were pointed out as the most promising compounds for the treatment of middle and late stages of AD.
Candesartan Attenuates Cisplatin-Induced Lung Injury by Modulating Oxidative Stress, Inflammation, and TLR-4/NF-κB, JAK1/STAT3, and Nrf2/HO-1 Signaling
Authors: Atwa Ahmed M. , Abd El-Ghafar Omnia A. M. , Hassanein Emad H. M. , Mahdi Somya E. , Sayed Ghadir A. , Alruhaimi Reem S. , Alqhtani Haifa A. , Alotaibi Mohammed F. , Mahmoud Ayman M.
Published: October 2022

Cisplatin (CIS) is an effective chemotherapeutic agent against different cancers. The use of CIS is associated with acute lung injury (ALI) and other adverse effects, and oxidative stress and inflammation were implicated in its toxic effects. Candesartan (CAN), an angiotensin II (Ang II) receptor blocker, showed beneficial effects against oxidative stress and inflammation. Therefore, this study investigated the potential of CAN to prevent CIS-induced oxidative stress, inflammation, and lung injury in rats, pointing to the involvement of TLR4/NF-κB, JAK1/STAT3, PPARγ, and Nrf2/HO-1 signaling. The rats received CAN (5 mg/kg) for 10 days and were challenged with a single dose of CIS (7 mg/kg) on day 7. CIS caused injury to the alveoli and the bronchial tree, increased lipid peroxidation, nitric oxide, myeloperoxidase, TLR-4, NF-κB p65, iNOS, TNF-α, IL-6, IL-1β, and caspase-3, and decreased cellular antioxidants and IL-6 in the lungs of rats. CAN effectively prevented tissue injury, suppressed TLR-4/ NF-κB signaling, and ameliorated oxidative stress, inflammatory markers, and caspase-3 in CIS-administered rats. CAN enhanced antioxidants and IL-10, decreased Ang II, increased Ang (1–7), suppressed the phosphorylation of JAK1 and STAT3, and upregulated SOCS3 in CIS-administered rats. These effects were associated with the downregulation of Keap1 and enhanced Nrf2, GCLC, HO-1, and PPARγ. In conclusion, CAN prevented CIS-induced lung injury by attenuating oxidative stress, suppressing TLR-4/NF-κB and JAK1/STAT3 signaling, Ang II, and pro-inflammatory mediators, and upregulating PPARγ, and Nrf2/HO-1 signaling.
Optimization of Zebrafish Larvae Sectioning for Mass Spectrometry Imaging
Authors: Yang Junhai , Rendino Lauren , Cassar Steven , Buck Wayne , Sawicki James , Talaty Nari , Wagner David
Published: October 2022

The utility of zebrafish is becoming more frequent due to lower costs and high similarities to humans. Zebrafish larvae are attractive subjects for drug screening and drug metabolism research. However, obtaining good quality zebrafish larvae sections for batch samples at designated planes, angles, and locations for comparison purposes is a challenging task. We report here the optimization of fresh frozen zebrafish larvae sectioning for mass spectrometry imaging. We utilized the gelatin solutions that were created at two different temperatures (50 and 85 °C) as embedding media. Gelatin-50 (gelatin created under 50 °C, solid gel under room temperature) was used to make a larvae-shaped mold and gelatin-85 (gelatin created under 85 °C, liquid under room temperature) was used to embed the larvae. H&E staining of sections shows well-preserved morphology and minimal histological interference. More importantly, the position of the larvae was well controlled resulting in more consistent sectioning of the larvae.
Carbon Dots for Killing Microorganisms: An Update since 2019
Authors: Lin Fengming , Wang Zihao , Wu Fu-Gen
Published: October 2022

Frequent bacterial/fungal infections and occurrence of antibiotic resistance pose increasing threats to the public and thus require the development of new antibacterial/antifungal agents and strategies. Carbon dots (CDs) have been well demonstrated to be promising and potent antimicrobial nanomaterials and serve as potential alternatives to conventional antibiotics. In recent years, great efforts have been made by many researchers to develop new carbon dot-based antimicrobial agents to combat microbial infections. Here, as an update to our previous relevant review (C 2019, 5, 33), we summarize the recent achievements in the utilization of CDs for microbial inactivation. We review four kinds of antimicrobial CDs including nitrogen-doped CDs, metal-containing CDs, antibiotic-conjugated CDs, and photoresponsive CDs in terms of their starting materials, synthetic route, surface functionalization, antimicrobial ability, and the related antimicrobial mechanism if available. In addition, we summarize the emerging applications of CD-related antimicrobial materials in medical and industry fields. Finally, we discuss the existing challenges of antimicrobial CDs and the future research directions that are worth exploring. We believe that this review provides a comprehensive overview of the recent advances in antimicrobial CDs and may inspire the development of new CDs with desirable antimicrobial activities.
Clinical Efficacy and Safety of Chinese Herbal Medicine in the Treatment of Uremic Pruritus: A Meta-Analysis of Randomized Controlled Trials
Authors: Lu Ping-Hsun , Lai Chien-Cheng , Lin I-Hsin , Tsai Fu-Ming , Lu Po-Hsuan
Published: October 2022

Uremic pruritus is a disturbing and refractory symptom in patients with advanced chronic kidney disease. Chinese herbal medicine has been reported to alleviate uremic pruritus. To investigate the effects of Chinese herbal medicine, we conducted a systematic review and meta-analysis on patients with uremic pruritus. We searched databases (prior to 3 May 2022) for randomized controlled trials on the effects of Chinese herbal medicine in treating uremic pruritus. Our meta-analysis included 3311 patients from 50 randomized controlled trials. In patients with uremic pruritus, adjunctive Chinese herbal medicine significantly improved overall effectiveness (risk ratio 1.29, 95% CI 1.23 to 1.35), quality of life, renal function, reduced pruritus score, and inflammatory biomarkers compared to control groups with hemodialysis alone or with anti-pruritic treatments. Chinese herbal medicine treatment showed a time-dependent tendency in improving the visual analog scale of dialysis patients. Compared to control groups, no significantly higher risk of adverse events in patients taking Chinese herbal medicine (risk ratio 0.60, 95% CI 0.22 to 1.63). Chinese herbal medicine appears to be effective and safe in complementing the treatment of patients with uremic pruritus.
Cu(II)-Catalysed Hydrocarboxylation of Imines Utilizing CO2 to Synthesize α-Unsaturated Aminocarboxylic Acids
Authors: Gordon Allen T. , Hosten Eric C. , Ogunlaja Adeniyi S.
Published: October 2022

Here, we report the Cu(II)-photocatalysed hydrocarboxylation of imines (C=N) from a series of synthesized Schiff Base derivatives, namely (E)-1-(4-((4-methylbenzylidene)amino)phenyl)ethanone, (E)-1-(3-((5-bromo-2-hydroxybenzylidene)amino)phenyl)ethanone, (E)-4-((5-bromo-2-hydroxybenzylidene)amino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one, and (E)-1,5-dimethyl-4-((4-methylbenzylidene)amino)-2-phenyl-1H-pyrazol-3(2H)-one, with carbon dioxide (CO2) to generate disubstituted amino acids. Under mild conditions (atmospheric pressure of CO2, room temperature, and 30 W Blue LED light), good to excellent yields confirming the formation of substituted amino acid unsaturated acid derivatives were obtained. Single crystal X-ray diffraction (SC-XRD) and UV-Vis diffuse reflectance spectroscopy (UV-Vis-DRS) confirmed the square pyramidal geometry of the Cu(II) photocatalyst. Docking and DFT calculations of the substituted amino acid unsaturated acid derivatives showed their potential as antimicrobial molecules.
Strategizing Drug Therapies in Pulmonary Hypertension for Improved Outcomes
Authors: Beckmann Taylor , Shelley Patrisha , Patel Darshan , Vorla Mounica , Kalra Dinesh K.
Published: October 2022

Pulmonary hypertension (PH) is characterized by a resting mean pulmonary artery pressure (PAP) of 20 mmHg or more and is a disease of multiple etiologies. Of the various types of PH, pulmonary arterial hypertension (PAH) is characterized by elevated resistance in the pulmonary arterial tree. It is a rare but deadly disease characterized by vascular remodeling of the distal pulmonary arteries. This paper focuses on PAH diagnosis and management including current and future treatment options. Over the last 15 years, our understanding of this progressive disease has expanded from the concept of vasoconstrictive/vasodilatory mismatch in the pulmonary arterioles to now a better appreciation of the role of genetic determinants, numerous cell signaling pathways, cell proliferation and apoptosis, fibrosis, thrombosis, and metabolic abnormalities. While knowledge of its pathophysiology has expanded, the majority of the treatments available today still modulate the same three vasodilatory pathways that have been targeted for over 30 years (endothelin, nitric oxide, and prostacyclin). While modifying these pathways may help improve symptoms and quality of life, none of these directly modify the underlying disease pathogenesis. However, there are now studies ongoing with new drugs that can prevent or reverse these underlying causes of PAH. This review discusses the evidence base for the current treatment algorithms for PAH, as well as discusses novel therapies in development.
Willardiine and Its Synthetic Analogues: Biological Aspects and Implications in Peptide Chemistry of This Nucleobase Amino Acid
Authors: Palumbo Rosanna , Omodei Daniela , Vicidomini Caterina , Roviello Giovanni N.
Published: October 2022

Willardiine is a nonprotein amino acid containing uracil, and thus classified as nucleobase amino acid or nucleoamino acid, that together with isowillardiine forms the family of uracilylalanines isolated more than six decades ago in higher plants. Willardiine acts as a partial agonist of ionotropic glutamate receptors and more in particular it agonizes the non-N-methyl-D-aspartate (non-NMDA) receptors of L-glutamate: ie. the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and kainate receptors. Several analogues and derivatives of willardiine have been synthesised in the laboratory in the last decades and these compounds show different binding affinities for the non-NMDA receptors. More in detail, the willardiine analogues have been employed not only in the investigation of the structure of AMPA and kainate receptors, but also to evaluate the effects of receptor activation in the various brain regions. Remarkably, there are a number of neurological diseases determined by alterations in glutamate signaling, and thus, ligands for AMPA and kainate receptors deserve attention as potential neurodrugs. In fact, similar to willardiine its analogues often act as agonists of AMPA and kainate receptors. A particular importance should be recognized to willardiine and its thymine-based analogue AlaT also in the peptide chemistry field. In fact, besides the naturally-occurring short nucleopeptides isolated from plant sources, there are different examples in which this class of nucleoamino acids was investigated for nucleopeptide development. The applications are various ranging from the realization of nucleopeptide/DNA chimeras for diagnostic applications, and nucleoamino acid derivatization of proteins for facilitating protein-nucleic acid interaction, to nucleopeptide-nucleopeptide molecular recognition for nanotechnological applications. All the above aspects on both chemistry and biotechnological applications of willardine/willardine-analogues and nucleopeptide will be reviewed in this work.
Hot-Melt Extrusion of the Thermo-Sensitive Peptidomimetic Drug Enalapril Maleate
Authors: Hoffmann Lena , Breitkreutz Jörg , Quodbach Julian
Published: October 2022

The aim of this research was the production of extrudates for the treatment of hypertension and heart failure and the investigation of the degradation of the peptidomimetic drug enalapril maleate (EM) during hot-melt extrusion (HME). A fast HPLC method was developed to quantify enalapril maleate and possible degradation products. Screening experiments revealed that the diketopiperazine derivative (Impurity D) was the main degradation product. Hot-melt extrusion of enalapril maleate with the polymer Soluplus® enabled extrusion at 100 °C, whereas a formulation with the polymer Eudragit® E PO could be extruded at only 70 °C. Extrusion at 70 °C prevented thermal degradation. A stabilizing molecular interaction between enalapril maleate and Eudragit® E PO was identified via FT-IR spectroscopy. Dissolution studies were carried out to study the influence of the formulation on the dissolution behavior of enalapril maleate. These promising results can be transferred to other thermo-sensitive and peptidomimetic drugs to produce extrudates which can be used, for instance, as feedstock material for the production of patient-specific dosage forms via Fused Deposition Modeling (FDM) 3D printing.
Gold Nanorod-Incorporated Halloysite Nanotubes Functionalized with Antibody for Superior Antibacterial Photothermal Treatment
Authors: Prinz Setter Ofer , Snoyman Iser , Shalash Ghazal , Segal Ester
Published: October 2022

The global spread of antibiotic-resistant strains, and the need to protect the microflora from non-specific antibiotics require more effective and selective alternatives. In this work, we demonstrate for the first time a superior antibacterial photothermal effect of plasmonic gold nanorods (AuNRs) via their incorporation onto natural clay halloysite nanotubes (HNTs), which were functionalized with anti-E. coli antibodies (Ab-HNTs). AuNRs were incorporated onto the Ab-HNTs through a facile freeze–thaw cycle, and antibody integrity following the incorporation was confirmed via infrared spectroscopy and fluorescence immunolabeling. The incorporation efficiency was studied using UV-Vis absorption and transmission electron microscopy (TEM). Mixtures of E. coli and AuNR-Ab-HNTs hybrids or free AuNRs were irradiated with an 808 nm laser at 3–4 W cm−2, and the resulting photothermal antibacterial activity was measured via plate count. The irradiated AuNR-Ab-HNTs hybrids exerted an 8-fold higher antibacterial effect compared to free AuNR under 3.5 W cm−2; whereas the latter induced a 6 °C-higher temperature elevation. No significant antibacterial activity was observed for the AuNR-Ab-HNTs hybrid against non-target bacteria species (Serratia marcescens and Staphylococcus epidermidis). These findings are ascribed to the localization of the photothermal ablation due to the binding of the antibody-functionalized clay to its target bacteria, as supported through TEM imaging. In the future, the HNTs-based selective carriers presented herein could be tailored with other antibacterial nanoparticles or against another microorganism via the facile adjustment of the immobilized antibody.
The Effect of Humidity on the Dissolution Kinetics and Tablet Properties of Immediate-Release Tablet Formulation Containing Lamotrigine
Authors: Lalić-Popović Mladena , Švonja Parezanović Gordana , Todorović Nemanja , Zeković Zoran , Pavlić Branimir , Milošević Nataša , Čanji Panić Jelena , Stjepanović Ana , Andrijević Ljiljana
Published: October 2022

This study aims to find the effects of high (75%) and low (30%) humidity conditions and its correlation with formulation composition on dissolution kinetics of lamotrigine (LMT) from prepared immediate-release tablets during one- and four-week periods. Two types of fillers microcrystalline cellulose (MCC) or anhydrous lactose (LAC), disintegrant sodium starch glycolate (NaSG, 0.5% or 4%), and lubricant magnesium stearate (MgST, 0.25% or 5%) were used. A three-factor two-stage complete factorial design (23) was used to assess the influence of the composition of the tested formulations. The tablets were produced by direct compression and characterized using a disintegration test, a resistance to crushing test, and dissolution tests (pH 1.2 and pH 6.8). Using Design Expert software, it was concluded that in addition to the effect of fillers on pH 6.8, NaSG has a significant impact after exposure to high and low humidity, as well as its interaction with LAC and MCC. In the dissolution medium pH 1.2, under conditions of high humidity, the content of MgST and NaSG and their interaction show a significant influence. The release rate of LMT was affected by humidity as well as type of excipients and their interactions.
Cyclodextrin Derivatives as Promising Solubilizers to Enhance the Biological Activity of Rosmarinic Acid
Authors: Stasiłowicz-Krzemień Anna , Rosiak Natalia , Płazińska Anita , Płaziński Wojciech , Miklaszewski Andrzej , Tykarska Ewa , Cielecka-Piontek Judyta
Published: October 2022

Rosmarinic acid (RA) is a natural antioxidant with neuroprotective properties; however, its preventive and therapeutic use is limited due to its slight solubility and poor permeability. This study aimed to improve RA physicochemical properties by systems formation with cyclodextrins (CDs): hydroxypropyl-α-CD (HP-α-CD), HP-β-CD, and HP-γ-CD, which were prepared by the solvent evaporation (s.e.) method. The interactions between components were determined by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Fourier Transform infrared spectroscopy (FTIR). The sites of interaction between RA and CDs were suggested as a result of in silico studies focused on assessing the interaction between molecules. The impact of amorphous systems formation on water solubility, dissolution rate, gastrointestinal (GIT) permeability, and biological activity was studied. RA solubility was increased from 5.869 mg/mL to 113.027 mg/mL, 179.840 mg/mL, and 194.354 mg/mL by systems formation with HP-α-CD, HP-β-CD, and HP-γ-CD, respectively. During apparent solubility studies, the systems provided an acceleration of RA dissolution. Poor RA GIT permeability at pH 4.5 and 5.8, determined by parallel artificial membrane permeability assay (PAMPA system), was increased; RA–HP-γ-CD s.e. indicated the greatest improvement (at pH 4.5 from Papp 6.901 × 10−7 cm/s to 1.085 × 10−6 cm/s and at pH 5.8 from 5.019 × 10−7 cm/s to 9.680 × 10−7 cm/s). Antioxidant activity, which was determined by DPPH, ABTS, CUPRAC, and FRAP methods, was ameliorated by systems; the greatest results were obtained for RA–HP-γ-CD s.e. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) was increased from 36.876% for AChE and 13.68% for BChE to a maximum inhibition of the enzyme (plateau), and enabled reaching IC50 values for both enzymes by all systems. CDs are efficient excipients for improving RA physicochemical and biological properties. HP-γ-CD was the greatest one with potential for future food or dietary supplement applications.
cGMP Analogues with Opposing Actions on CNG Channels Selectively Modulate Rod or Cone Photoreceptor Function
Authors: Wucherpfennig Sophie , Haq Wadood , Popp Valerie , Kesh Sandeep , Das Soumyaparna , Melle Christian , Rentsch Andreas , Schwede Frank , Paquet-Durand François , Nache Vasilica
Published: October 2022

The vertebrate retina harbors rod and cone photoreceptors. Human vision critically depends on cone photoreceptor function. In the phototransduction cascade, cGMP activates distinct rod and cone isoforms of the cyclic nucleotide-gated (CNG) channel. Excessive cGMP levels initiate a pathophysiological rollercoaster, which starts with CNG channel over-activation, typically in rod photoreceptors. This triggers cell death of rods first, and then cones, and is the root cause of many blinding retinal diseases, including Retinitis pigmentosa. While targeting of CNG channels has been proposed for therapeutic purposes, thus far, it has not been possible to inhibit rod CNG channels without compromising cone function. Here, we present a novel strategy, based on cGMP analogues with opposing actions on CNG channels, which enables the selective modulation of either rod or cone photoreceptor activity. The combined treatment with the weak rod-selective CNG-channel inhibitor (Rp-8-Br-PET-cGMPS) and the cone-selective CNG-channel activator (8-pCPT-cGMP) essentially normalized rod CNG-channel function while preserving cone functionality at physiological and pathological cGMP levels. Hence, combinations of cGMP analogues with desired properties may elegantly address the isoform-specificity problem in future pharmacological therapies. Moreover, this strategy may allow for improvements in visual performance in certain light environments.
SAR Study and Molecular Mechanism Investigation of Novel Naphthoquinone-furan-2-cyanoacryloyl Hybrids with Antitumor Activity
Authors: Liu Pingxian , Fan Dongmei , Qiao Wenliang , He Xinlian , Zhang Lidan , Jiang Yunhan , Yang Tao
Published: October 2022

A series of novel naphthoquinone-furan-2-cyanoacryloyl hybrids were designed; they were synthesized and preliminarily evaluated for their anti-proliferative activities in vitro against several cancer cell lines and normal cells. The most potent compound, 5c, inhibited the proliferation of HeLa cells (IC50 value of 3.10 ± 0.02 μM) and colony survival, and it induced apoptosis while having relatively weaker effects on normal cells. Compound 5c also triggered ROS generation and accumulation, thus partially contributing to the observed cell apoptosis. A Western blotting analysis demonstrated that compound 5c inhibited the phosphorylation of STAT3. Furthermore, a biolayer interferometry (BLI) analysis confirmed that compound 5c had a direct effect on STAT3, with a KD value of 13.0 μM. Molecular docking showed that 5c specifically occupied the subpockets in the SH2 domain, thereby blocking the whole transmission signaling process. Overall, this study provides an important structural reference for the development of effective antitumor agents.
Biosynthetic Silver Nanoparticles Inhibit the Malignant Behavior of Gastric Cancer Cells and Enhance the Therapeutic Effect of 5-Fluorouracil by Promoting Intracellular ROS Generation and Apoptosis
Authors: Yuan Jingwen , Khan Shahid Ullah , Luo Jiajun , Jiang Yue , Yang Yu , Yan Junfeng , Tong Qiang
Published: October 2022

(1) Background: Gastric cancer (GC) is the fourth leading cause of cancer death worldwide. Silver nanoparticles (Ag-NPs) have been increasingly used in the diagnosis and treatment of cancer due to their physicochemical properties. This study investigated the role of a kind of biosynthetic silver nanoparticle (b-Ag) in the development of GC, the enhancement of 5-fluorouracil (5F), and its mechanism. (2) Methods: X-ray, transmission electron microscopy (TEM), and UV absorbance were used to detect the characterizations of AgNPs. CCK8, Colony formation and a Transwell assay were performed to confirm the malignant behaviors of GC. DCFH-DA and DHE were used to detect intracellular reactive oxygen species (ROS). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression of apoptosis-related genes. (3) Results: Compared with the chemosynthetic silver nanoparticles (c-Ag), b-Ag had a stronger cytokilling effect, and it had a better inhibition on the malignant phenotype of GC when combined with 5F. The b-Ag increased the expression of Bax and P53 while decreasing the expression of Bcl2. It also promoted the generation of intracellular ROS. (4) Conclusions: By promoting cell apoptosis and increasing intracellular ROS, b-Ag inhibited the development of GC and enhanced the inhibition of 5F on GC.