bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing the Concepts of Homeostasis, Homeorhesis, Allostasis, Elasticity, Flexibility and Plasticity of Brain Function
Authors: Pereira Alfredo
Published: November 2021

I discuss some concepts advanced for the understanding of the complex dynamics of brain functions, and relate them to approaches in affective, cognitive and action neurosciences. These functions involve neuro-glial interactions in a dynamic system that receives sensory signals from the outside of the central nervous system, processes information in frequency, amplitude and phase-modulated electrochemical waves, and control muscles and glands to generate behavioral patterns. The astrocyte network is in charge of controlling global electrochemical homeostasis, and Hodgkin–Huxley dynamics drive the bioelectric homeostasis of single neurons. In elastic processes, perturbations cause instability, but the system returns to the basal equilibrium. In allostatic processes, perturbations elicit a response from the system, reacting to the deviation and driving the system to stable states far from the homeostatic equilibrium. When the system does not return to a fixed point or region of the state space, the process is called homeorhetic, and may present two types of evolution: (a) In flexible processes, there are previously existing “attractor” stable states that may be achieved after the perturbation, depending on context; (b) In plastic processes, the homeostatic set point(s) is(are) changed; the system is in a process of adaptation, in which the allostatic forces do not drive it back to the previous set point, but project to the new one. In the temporal phase from the deviant state to the recovery of stability, the system generates sensations that indicate if the recovery is successful (pleasure-like sensations) or if there is a failure (pain-like sensations).
A Multidisciplinary Perspective of Ultra-Processed Foods and Associated Food Processing Technologies: A View of the Sustainable Road Ahead
Authors: Capozzi Francesco , Magkos Faidon , Fava Fabio , Milani Gregorio Paolo , Agostoni Carlo , Astrup Arne , Saguy Israel Sam
Published: November 2021

Ultra-processed foods (UPFs) are negatively perceived by part of the scientific community, the public, and policymakers alike, to the extent they are sometimes referred to as not “real food”. Many observational surveys have linked consumption of UPFs to adverse health outcomes. This narrative synthesis and scientific reappraisal of available evidence aims to: (i) critically evaluate UPF-related scientific literature on diet and disease and identify possible research gaps or biases in the interpretation of data; (ii) emphasize the innovative potential of various processing technologies that can lead to modifications of the food matrix with beneficial health effects; (iii) highlight the possible links between processing, sustainability and circular economy through the valorisation of by-products; and (iv) delineate the conceptual parameters of new paradigms in food evaluation and classification systems. Although greater consumption of UPFs has been associated with obesity, unfavorable cardiometabolic risk factor profiles, and increased risk for non-communicable diseases, whether specific food processing techniques leading to ultra-processed formulations are responsible for the observed links between UPFs and various health outcomes remains elusive and far from being understood. Evolving technologies can be used in the context of sustainable valorisation of food processing by-products to create novel, low-cost UPFs with improved nutritional value and health potential. New paradigms of food evaluation and assessment should be funded and developed on several novel pillars—enginomics, signalling, and precision nutrition—taking advantage of available digital technologies and artificial intelligence. Research is needed to generate required scientific knowledge to either expand the current or create new food evaluation and classification systems, incorporating processing aspects that may have a significant impact on health and wellness, together with factors related to the personalization of foods and diets, while not neglecting recycling and sustainability aspects. The complexity and the predicted immense size of these tasks calls for open innovation mentality and a new mindset promoting multidisciplinary collaborations and partnerships between academia and industry.
Effect of a Chronic Intake of the Natural Sweeteners Xylitol and Erythritol on Glucose Absorption in Humans with Obesity
Authors: Bordier Valentine , Teysseire Fabienne , Schlotterbeck Götz , Senner Frank , Beglinger Christoph , Meyer-Gerspach Anne Christin , Wölnerhanssen Bettina K.
Published: November 2021

In patients with obesity, accelerated nutrients absorption is observed. Xylitol and erythritol are of interest as alternative sweeteners, and it has been shown in rodent models that their acute ingestion reduces intestinal glucose absorption. This study aims to investigate whether a chronic intake of xylitol and erythritol impacts glucose absorption in humans with obesity. Forty-six participants were randomized to take either 8 g of xylitol or 12 g of erythritol three times a day for five to seven weeks, or to be part of the control group (no substance). Before and after the intervention, intestinal glucose absorption was assessed during an oral glucose tolerance test with 3-Ortho-methyl-glucose (3-OMG). The effect of xylitol or erythritol intake on the area under the curve for 3-OMG concentration was not significant. Neither the time (pre or post intervention), nor the group (control, xylitol, or erythritol), nor the time-by-group interaction effects were significant (p = 0.829, p = 0.821, and p = 0.572, respectively). Therefore, our results show that a chronic intake of the natural sweeteners xylitol and erythritol does not affect intestinal glucose absorption in humans with obesity.
Association between Plant-Based Dietary Patterns and Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis of Prospective Cohort Studies
Authors: Gan Zuo Hua , Cheong Huey Chiat , Tu Yu-Kang , Kuo Po-Hsiu
Published: November 2021

Plant-based diets, characterized by a higher consumption of plant foods and a lower consumption of animal foods, are associated with a favorable cardiovascular disease (CVD) risk, but evidence regarding the association between plant-based diets and CVD (including coronary heart disease (CHD) and stroke) incidence remain inconclusive. A literature search was conducted using the PubMed, EMBASE and Web of Science databases through December 2020 to identify prospective observational studies that examined the associations between plant-based diets and CVD incidence among adults. A systematic review and a meta-analysis using random effects models and dose–response analyses were performed. Ten studies describing nine unique cohorts were identified with a total of 698,707 participants (including 137,968 CVD, 41,162 CHD and 13,370 stroke events). Compared with the lowest adherence, the highest adherence to plant-based diets was associated with a lower risk of CVD (RR 0.84; 95% CI 0.79–0.89) and CHD (RR 0.88; 95% CI 0.81–0.94), but not of stroke (RR 0.87; 95% CI 0.73–1.03). Higher overall plant-based diet index (PDI) and healthful PDI scores were associated with a reduced CVD risk. These results support the claim that diets lower in animal foods and unhealthy plant foods, and higher in healthy plant foods are beneficial for CVD prevention. Protocol was published in PROSPERO (No. CRD42021223188).
Single Nucleotide Polymorphisms in Close Proximity to the Fibroblast Growth Factor 21 (FGF21) Gene Found to Be Associated with Sugar Intake in a Swedish Population
Authors: Janzi Suzanne , González-Padilla Esther , Najafi Kevin , Ramne Stina , Ahlqvist Emma , Borné Yan , Sonestedt Emily
Published: November 2021

Hereditary mechanisms are partially responsible for individual differences in sensitivity to and the preference for sweet taste. The primary aim of this study was to examine the associations between 10 genetic variants and the intake of total sugar, added sugar, and sugars with sweet taste (i.e., monosaccharides and sucrose) in a middle-aged Swedish population. Two single nucleotide polymorphisms (SNPs) within the Fibroblast grow factor 21 (FGF21) gene, seven top hits from a genome-wide association study (GWAS) on total sugar intake, and one SNP within the fat mass and obesity associated (FTO) gene (the only SNP reaching GWAS significance in a previous study), were explored in relation to various forms of sugar intake in 22,794 individuals from the Malmö Diet and Cancer Study, a population-based cohort for which data were collected between 1991–1996. Significant associations (p = 6.82 × 10−7 − 1.53 × 10−3) were observed between three SNPs (rs838145, rs838133, and rs8103840) in close relation to the FGF21 gene with high Linkage Disequilibrium, and all the studied sugar intakes. For the rs11642841 within the FTO gene, associations were found exclusively among participants with a body mass index ≥ 25 (p < 5 × 10−3). None of the remaining SNPs studied were associated with sugar intake in our cohort. A further GWAS should be conducted to identify novel genetic variants associated with the intake of sugar.
Association between Free Sugars Intake and Excessive Daytime Sleepiness among Chinese Adolescents
Authors: Xi Yue , Lin Qian , Yang Qiping , Li Fang , Liu Hanmei , Luo Jing , Ouyang Yufeng , Sun Minghui , Yong Cuiting , Xiang Caihong , Zheng Wenya
Published: November 2021

This study aimed to investigate the prevalence of excessive daytime sleepiness (EDS) and explore the association between free sugars intake and EDS. In this cross-sectional study, a total of 1517 middle school students (808 boys and 707 girls) aged 12~14 years were recruited. The study was conducted in Changsha city, China. Adolescents completed an online questionnaire, including the Epworth Sleepiness Scale (ESS), sleep characteristics, a 12-item Food Frequency Questionnaire (FFQ), and other self-reported information. The ESS score ≥ ten was defined as EDS. The anthropometric indices, including height, weight, and waist circumference, were measured and recorded by uniformly trained assistants. Statistical analyses included the Chi-square test and binary logistic regression model. The mean ESS score and free sugars consumption were 6.8 ± 3.9 points and 53.1 ± 44.7 g/d, respectively. The prevalence of EDS among adolescents was 22.5%, and more girls than boys had EDS (26.1% vs. 19.4%, p < 0.05). An exceeded free sugars intake was positively associated with EDS, with the adjusted Odds Ratio (OR) with its 95% Confident Interval (95% CI) of 1.366 (1.060~1.761, p < 0.05). EDS and excessive consumption of free sugars are commonly found among Chinese adolescents. Further studies are needed to confirm whether free sugars restriction can be meaningful to improve daytime drowsiness in those with EDS.
Beta-Glucans from Fungi: Biological and Health-Promoting Potential in the COVID-19 Pandemic Era
Authors: Mirończuk-Chodakowska Iwona , Kujawowicz Karolina , Witkowska Anna Maria
Published: November 2021

Beta-glucans comprise a group of polysaccharides of natural origin found in bacteria, algae, and plants, e.g., cereal seeds, as well as microfungi and macrofungi (mushrooms), which are characterized by diverse structures and functions. They are known for their metabolic and immunomodulatory properties, including anticancer, antibacterial, and antiviral. Recent reports suggest a potential of beta-glucans in the prevention and treatment of COVID-19. In contrast to β-glucans from other sources, β-glucans from mushrooms are characterized by β-1,3-glucans with short β-1,6-side chains. This structure is recognized by receptors located on the surface of immune cells; thus, mushroom β-glucans have specific immunomodulatory properties and gained BRM (biological response modifier) status. Moreover, mushroom beta-glucans also owe their properties to the formation of triple helix conformation, which is one of the key factors influencing the bioactivity of mushroom beta-glucans. This review summarizes the latest findings on biological and health-promoting potential of mushroom beta-glucans for the treatment of civilization and viral diseases, with particular emphasis on COVID-19.
Effect of Standardized Grape Powder Consumption on the Gut Microbiome of Healthy Subjects: A Pilot Study
Authors: Yang Jieping , Kurnia Patrick , Henning Susanne M. , Lee Rupo , Huang Jianjun , Garcia Michael C. , Surampudi Vijaya , Heber David , Li Zhaoping
Published: November 2021

Grapes provide a rich source of polyphenols and fibers. This study aimed to evaluate the effect of the daily consumption of 46 g of whole grape powder, providing the equivalent of two servings of California table grapes, on the gut microbiome and cholesterol/bile acid metabolism in healthy adults. This study included a 4-week standardization to a low-polyphenol diet, followed by 4 weeks of 46 g of grape powder consumption while continuing the low-polyphenol diet. Compared to the baseline, 4 weeks of grape powder consumption significantly increased the alpha diversity index of the gut microbiome. There was a trend of increasing Verrucomicrobia (p = 0.052) at the phylum level, and a significant increase in Akkermansia was noted. In addition, there was an increase in Flavonifractor and Lachnospiraceae_UCG-010, but a decrease in Bifidobacterium and Dialister at the genus level. Grape powder consumption significantly decreased the total cholesterol by 6.1% and HDL cholesterol by 7.6%. There was also a trend of decreasing LDL cholesterol by 5.9%, and decreasing total bile acid by 40.9%. Blood triglyceride levels and body composition were not changed by grape powder consumption. In conclusion, grape powder consumption significantly modified the gut microbiome and cholesterol/bile acid metabolism.
The Effects of 6 Weeks of Tribulus terrestris L. Supplementation on Body Composition, Hormonal Response, Perceived Exertion, and CrossFit® Performance: A Randomized, Single-Blind, Placebo-Controlled Study
Authors: Fernández-Lázaro Diego , Mielgo-Ayuso Juan , del Valle Soto Miguel , Adams David P. , González-Bernal Jerónimo J. , Seco-Calvo Jesús
Published: November 2021

Tribulus terrestris L. (TT) supplementation have been shown to enhance sports performance in many but not all studies. Moreover, data regarding the potential impact of TT supplementation on CrossFit® endurance is limited. This study aimed to determine whether TT supplementation improve body composition, hormonal response, and performance among CrossFit® athletes. In a randomized, single-blind, placebo-controlled trial, a total of 30 healthy CrossFit®-trained males were randomly allocated to receive either 770 mg of TT supplementation or a placebo daily for 6 weeks. Body mass, fat mass, fat composition, testosterone and cortisol levels, and CrossFit® performance (5 common Workouts of the Day: back squat, bench press, dead lift, Grace, and CrossFit® Total) were assessed before and after intervention. There were no significant group x time interactions for the outcomes of the study except for testosterone levels and bench press performance (p < 0.05). TT supplementation did not impact enhance performance or body composition in CrossFit® male athletes. However, TT supplementation may act as a testosterone booster helping the recovery after physical loads and mitigating fatigue.
Diet Quality and Risk of Parkinson’s Disease: The Rotterdam Study
Authors: Strikwerda Anne J. , Dommershuijsen Lisanne J. , Ikram M. Kamran , Voortman Trudy
Published: November 2021

The Mediterranean diet has been associated with the risk of Parkinson’s disease (PD), but limited research has been performed on other dietary patterns. We studied the relationship between overall diet quality and PD risk in the general population. We included 9414 participants from the Rotterdam Study, a prospective population-based study in the Netherlands. Diet was defined using a Dutch diet quality score, a Mediterranean diet score and data-driven dietary patterns constructed with principal component analysis (PCA). During an average follow-up of 14.1 years, PD was diagnosed in 129 participants. We identified a ‘Prudent’, ‘Unhealthy’ and ‘Traditional Dutch’ pattern from the PCA. We found a possible association between the Mediterranean diet (Hazard ratio (HR) per standard deviation (SD) 0.89 (95% confidence interval (CI) 0.74–1.07)), the ‘Prudent’ pattern (HR per SD 0.81 (95% CI 0.61–1.08)) and the risk of PD. However, no associations with PD risk were found for the Dutch diet quality score (HR per SD 0.93 (95% CI 0.77–1.12)), the ‘Unhealthy’ pattern (HR per SD 1.05 (95% CI 0.85–1.29)) or the ‘Traditional Dutch’ pattern (HR per SD 0.90 (95% CI 0.69–1.17)). In conclusion, our results corroborate previous findings of a possible protective effect of the Mediterranean diet. Further research is warranted to study the effect of other dietary patterns on PD risk.
Antioxidant, Anti-Inflammatory, and Immunomodulatory Properties of Tea—The Positive Impact of Tea Consumption on Patients with Autoimmune Diabetes
Authors: Winiarska-Mieczan Anna , Tomaszewska Ewa , Jachimowicz Karolina
Published: November 2021

The physiological markers of autoimmune diabetes include functional disorders of the antioxidative system as well as progressing inflammation and the presence of autoantibodies. Even though people with type 1 diabetes show genetic predispositions facilitating the onset of the disease, it is believed that dietary factors can stimulate the initiation and progression of the disease. This paper analyses the possibility of using tea as an element of diet therapy in the treatment of type 1 diabetes. Based on information available in literature covering the last 10 years, the impact of regular tea consumption or diet supplements containing tea polyphenols on the oxidative status as well as inflammatory and autoimmune response of the organism was analyzed. Studies conducted on laboratory animals, human patients, and in vitro revealed positive effects of the consumption of tea or polyphenols isolated therefrom on the diabetic body. Few reports available in the literature pertain to the impact of tea on organisms affected by type 1 diabetes as most (over 85%) have focused on cases of type 2 diabetes. It has been concluded that by introducing tea into the diet, it is possible to alleviate some of the consequences of oxidative stress and inflammation, thus limiting their destructive impact on the patients’ organisms, consequently improving their quality of life, regardless of the type of diabetes. Furthermore, elimination of inflammation should reduce the incidence of immune response. One should consider more widespread promotion of tea consumption by individuals genetically predisposed to diabetes, especially considering the drink’s low price, easy availability, overall benefits to human health, and above all, the fact that it can be safely used over extended periods of time, regardless of the patient’s age.
Knowledge on the Complementary Feeding of Infants Older than Six Months among Mothers Following Vegetarian and Traditional Diets
Authors: Kostecka Malgorzata , Kostecka-Jarecka Joanna
Published: November 2021

Solid foods should be introduced not later than the age of six months, regardless of whether the family adheres to a traditional, vegetarian, or vegan diet. The aim of this study was to compare the knowledge on the complementary feeding of infants older than six months among mothers who adhere to traditional and vegetarian diets and to identify problems that require the assistance of a dietician. A total of 251 mothers of children aged 10–12 months participated in the study. Only 10% of vegetarian mothers declared that they had placed their children on a vegetarian diet, whereas 36 mothers adhered to a lacto-ovo-vegetarian diet during complementary feeding in the first year of life. Mothers adhering to a traditional diet were characterized by lower levels of knowledge (4.1 ± 2.3 points) than vegetarian mothers (5.3 ± 2.1 points). Mothers following a traditional diet were more likely to indicate a higher than recommended number of daily meals (OR = 1.76; Cl: 1.31–1.97, p < 0.001). Significant differences were noted in the respondents’ adherence to the BLW method, which was more readily implemented by vegan (p < 0.05) and lacto-vegetarian (p < 0.05) mothers and was least popular among mothers following a traditional diet (OR = 0.81; CI: 0.66–1.23, p < 0.04). Vegetarian mothers unnecessarily delayed the introduction of gluten and potentially allergizing foods to the children’s diets, sometimes even past the age of 12 months.
Effects of Peanut Protein Supplementation on Resistance Training Adaptations in Younger Adults
Authors: Sexton Casey L. , Smith Morgan A. , Smith Kristen S. , Osburn Shelby C. , Godwin Joshua S. , Ruple Bradley A. , Hendricks Alex M. , Mobley Christopher B. , Goodlett Michael D. , Frugé Andrew D. , Young Kaelin C. , Roberts Michael D.
Published: November 2021

Protein supplementation is a commonly employed strategy to enhance resistance training adaptations. However, little research to date has examined if peanut protein supplementation is effective in this regard. Thus, we sought to determine if peanut protein supplementation (PP; 75 total g/d of powder providing 30 g/d protein, >9.2 g/d essential amino acids, ~315 kcal/d) affected resistance training adaptations in college-aged adults. Forty-seven college-aged adults (n = 34 females, n = 13 males) with minimal prior training experience were randomly assigned to a PP group (n = 18 females, n = 5 males) or a non-supplement group (CTL; n = 16 females, n = 8 males) (ClinicalTrials.gov trial registration NCT04707963; registered 13 January 2021). Body composition and strength variables were obtained prior to the intervention (PRE). Participants then completed 10 weeks of full-body resistance training (twice weekly) and PP participants consumed their supplement daily. POST measures were obtained 72 h following the last training bout and were identical to PRE testing measures. Muscle biopsies were also obtained at PRE, 24 h following the first exercise bout, and at POST. The first two biopsy time points were used to determine myofibrillar protein synthesis (MyoPS) rates in response to a naïve training bout with or without PP, and the PRE and POST biopsies were used to determine muscle fiber adaptations in females only. Dependent variables were analyzed in males and females separately using two-way (supplement × time) repeated measures ANOVAs, unless otherwise stated. The 24-h integrated MyoPS response to the first naïve training bout was similar between PP and CTL participants (dependent samples t-test p = 0.759 for females, p = 0.912 for males). For males, the only significant supplement × time interactions were for DXA-derived fat mass (interaction p = 0.034) and knee extensor peak torque (interaction p = 0.010); these variables significantly increased in the CTL group (p < 0.05), but not the PP group. For females, no significant supplement × time interactions existed, although interactions for whole body lean tissue mass (p = 0.088) and vastus lateralis thickness (p = 0.099) approached significance and magnitude increases in these characteristics favored the PP versus CTL group. In summary, this is the second study to determine the effects of PP supplementation on resistance training adaptations. While PP supplementation did not significantly enhance training adaptations, the aforementioned trends in females, the limited n-size in males, and this being the second PP supplementation study warrant more research to determine if different PP dosing strategies are more effective than the current approach.
Experimental Induction of Tenacibaculosis in Atlantic Salmon (Salmo salar L.) Using Tenacibaculum maritimum, T. dicentrarchi, and T. finnmarkense
Authors: Nowlan Joseph P. , Britney Scott R. , Lumsden John S. , Russell Spencer
Published: November 2021

There is a limited understanding of the pathogenesis of tenacibaculosis in Atlantic salmon (Salmo salar L.) and there are few reproducible exposure models for comparison. Atlantic salmon were exposed via bath to Tenacibaculum maritimum, T. dicentrarchi, or T. finnmarkense, and were then grouped with naïve cohabitants. Mortalities had exaggerated clinical signs of mouthrot, a presentation of tenacibaculosis characterized by epidermal ulceration and yellow plaques, on the mouth and less frequently on other tissues. Histopathology showed tissue spongiosis, erosion, ulceration, and necrosis ranging from mild to marked, locally to regionally extensive with mats of intralesional bacteria on the rostrum, vomer, gill rakers, gill filaments, and body surface. Exposure to T. maritimum resulted in less than a 0.4 probability of survival for both exposed and cohabitants until Day 21. Exposures to T. dicentrarchi resulted in 0 and 0.55 (exposed), and 0.8 and 0.9 (cohabitant) probability of survival to Day 12 post-exposure, while T. finnmarkense had a 0.9 probability of survival to Day 12 for all groups. This experimental infection model will be useful to further investigate the pathogenesis of tenacibaculosis, its treatment, and immunity to Tenacibaculum species.
Metabolic Profile and Mycoherbicidal Activity of Three Alternaria alternata Isolates for the Control of Convolvulus arvensis, Sonchus oleraceus, and Xanthium strumarium
Authors: Abdessemed Nesma , Staropoli Alessia , Zermane Nadjia , Vinale Francesco
Published: November 2021

Alternaria alternata isolates C1, S1, and X3 were isolated respectively from the weeds Convolvulus arvensis, Sonchus oleraceus, and Xanthium strumarium in Algiers during 2016 and identified by morphological and molecular analyses. The aim of this investigation was to chemically characterize the exometabolome of these fungi and to evaluate the myco-herbicidal potential of their culture filtrates, crude extracts, or fractions towards target weeds. Results revealed a great heterogeneity in the biochemical profiles of the exometabolome with the remarkable presence of two compounds: tenuazonic acid (TeA) and triprenyl phenol-7 (SMTP-7). To the best of our knowledge, SMTP-7—found in all the isolates—as well as 12-methoxycitromycin detected in the culture filtrate of isolate C1, have never been reported to be produced by A. alternata. Some fractions of isolates C1 and S1 showed symptoms (necrosis and chlorosis) on the detached leaves of C. arvensis and S. oleraceus, respectively with up to 100% phytotoxic effect at low concentration. In conclusion, biochemical characterization revealed great difference of C1, S1, and X3 exometabolome that is likely to explain the difference in their phytotoxic activity. Some fractions (d1, e1, h1, i1, a2, and f2) of isolates C1 and S1 of A. alternata caused severe necrosis and chlorosis on the injured detached leaves of C. arvensis and S. oleraceus, respectively.
Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells
Authors: Boulos Joelle C. , Saeed Mohamed E. M. , Chatterjee Manik , Bülbül Yagmur , Crudo Francesco , Marko Doris , Munder Markus , Klauck Sabine M. , Efferth Thomas
Published: November 2021

Crizotinib was a first generation of ALK tyrosine kinase inhibitor approved for the treatment of ALK-positive non-small-cell lung carcinoma (NSCLC) patients. COMPARE and cluster analyses of transcriptomic data of the NCI cell line panel indicated that genes with different cellular functions regulated the sensitivity or resistance of cancer cells to crizotinib. Transcription factor binding motif analyses in gene promoters divulged two transcription factors possibly regulating the expression of these genes, i.e., RXRA and GATA1, which are important for leukemia and erythroid development, respectively. COMPARE analyses also implied that cell lines of various cancer types displayed varying degrees of sensitivity to crizotinib. Unexpectedly, leukemia but not lung cancer cells were the most sensitive cells among the different types of NCI cancer cell lines. Re-examining this result in another panel of cell lines indeed revealed that crizotinib exhibited potent cytotoxicity towards acute myeloid leukemia and multiple myeloma cells. P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells were cross-resistant to crizotinib. NCI-H929 multiple myeloma cells were the most sensitive cells. Hence, we evaluated the mode of action of crizotinib on these cells. Although crizotinib is a TKI, it showed highest correlation rates with DNA topoisomerase II inhibitors and tubulin inhibitors. The altered gene expression profiles after crizotinib treatment predicted several networks, where TOP2A and genes related to cell cycle were downregulated. Cell cycle analyses showed that cells incubated with crizotinib for 24 h accumulated in the G2M phase. Crizotinib also increased the number of p-H3(Ser10)-positive NCI-H929 cells illustrating crizotinib’s ability to prevent mitotic exit. However, cells accumulated in the sub-G0G1 fraction with longer incubation periods, indicating apoptosis induction. Additionally, crizotinib disassembled the tubulin network of U2OS cells expressing an α-tubulin-GFP fusion protein, preventing migration of cancer cells. This result was verified by in vitro tubulin polymerization assays. In silico molecular docking also revealed a strong binding affinity of crizotinib to the colchicine and Vinca alkaloid binding sites. Taken together, these results demonstrate that crizotinib destabilized microtubules. Additionally, the decatenation assay showed that crizotinib partwise inhibited the catalytic activity of DNA topoisomerase II. In conclusion, crizotinib exerted kinase-independent cytotoxic effects through the dual inhibition of tubulin polymerization and topoisomerase II and might be used to treat not only NSCLC but also multiple myeloma.
Diversity-Oriented Synthesis: Amino Acetophenones as Building Blocks for the Synthesis of Natural Product Analogs
Authors: Eymery Mathias , Tran-Nguyen Viet-Khoa , Boumendjel Ahcène
Published: November 2021

Diversity-Oriented Synthesis (DOS) represents a strategy to obtain molecule libraries with diverse structural features starting from one common compound in limited steps of synthesis. During the last two decades, DOS has become an unmissable strategy in organic synthesis and is fully integrated in various drug discovery processes. On the other hand, natural products with multiple relevant pharmacological properties have been extensively investigated as scaffolds for ligand-based drug design. In this article, we report the amino dimethoxyacetophenones that can be easily synthesized and scaled up from the commercially available 3,5-dimethoxyaniline as valuable starting blocks for the DOS of natural product analogs. More focus is placed on the synthesis of analogs of flavones, coumarins, azocanes, chalcones, and aurones, which are frequently studied as lead compounds in drug discovery.
Studies of Potency and Efficacy of an Optimized Artemisinin-Quinoline Hybrid against Multiple Stages of the Plasmodium Life Cycle
Authors: Quadros Helenita C. , Çapcı Aysun , Herrmann Lars , D’Alessandro Sarah , Fontinha Diana , Azevedo Raquel , Villarreal Wilmer , Basilico Nicoletta , Prudêncio Miguel , Tsogoeva Svetlana B. , Moreira Diogo R. M.
Published: November 2021

A recently developed artemisinin-quinoline hybrid, named 163A, has been shown to display potent activity against the asexual blood stage of Plasmodium, the malaria parasite. In this study, we determined its in vitro cytotoxicity to mammalian cells, its potency to suppress P. berghei hepatic infection and to decrease the viability of P. falciparum gametocytes, in addition to determining whether the drug exhibits efficacy of a P. berghei infection in mice. This hybrid compound has a low level of cytotoxicity to mammalian cells and, conversely, a high level of selectivity. It is potent in the prevention of hepatic stage development as well as in killing gametocytes, denoting a potential blockage of malaria transmission. The hybrid presents a potent inhibitory activity for beta-hematin crystal formation, in which subsequent assays revealed that its endoperoxide component undergoes bioactivation by reductive reaction with ferrous heme towards the formation of heme-drug adducts; in parallel, the 7-chloroquinoline component has binding affinity for ferric hemin. Both structural components of the hybrid co-operate to enhance the inhibition of beta-hematin, and this bitopic ligand property is essential for arresting the growth of asexual blood parasites. We demonstrated the in vivo efficacy of the hybrid as an erythrocytic schizonticide agent in comparison to a chloroquine/artemisinin combination therapy. Collectively, the findings suggest that the bitopic property of the hybrid is highly operative on heme detoxification suppression, and this provides compelling evidence for explaining the action of the hybrid on the asexual blood stage. For sporozoite and gametocyte stages, the hybrid conserves the potency typically observed for endoperoxide drugs, and this is possibly achieved due to the redox chemistry of endoperoxide components with ferrous heme.
Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones
Authors: Gargantilla Marta , López-Fernández José , Camarasa Maria-Jose , Persoons Leentje , Daelemans Dirk , Priego Eva-Maria , Pérez-Pérez María-Jesús
Published: November 2021

The nuclear export receptor exportin-1 (XPO1, CRM1) mediates the nuclear export of proteins that contain a leucine-rich nuclear export signal (NES) towards the cytoplasm. XPO1 is considered a relevant target in different human diseases, particularly in hematological malignancies, tumor resistance, inflammation, neurodegeneration and viral infections. Thus, its pharmacological inhibition is of significant therapeutic interest. The best inhibitors described so far (leptomycin B and SINE compounds) interact with XPO1 through a covalent interaction with Cys528 located in the NES-binding cleft of XPO1. Based on the well-established feature of chalcone derivatives to react with thiol groups via hetero-Michael addition reactions, we have synthesized two series of chalcones. Their capacity to react with thiol groups was tested by incubation with GSH to afford the hetero-Michael adducts that evolved backwards to the initial chalcone through a retro-Michael reaction, supporting that the covalent interaction with thiols could be reversible. The chalcone derivatives were evaluated in antiproliferative assays against a panel of cancer cell lines and as XPO1 inhibitors, and a good correlation was observed with the results obtained in both assays. Moreover, no inhibition of the cargo export was observed when the two prototype chalcones 9 and 10 were tested against a XPO1-mutated Jurkat cell line (XPO1C528S), highlighting the importance of the Cys at the NES-binding cleft for inhibition. Finally, their interaction at the molecular level at the NES-binding cleft was studied by applying the computational tool CovDock.
Formulation and Development of Oral Fast-Dissolving Films Loaded with Nanosuspension to Augment Paroxetine Bioavailability: In Vitro Characterization, Ex Vivo Permeation, and Pharmacokinetic Evaluation in Healthy Human Volunteers
Authors: Elshafeey Ahmed Hassen , El-Dahmy Rania Moataz
Published: November 2021

Paroxetine (PX) is the most potent serotonin reuptake inhibitor utilized in depression and anxiety treatment. It has drawbacks, such as having a very bitter taste, low water solubility, and undergoing extensive first pass metabolism, leading to poor oral bioavailability (<50%). This work aimed to develop and optimize palatable oral fast-dissolving films (OFDFs) loaded with a paroxetine nanosuspension. A PX nanosuspension was prepared to increase the PX solubility and permeability via the buccal mucosa. The OFDFs could increase PX bioavailability due to their rapid dissolution in saliva, without needing water, and the rapid absorption of the loaded drug through the buccal mucosa, thus decreasing the PX metabolism in the liver. OFDFs also offer better convenience to patients with mental illness, as well as pediatric, elderly, and developmentally disabled patients. The PX nanosuspension was characterized by particle size, poly dispersity index, and zeta potential. Twelve OFDFs were formulated using a solvent casting technique. A 22 × 31 full factorial design was applied to choose the optimized OFDF, utilizing Design-Expert® software (Stat-Ease Inc., Minneapolis, MN, USA). The optimized OFDF (F1) had a 3.89 ± 0.19 Mpa tensile strength, 53.08 ± 1.28% elongation%, 8.12 ± 0.13 MPa Young’s modulus, 17.09 ± 1.30 s disintegration time, and 96.02 ± 3.46% PX dissolved after 10 min. This optimized OFDF was subjected to in vitro dissolution, ex vivo permeation, stability, and palatability studies. The permeation study, using chicken buccal pouch, revealed increased drug permeation from the optimized OFDF; with a more than three-fold increase in permeation over the pure drug. The relative bioavailability of the optimized OFDF in comparison with the market tablet was estimated clinically in healthy human volunteers and was found to be 178.43%. These findings confirmed the success of the OFDFs loaded with PX nanosuspension for increasing PX bioavailability.
Pharmaceutical Aspects of Nanocarriers for Smart Anticancer Therapy
Authors: Hwang Seung Rim , Chakraborty Kushal , An Jeong Man , Mondal Jagannath , Yoon Hong Yeol , Lee Yong-kyu
Published: November 2021

Drug delivery to tumor sites using nanotechnology has been demonstrated to overcome the drawbacks of conventional anticancer drugs. Altering the surface shape and geometry of nanocomposites alters their chemical properties, which can confer multiple attributes to nanocarriers for the treatment of cancer and their use as imaging agents for cancer diagnosis. However, heterogeneity and blood flow in human cancer limit the distribution of nanoparticles at the site of tumor tisues. For targeted delivery and controlled release of drug molecules in harsh tumor microenvironments, smart nanocarriers combined with various stimuli-responsive materials have been developed. In this review, we describe nanomaterials for smart anticancer therapy as well as their pharmaceutical aspects including pharmaceutical process, formulation, controlled drug release, drug targetability, and pharmacokinetic or pharmacodynamic profiles of smart nanocarriers. Inorganic or organic-inorganic hybrid nanoplatforms and the electrospinning process have also been briefly described here.
Wide Area Uniform Illumination Scheme Using LED Matrix for Optogenetic Cardiac Pacing
Authors: Izadi Ida , Dusend Vanessa , Takrouni Abdulaziz , Nudds Noreen , Gradkowski Kamil , O’Brien Peter , Sasse Philipp , Corbett Brian
Published: November 2021

Control of heart rhythm is vital in the case of arrhythmia. Cardiac optogenetics is a promising technique to replace electrical stimulation in a next generation of pacemakers and defibrillators. Therefore, further research towards optimizing light delivery methods is essential. A major requirement is the uniform stimulation of all cells in the area of interest while reducing side effects such as photodamage. Here, a 2 × 2 blue (470 nm, InGaN-based) light-emitting diode (LED) optoelectronic module for uniform ex vivo cardiac muscle illumination is demonstrated. It satisfies two important requirements in optogenetics, which are high illumination homogeneity and high irradiance. CCD camera images show an average 90% homogeneity over the central illumination area of close to 38 mm2 at 1 cm distance from the light source. The module is used to perform physiological experiments on channelrhodopsin 2-expressing Langendorff-perfused mouse hearts. Successful ventricular pacing is obtained for an optical power density threshold below 2 mW/mm2 with light pulses as short as 1 ms. For 10 ms long pulses, the threshold was below 0.2 mW/mm2. The large homogeneous illumination area enabled optogenetic pacing with less than half the optical power of previous attempts with smaller areas of 2 mm2 and thus, presumably, will result in less phototoxicity.
Potential Importance of Molybdenum Priming to Metabolism and Nutritive Value of Canavalia spp. Sprouts
Authors: Okla Mohammad K. , Akhtar Nosheen , Alamri Saud A. , Al-Qahtani Salem Mesfir , Ismail Ahmed , Abbas Zahid Khurshid , AL-Ghamdi Abdullah A. , Qahtan Ahmad A. , Soufan Walid H. , Alaraidh Ibrahim A. , Selim Samy , AbdElgawad Hamada
Published: November 2021

Molybdenum ions (Mo) can improve plants’ nutritional value primarily by enhancing nitrogenous metabolism. In this study, the comparative effects of seed priming using Mo were evaluated among sproutings of Canavalia species/cultivars, including Canavalia ensiformis var. gladiata (CA1), Canavalia ensiformis var. truncata Ricker (CA2), and Canavalia gladiata var. alba Hisauc (CA3). Mo impacts on growth, metabolism (e.g., nitrogen and phenolic metabolism, pigment and total nutrient profiles), and biological activities were assayed. Principal component analysis (PCA) was used to correlate Mo-mediated impacts. The results showed that Mo induced photosynthetic pigments that resulted in an improvement in growth and increased biomass. The N content was increased 0.3-fold in CA3 and 0.2-fold in CA1 and CA2. Enhanced nitrogen metabolism by Mo provided the precursors for amino acids, protein, and lipid biosynthesis. At the secondary metabolic level, phenolic metabolism-related precursors and enzyme activities were also differentially increased in Canavalia species/cultivars. The observed increase in metabolism resulted in the enhancement of the antioxidant (2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) free radical scavenging, 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), ferric reducing antioxidant power (FRAP)) and antidiabetic potential (Glycemic index (GI) and inhibition activity of α-amylase, and α-glucosidase) of species. The antioxidant activity increased 20% in CA3, 14% in CA1, and 8% in CA2. Furthermore, PCA showed significant variations not only between Mo-treated and untreated samples but also among Canavalia species. Overall, this study indicated that the sprouts of Canavalia species have tremendous potential for commercial usage due to their high nutritive value, which can be enhanced further with Mo treatment to accomplish the demand for nutritious feed.
Genotype by Trait Interaction (GT) in Maize Hybrids on Complete Fertilizer
Authors: Mousavi Seyed Mohammad Nasir , Bojtor Csaba , Illés Árpád , Nagy János
Published: November 2021

We investigated the interaction between genotype by trait, and an experiment was conducted at the University of Debrecen. Two maize cultivars, FAO340 and FAO410, were studied in a randomized complete block design with four replications. This experiment was applied to the six fertilization treatments. Fertilizer levels were NPK0 (control) (N:0, P2O5:0, K2O:0), NPK1 (N:30, P2O5:23, K2O:27), NPK2 (N:60, P2O5:46, K2O:54), NPK3 (N:90, P2O5:69, K2O:81), NPK4 (N:120, P2O5:92, K2O:108), and NPK5 (N:150, P2O5:115, K2O:135). The first principal component showed 54.24%, and the second principal component showed 20.75%, which explained the total squares interaction using the AMMI model in the case of the FAO410 hybrid. As regards the FAO340 hybrid, the first principal component showed 58.18%, and the second principal component showed 18.04%, explaining the total squares interaction using the AMMI model in the FAO410 hybrid. In the GGE biplot on FAO410, the first and the second principal components covered 91.20% of the total data in this analysis. Accordingly, the desirable treatment was NPK5, followed by NPK4, NPK2, NPK3, NPK1, and NPK0. NPK4 and NPK5 had the most desirable treatments for the number of seeds per row, chlorophyll, weight of 1000 seeds, and stem diameter in the case of the FAO410 hybrid.
Effects of Siliceous Natural Nanomaterials Applied in Combination with Foliar Fertilizers on Physiology, Yield and Fruit Quality of the Apricot and Peach Trees
Authors: Moale Cristina , Ghiurea Marius , Sîrbu Carmen Eugenia , Somoghi Raluca , Cioroianu Traian Mihai , Faraon Victor Alexandru , Lupu Carmen , Trică Bogdan , Constantinescu-Aruxandei Diana , Oancea Florin
Published: November 2021

Siliceous natural nanomaterials (SNNMs), i.e., diatomaceous earth and natural zeolites, have a nanoporous structure with large active surfaces that adsorb cations or polarized molecules. Such nanoporous feature determines the effects related to SNNM utilization as low-risk plant protectants and soil improvers. This work used SNNMs from Romanian quarries as carriers for foliar fertilizers applied to stone-fruit trees, apricot and peach. We determined the effects of SNNMs on the physiology, yield and fruit quality of the treated stone-fruit trees. SNNM application determined impacts specific to the formation of particle films on leaves: reduced leaf temperature (up to 4.5 °C) and enhanced water use efficiency (up to 30%). Foliar fertilizers’ effects on yield are amplified by their application with SNNMs. Yield is increased up to 8.1% by the utilization of SNNMs with foliar fertilizers, compared to applying foliar fertilizer alone. Diatomaceous earth and natural zeolites promote the accumulation of polyphenols in apricot and peach fruits. The combined application of SNNMs and foliar fertilizer enhance the performance of peach and apricot trees.
Machine Learning-Mediated Development and Optimization of Disinfection Protocol and Scarification Method for Improved In Vitro Germination of Cannabis Seeds
Authors: Pepe Marco , Hesami Mohsen , Jones Andrew Maxwell Phineas
Published: November 2021

In vitro seed germination is a useful tool for developing a variety of biotechnologies, but cannabis has presented some challenges in uniformity and germination time, presumably due to the disinfection procedure. Disinfection and subsequent growth are influenced by many factors, such as media pH, temperature, as well as the types and levels of contaminants and disinfectants, which contribute independently and dynamically to system complexity and nonlinearity. Hence, artificial intelligence models are well suited to model and optimize this dynamic system. The current study was aimed to evaluate the effect of different types and concentrations of disinfectants (sodium hypochlorite, hydrogen peroxide) and immersion times on contamination frequency using the generalized regression neural network (GRNN), a powerful artificial neural network (ANN). The GRNN model had high prediction performance (R2 > 0.91) in both training and testing. Moreover, a genetic algorithm (GA) was subjected to the GRNN to find the optimal type and level of disinfectants and immersion time to determine the best methods for contamination reduction. According to the optimization process, 4.6% sodium hypochlorite along with 0.008% hydrogen peroxide for 16.81 min would result in the best outcomes. The results of a validation experiment demonstrated that this protocol resulted in 0% contamination as predicted, but germination rates were low and sporadic. However, using this sterilization protocol in combination with the scarification of in vitro cannabis seed (seed tip removal) resulted in 0% contamination and 100% seed germination within one week.