bluuebunny/crossref_metadata_2025 huggingface dataset:
Triggering RNA Interference by Photoreduction under Red Light Irradiation
Authors: Rühle Jennifer , Klemt Insa , Mokhir Andriy
Published: May 2023

RNA interference (RNAi) using small interfering RNAs (siRNAs) is a powerful tool to target any protein of interest and is becoming more suitable for in vivo applications due to recent developments in RNA delivery systems. To exploit RNAi for cancer treatment, it is desirable to increase its selectivity, e.g., by a prodrug approach to activate the siRNAs upon external triggering, e.g., by using light. Red light is especially well suited for in vivo applications due to its low toxicity and higher tissue penetration. Known molecular (not nanoparticle-based) red-light-activatable siRNA prodrugs rely on singlet oxygen (1O2)-mediated chemistry. 1O2 is highly cytotoxic. Additionally, one of the side products in the activation of the known siRNA prodrugs is anthraquinone, which is also toxic. We herein report on an improved redlight-activatable siRNA prodrug, which does not require 1O2 for its activation. In fact, the 5′ terminus of the antisense strand is protected with an electron-rich azobenzene promoiety. It is reduced and cleaved upon red light exposure in the presence of Sn(IV)(pyropheophorbide a)dichloride acting as a catalyst and ascorbate as a bulk reducing agent. We confirmed the prodrug activation upon red light irradiation both in cell-free settings and in human ovarian cancer A2780 cells.
Valorization of Fibrous Plant-Based Food Waste as Biosorbents for Remediation of Heavy Metals from Wastewater—A Review
Authors: Karim Ahasanul , Raji Zarifeh , Karam Antoine , Khalloufi Seddik
Published: May 2023

Mobilization of heavy metals in the environment has been a matter of concern for several decades due to their toxicity for humans, environments, and other living organisms. In recent years, use of inexpensive and abundantly available biosorbents generated from fibrous plant-based food-waste materials to remove heavy metals has garnered considerable research attention. The aim of this review is to investigate the applicability of using fibrous plant-based food waste, which comprises different components such as pectin, hemicellulose, cellulose, and lignin, to remove heavy metals from wastewater. This contribution confirms that plant-fiber-based food waste has the potential to bind heavy metals from wastewater and aqueous solutions. The binding capacities of these biosorbents vary depending on the source, chemical structure, type of metal, modification technology applied, and process conditions used to improve functionalities. This review concludes with a discussion of arguments and prospects, as well as future research directions, to support valorization of fibrous plant-based food waste as an efficient and promising strategy for water purification.
Synthesis of Eu3+-Doped NaGd9Si6O26 Sub-Microcrystals from a NaGdF4@SiO2 Structure
Authors: Du Tianyun , Xue Xiaojie , Han Xiuxun
Published: May 2023

Rare earth silicate phosphors of high quantum efficiency with a stable performance are promising materials in the fields of display and illumination. The grain sizes of products synthesized via the conventional solid-state reaction method are usually too large to satisfy the requirements of color cast and extraction efficiency in high-resolution light-emitting devices (LEDs). We designed a synthetic route and successfully fabricated rare earth silicate NaGd9Si6O26 (NGSO) sub-microcrystals with a size ranging from 550 to 1200 nm. The reaction mechanism and optical properties were systematically investigated. The quantum efficiency of Eu3+-activated NGSO sub-microcrystals was about 36.6%. The LED encapsulated with these sub-microcrystals showed lower color deviation and higher lumen efficiency and lumen flux compared to that with NGSO fabricated using the conventional solid state reaction method.
Thiocarbonyl Derivatives of Natural Chlorins: Synthesis Using Lawesson’s Reagent and a Study of Their Properties
Authors: Pogorilyy Viktor , Ostroverkhov Petr , Efimova Valeria , Plotnikova Ekaterina , Bezborodova Olga , Diachkova Ekaterina , Vasil’ev Yuriy , Pankratov Andrei , Grin Mikhail
Published: May 2023

The development of sulfur-containing pharmaceutical compounds is important in the advancement of medicinal chemistry. Photosensitizers (PS) that acquire new properties upon incorporation of sulfur-containing groups or individual sulfur atoms into their structure are not neglected, either. In this work, a synthesis of sulfur-containing derivatives of natural chlorophyll a using Lawesson’s reagent was optimized. Thiocarbonyl chlorins were shown to have a significant bathochromic shift in the absorption and fluorescence bands. The feasibility of functionalizing the thiocarbonyl group at the macrocycle periphery by formation of a Pt(II) metal complex in the chemotherapeutic agent cisplatin was shown. The chemical stability of the resulting conjugate in aqueous solution was studied, and it was found to possess a high cytotoxic activity against sarcoma S37 tumor cells that results from the combined photodynamic and chemotherapeutic effect on these cells.
Docosahexaenoic Acid Promotes Cd Excretion by Restoring the Abundance of Parabacteroides in Cd-Exposed Mice
Authors: Liao Jianzhen , Bi Siyuan , Fang Zhijia , Deng Qi , Chen Yinyan , Sun Lijun , Jiang Yongqing , Huang Linru , Gooneratne Ravi
Published: May 2023

As a common harmful pollutant, cadmium (Cd) can easily enter the human body through the food chain, posing a major threat to human health. Gut microbiota play a key role in Cd absorption. Docosahexaenoic acid (DHA) is thought to have a potential role in the treatment of Cd poisoning. This study investigated the therapeutic effect and mechanism of DHA in Cd-exposed mice from the perspective of the gut microbiota. The results showed that DHA significantly increased the Cd content in feces and decreased the Cd accumulation in the organs of mice. The gut microbiota results showed that DHA significantly restored the abundance of Parabacteroides in the gut microbiota of Cd-exposed mice. Parabacteroides distasonis (P. distasonis), a representative strain of the Parabacteroides, also showed Cd- and toxicity-reduction capabilities. P. distasonis significantly restored the gut damage caused by Cd exposure. At the same time, P. distasonis reduced the Cd content in the liver, spleen, lung, kidneys, gut, and blood to varying degrees and significantly increased the Cd content in feces. The succinic acid produced by P. distasonis plays an important role in promoting Cd excretion in Cd-exposed mice. Therefore, these results suggest that P. distasonis may have a potential role in DHA-mediated Cd excretion in Cd-exposed mice.
Development and Validation of Green and High-Throughput Microwell Spectrophotometric Assay for the Determination of Selective Serotonin Reuptake Inhibitors in Their Pharmaceutical Dosage Forms
Authors: Darwish Ibrahim A. , Alzoman Nourah Z.
Published: May 2023

This study describes the development and validation of a new green and high-throughput microwell spectrophotometric assay (MW-SPA) for the determination of three selective serotonin reuptake inhibitors (SSRIs) in their pharmaceutical dosage forms. These SSRIs are fluoxetine, fluvoxamine, and paroxetine, the most prescribed drugs for the treatment of depression. The proposed assay was based on the formation of orange-colored N-substituted naphthoquinone derivatives upon the reaction of SSRIs with 1,2-naphthoquinone-4-sulphonate (NQS) in alkaline media. The assay was conducted in 96-microwell assay plates, and the absorbances of the reaction products were measured by a microplate reader at their maximum absorbance wavelengths. The optimum conditions of the reaction were refined and established. Under these conditions, calibration curves were generated, and linear regression equations were computed. The linear relations between the absorbances and drug concentrations were linear with good correlation coefficients (0.9992–0.9997) in the range of 2–80 µg/mL. The assay limits of detection were in the range of 1.5–4.2 µg/mL. The precision was satisfactory as the values of relative standard deviation did not exceed 1.70%. The accuracy of the assay was ≥98.2%. The proposed MW-SPA was successfully applied to the analysis of the SSRIs in their pharmaceutical dosage forms with acceptable accuracy and precision; the label claims were 99.2–100.5% (±0.96–1.35%). The results of the proposed MW-SPA were compared with those of the official/pre-validated assays by statistical analysis with respect to the accuracy (by t-test) and precision (by F-test). No significant differences were found between the calculated and theoretical values of the t- and F-tests at the 95% confidence level, proving similar accuracy and precision in the determination of SSRIs by both assays. The greenness of the proposed assay was confirmed by two metric tools. In addition, the assay is characterized with a high-throughput property which enables the simultaneous analysis of many samples in a short time. Therefore, the assay is a valuable tool for rapid routine application in pharmaceutical quality control units for the determination of the investigated SSRIs.
A MD Simulation Prediction for Regulation of N-Terminal Modification on Binding of CD47 to CD172a in a Force-Dependent Manner
Authors: Zhao Yang , Fang Liping , Guo Pei , Fang Ying , Wu Jianhua
Published: May 2023

Cancer cells can evade immune surveillance through binding of its transmembrane receptor CD47 to CD172a on myeloid cells. CD47 is recognized as a promising immune checkpoint for cancer immunotherapy inhibiting macrophage phagocytosis. N-terminal post-translated modification (PTM) via glutaminyl cyclase is a landmark event in CD47 function maturation, but the molecular mechanism underlying the mechano-chemical regulation of the modification on CD47/CD172a remains unclear. Here, we performed so-called “ramp-clamp” steered molecular dynamics (SMD) simulations, and found that the N-terminal PTM enhanced interaction of CD172a with CD47 by inducing a dynamics-driven contraction of the binding pocket of the bound CD172a, an additional constraint on CYS15 on CD47 significantly improved the tensile strength of the complex with or without PTM, and a catch bond phenomenon would occur in complex dissociation under tensile force of 25 pN in a PTM-independent manner too. The residues GLN52 and SER66 on CD172a reinforced the H-bonding with their partners on CD47 in responding to PTM, while ARG69 on CD172 with its partner on CD47 might be crucial in the structural stability of the complex. This work might serve as molecular basis for the PTM-induced function improvement of CD47, should be helpful for deeply understanding CD47-relevant immune response and cancer development, and provides a novel insight in developing of new strategies of immunotherapy targeting this molecule interaction.
Investigation of Fenebrutinib Metabolism and Bioactivation Using MS3 Methodology in Ion Trap LC/MS
Authors: Alsibaee Aishah M. , Aljohar Haya I. , Attwa Mohamed W. , Abdelhameed Ali S. , Kadi Adnan A.
Published: May 2023

Fenebrutinib is an orally available Bruton tyrosine kinase inhibitor. It is currently in multiple phase III clinical trials for the management of B-cell tumors and autoimmune disorders. Elementary in-silico studies were first performed to predict susceptible sites of metabolism and structural alerts for toxicities by StarDrop WhichP450™ module and DEREK software; respectively. Fenebrutinib metabolites and adducts were characterized in-vitro in rat liver microsomes (RLM) using MS3 method in Ion Trap LC-MS/MS. Formation of reactive and unstable intermediates was explored using potassium cyanide (KCN), glutathione (GSH) and methoxylamine as trapping nucleophiles to capture the transient and unstable iminium, 6-iminopyridin-3(6H)-one and aldehyde intermediates, respectively, to generate a stable adducts that can be investigated and analyzed using mass spectrometry. Ten phase I metabolites, four cyanide adducts, five GSH adducts and six methoxylamine adducts of fenebrutinib were identified. The proposed metabolic reactions involved in formation of these metabolites are hydroxylation, oxidation of primary alcohol to aldehyde, n-oxidation, and n-dealkylation. The mechanism of reactive intermediate formation of fenebrutinib can provide a justification of the cause of its adverse effects. Formation of iminium, iminoquinone and aldehyde intermediates of fenebrutinib was characterized. N-dealkylation followed by hydroxylation of the piperazine ring is proposed to cause the bioactivation to iminium intermediates captured by cyanide. Oxidation of the hydroxymethyl group on the pyridine moiety is proposed to cause the generation of reactive aldehyde intermediates captures by methoxylamine. N-dealkylation and hydroxylation of the pyridine ring is proposed to cause formation of iminoquinone reactive intermediates captured by glutathione. FBB and several phase I metabolites are bioactivated to fifteen reactive intermediates which might be the cause of adverse effects. In the future, drug discovery experiments utilizing this information could be performed, permitting the synthesis of new drugs with better safety profile. Overall, in silico software and in vitro metabolic incubation experiments were able to characterize the FBB metabolites and reactive intermediates using the multistep fragmentation capability of ion trap mass spectrometry.
Optimization and Validation of a Method to Determine Enolones and Vanillin Derivatives in Wines—Occurrence in Spanish Red Wines and Mistelles
Authors: Bueno Mónica , Zapata Julián , Culleré Laura , Franco-Luesma Ernesto , de-la-Fuente-Blanco Arancha , Ferreira Vicente
Published: May 2023

Understanding the chemical nature of wine aroma demands accurate quantitative determinations of different odor-active compounds. Quantitative determinations of enolones (maltol, furaneol, homofuraneol, and sotolon) and vanillin derivatives (vanillin, methyl vanillate, ethyl vanillate, and acetovanillone) at low concentrations are complicated due to their high polarity. For this reason, this paper presents an improved and automated version for the accurate measure of these common trace wine polar compounds (enolones and vanillin derivatives). As a result, a faster and more user-friendly method with a reduction of organic solvents and resins was developed and validated. The optimization of some stages of the solid phase extraction (SPE) process, such as washing with an aqueous solution containing 1% NaHCO3 at pH 8, led to cleaner extracts and solved interference problems. Due to the polarity of these type of compounds, an optimization of the large volume injection was also carried out. Finally, a programmable temperature vaporization (PTV) quartz glass inlet liner without wool was used. The injector temperature was raised to 300 °C in addition to applying a pressure pulse of 180 kPa for 4 min. Matrix effects were solved by the use of adequate internal standards, such as ethyl maltol and 3′,4′-(methylenedioxy)acetophenone. Method figures of merit were highly satisfactory: good linearity (r2 > 0.98), precision (relative standard deviation, RSD < 10%), high recovery (RSD > 89%), and low detection limits (<0.7 μg/L). Enolones and vanillin derivatives are associated with wine aging. For this reason, the methodology was successfully applied to the quantification of these compounds in 16 Spanish red wines and 12 mistelles. Odor activity values (OAV) indicate that furaneol should be considered an aroma impact odorant in red wines and mistelles (OAV > 1) while homofuraneol and sotolon could also produce changes in their aroma perceptions (0.1 < OAV < 1).
The Impact of Fermentation Temperature and Cap Management on Selected Volatile Compounds and Temporal Sensory Characteristics of Grenache Wines from the Central Coast of California
Authors: Stoffel Emily S. , Robertson Taylor M. , Catania Anibal A. , Casassa L. Federico
Published: May 2023

Grenache wines from the Central Coast of California were subjected to different alcoholic fermentation temperature regimes (Cold, Cold/Hot, Hot) and cap management protocols, namely, punch down (PD), or no punch down (No PD), to determine the effect of these practices on the color, aroma, and the retronasal and mouthfeel sensory characteristics of the resulting wines. Descriptive analysis (n = 8, line scale rating 0–15) results indicated that the combination of a hot fermentation temperature and no punch downs led to a significantly higher intensity in perceived color saturation (7.89) and purple hue (8.62). A two-way analysis of variance (ANOVA) showed that cap management was significantly more impactful on the perception of orthonasal aromas than fermentation temperature. The reduction aroma was significantly higher in No PD wines (5.02) compared to PD wines (3.50), while rose and hot aromas had significantly higher intensity perception for PD wines (5.18, 6.80) than for No PD wines (6.80, 6.14). Conversely, analysis of selected volatile compounds indicated that fermentation temperature was more impactful than cap management regime. Cold/Hot wines had higher concentrations of important esters such as ethyl hexanoate (650 µg/L) and isoamyl acetate (992 µg/L). Cold wines had a higher concentration of β-damascenone (0.719 µg/L). TCATA evaluation (n = 8) indicated that Cold/Hot PD wines had a significantly higher citation proportion of fruit flavor (1.0) and velvet astringency perception (0.80) without significant reduction flavors. Finally, the present study represents a contribution with the main volatile compounds (e.g., β-damascenone and esters in the Cold and Cold/Hot fermented wines, respectively; hexanol in PD wines, which may be potentially responsible for a hot mouthfeel), and sensory characteristics (red fruit, tropical fruit, white pepper, and rose) of Grenache wines grown in the Mediterranean climate of the Central Coast of California.
Honey Quality Control: Review of Methodologies for Determining Entomological Origin
Authors: Mohamadzade Namin Saeed , Ghosh Sampat , Jung Chuleui
Published: May 2023

Honey is a widely consumed natural product, and its entomological origin can significantly influence its market value. Therefore, traceability of the entomological origin of honey should also be considered in honey quality control protocols. Although several methods exist, such as physicochemical characterization and bioactivity profiling of honey of different entomological origins, the most promising three methods for entomological authentication of honey include protein-based identification, chemical profiling, and a DNA-based method. All of these methods can be applied for reliable identification of the entomological origin of honey. However, as the honey is a complex matrix, the inconsistency of the results obtained by these methods is a pragmatic challenge, and therefore, the use of each method in all the cases is questionable. Most of these methodologies can be used for authentication of newly harvested honey and it is worth understanding the possibility of using these methods for authentication of relatively old samples. Most probably, using DNA-based methods targeting small fragments of DNA can provide the best result in old samples, however, the species-specific primers targeting short fragments are limited and not available for all species. Therefore, using universal primers in combination with a DNA metabarcoding approach can be a good solution that requires further investigation. This present article describes the applications of different methods, their pros, and their cons to identify honey based on entomological origin.
Synthesis, Pharmacological Evaluation, and Molecular Modeling of Lappaconitine–1,5-Benzodiazepine Hybrids
Authors: Cheremnykh Kirill , Bryzgalov Arkadiy , Baev Dmitry , Borisov Sergey , Sotnikova Yulia , Savelyev Victor , Tolstikova Tatyana , Sagdullaev Shamansur , Shults Elvira
Published: May 2023

Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, have long interested scientists due to their medicinal uses and infamous toxicity which has limited the clinical application of the native compound. Alkaloid lappaconitine extracted from various Aconitum and Delphinium species has displayed extensive bioactivities and active ongoing research to reduce its adverse effects. A convenient route to construct hybrid molecules containing diterpenoid alkaloid lappaconitine and 3H-1,5-benzodiazepine fragments was proposed. The key stage involved the formation of 5′-alkynone-lappaconitines in situ by acyl Sonogashira coupling of 5′-ethynyllappaconitine, followed by cyclocondensation with o-phenylenediamine. New hybrid compounds showed low toxicity and outstanding analgesic activity in experimental pain models, which depended on the nature of the substituent in the benzodiazepine nucleus. An analogous dependence was also shown for the antiarrhythmic activity in the epinephrine arrhythmia test in vivo. Studies on the isolated atrium have shown that the mechanism of action of the new compounds is included the blockade of beta-adrenergic receptors and potassium channels. Molecular docking analysis was conducted to determine the binding potential of target molecules with the voltage-gated sodium channel NaV1.5. All obtained results provide a basis for future rational modifications of lappaconitine, reducing side effects, while retaining its therapeutic effects.
Crystallization of Copper Films on Sapphire Substrate for Large-Area Single-Crystal Graphene Growth
Authors: Komlenok Maxim , Pivovarov Pavel , Popovich Alexey , Cheverikin Vladimir , Romshin Alexey , Rybin Maxim , Obraztsova Elena
Published: May 2023

Chemical vapor deposition synthesis of graphene on polycrystalline copper substrates from methane is a promising technique for industrial production and application. However, the quality of grown graphene can be improved by using single-crystal copper (111). In this paper, we propose to synthesize graphene on epitaxial single-crystal Cu film deposited and recrystallized on a basal-plane sapphire substrate. The effect of film thickness, temperature, and time of annealing on the size of copper grains and their orientation is demonstrated. Under optimized conditions, the copper grains with the (111) orientation and a record size of several millimeters are obtained, and the single-crystal graphene is grown over their entire area. The high quality of synthesized graphene has been confirmed by Raman spectroscopy, scanning electron microscopy, and the sheet resistance measurements by the four point probe method.
Foods and Nutrients at Risk for Insufficient Intake by Community-Dwelling Healthy Older Women Eating Alone and Together in Japan—A Preliminary Finding
Authors: Takiguchi Tomoya , Nishijo Muneko , Kaneko Noriko , Yoshita Katsushi , Arai Yusuke , Demura Noboru , Nishino Yoshikazu
Published: May 2023

Eating alone and poor dental status have been reported to influence dietary intake in older adults. First, we compared nutrient and food intake and dental markers between women eating alone and together, who participated in a home health management program conducted by Kanazawa Medical University. The results showed the significantly higher intake of fresh fruit and some micro-nutrients and a lower decayed, missing, and filled teeth (DMFT) index (better dental status) in women eating alone after adjusting for age, suggesting that dental status may mediate the association between commensality and dietary intake. Then, we investigated nutrients and foods at risk for insufficient intake and associated with increasing dental markers. The risks for the insufficient intake of protein and n-3 and n-6 polyunsaturated fatty acids (PUFAs) were significantly increased with an increasing DMFT index. The risk for n-3 PUFA intake also increased with increasing numbers of missing teeth in women. Foods at risk for insufficient consumption included beans for women with an increasing DMFT index and green and yellow vegetables, fresh fruits, and meat and fish for women with increasing numbers of missing teeth. These findings suggest that good health management, including the treatment of decayed teeth, is important for the prevention of malnutrition in community-dwelling healthy older women.
Initiatives to Reduce the Content of Sodium in Food Products and Meals and Improve the Population’s Health
Authors: Jachimowicz-Rogowska Karolina , Winiarska-Mieczan Anna
Published: May 2023

Table salt is the main source of sodium (Na) in the human diet. Excessive supply of Na in a diet is strongly linked to many non-communicable human diseases, such as hypertension, obesity and stomach cancer. The World Health Organization recommends that daily intake of salt in adult diets should be kept below 5 g/person/day, which corresponds to 2 g Na/person/day. However, on average, adults consume about 9–10 g/person/day, and children and young people about 7–8 g/person/day. Initiatives to reduce salt intake include modifications of food composition in collaboration with the food industry, education of consumers, salt marking on foodstuff labels and taxation of salt. A need also exists to educate society so that they choose low-sodium products. In view of the food technology and amount of salt intake, the most important and the easiest change to make is to reduce the content of salt in baked goods. This paper analyses the results of surveys regarding strategies to reduce salt content in food products and considers multifaceted initiatives to reduce salt intake as a possible efficient method of improving the population’s health status.
Blueberries Improve Abdominal Symptoms, Well-Being and Functioning in Patients with Functional Gastrointestinal Disorders
Authors: Wilder-Smith Clive H. , Materna Andrea , Olesen Søren S.
Published: May 2023

Blueberries beneficially modulate physiologic mechanisms relevant to the pathogenesis of functional gastrointestinal disorders (FGID). Forty-three patients with FGID received freeze-dried blueberries (equivalent to 180 g fresh blueberries) or sugar and energy-matched placebo in a double-blind, randomized, cross-over study. After 6 weeks of treatment, the differences in Gastrointestinal Clinical Rating Scale (GSRS) scores and abdominal symptom relief were compared as primary outcome measures. The quality of life and life functioning ratings (OQ45.2 questionnaire), Bristol stool scales, and fructose breath test results constituted secondary outcome measures. Blueberry treatment resulted in more patients with relevant abdominal symptom relief compared to placebo (53% vs. 30%, p = 0.03). Total and pain GSRS scores improved insignificantly (mean treatment differences [95% CI]: −3.4 [−7.4 to 0.6] (p = 0.09) and −1.0 [−2.2 to 0.1] (p = 0.08), respectively). OQ45.2 scores improved during blueberry treatment compared to placebo (treatment difference −3.2 [95% CI: −5.6 to −0], p = 0.01). Treatment effect differences for the further measures did not reach statistical significance. Blueberries relieved abdominal symptoms and improved general markers of well-being, quality of life, and life functioning more than placebo in patients with FGID. Consequently, the polyphenol and fiber components of blueberries exert broad beneficial effects separate from the sugars present in both treatments.
Long-Term Soft-Food Rearing in Young Mice Alters Brain Function and Mood-Related Behavior
Authors: Furukawa Masae , Tada Hirobumi , Raju Resmi , Wang Jingshu , Yokoi Haruna , Yamada Mitsuyoshi , Shikama Yosuke , Matsushita Kenji
Published: May 2023

The relationship between caloric and nutrient intake and overall health has been extensively studied. However, little research has focused on the impact of the hardness of staple foods on health. In this study, we investigated the effects of a soft diet on brain function and behavior in mice from an early age. Mice fed a soft diet for six months exhibited increased body weight and total cholesterol levels, along with impaired cognitive and motor function, heightened nocturnal activity, and increased aggression. Interestingly, when these mice were switched back to a solid diet for three months, their weight gain ceased, total cholesterol levels stabilized, cognitive function improved, and aggression decreased, while their nocturnal activity remained high. These findings suggest that long-term consumption of a soft diet during early development can influence various behaviors associated with anxiety and mood regulation, including weight gain, cognitive decline, impaired motor coordination, increased nocturnal activity, and heightened aggression. Therefore, the hardness of food can impact brain function, mental well-being, and motor skills during the developmental stage. Early consumption of hard foods may be crucial for promoting and maintaining healthy brain function.
Study of the Relationship between Mucosal Immunity and Commensal Microbiota: A Bibliometric Analysis
Authors: Wang Shiqi , Wu Jialin , Ran Duo , Ou Guosen , Chen Yaokang , Xu Huachong , Deng Li , Chen Xiaoyin
Published: May 2023

This study presents the first bibliometric evaluation and systematic analysis of publications related to mucosal immunity and commensal microbiota over the last two decades and summarizes the contribution of countries, institutions, and scholars in the study of this field. A total of 1423 articles related to mucosal immunity and commensal microbiota in vivo published in 532 journals by 7774 authors from 1771 institutions in 74 countries/regions were analyzed. The interaction between commensal microbiota in vivo and mucosal immunity is essential in regulating the immune response of the body, maintaining communication between different kinds of commensal microbiota and the host, and so on. Several hot spots in this field have been found to have received extensive attention in recent years, especially the effects of metabolites of key strains on mucosal immunity, the physiopathological phenomena of commensal microbiota in various sites including the intestine, and the relationship between COVID-19, mucosal immunity and microbiota. We hope that the full picture of the last 20 years in this research area provided in this study will serve to deliver necessary cutting-edge information to relevant researchers.
No Evidence That Circulating GLP-1 or PYY Are Associated with Increased Satiety during Low Energy Diet-Induced Weight Loss: Modelling Biomarkers of Appetite
Authors: Lim Jia Jiet , Liu Yutong , Lu Louise W. , Sequeira Ivana R. , Poppitt Sally D.
Published: May 2023

Bariatric surgery and pharmacology treatments increase circulating glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), in turn promoting satiety and body weight (BW) loss. However, the utility of GLP-1 and PYY in predicting appetite response during dietary interventions remains unsubstantiated. This study investigated whether the decrease in hunger observed following low energy diet (LED)-induced weight loss was associated with increased circulating ‘satiety peptides’, and/or associated changes in glucose, glucoregulatory peptides or amino acids (AAs). In total, 121 women with obesity underwent an 8-week LED intervention, of which 32 completed an appetite assessment via a preload challenge at both Week 0 and Week 8, and are reported here. Visual analogue scales (VAS) were administered to assess appetite-related responses, and blood samples were collected over 210 min post-preload. The area under the curve (AUC0-210), incremental AUC (iAUC0-210), and change from Week 0 to Week 8 (∆) were calculated. Multiple linear regression was used to test the association between VAS–appetite responses and blood biomarkers. Mean (±SEM) BW loss was 8.4 ± 0.5 kg (−8%). Unexpectedly, the decrease in ∆AUC0-210 hunger was best associated with decreased ∆AUC0-210 GLP-1, GIP, and valine (p < 0.05, all), and increased ∆AUC0-210 glycine and proline (p < 0.05, both). The majority of associations remained significant after adjusting for BW and fat-free mass loss. There was no evidence that changes in circulating GLP-1 or PYY were predictive of changes in appetite-related responses. The modelling suggested that other putative blood biomarkers of appetite, such as AAs, should be further investigated in future larger longitudinal dietary studies.
Assessment of Areca Nut Bioactivities in Western Diet-Induced Mice NAFLD Model
Authors: Yi Shuhan , Chen Keyu , Sakao Kozue , Ikenaga Makoto , Wang Yuanliang , Hou De-Xing
Published: May 2023

The areca nut is often consumed as a chewing food in the Asian region. Our previous study revealed that the areca nut is rich in polyphenols with high antioxidant activity. In this study, we further assessed the effects and molecular mechanisms of the areca nut and its major ingredients on a Western diet-induced mice dyslipidemia model. Male C57BL/6N mice were divided into five groups and fed with a normal diet (ND), Western diet (WD), WD with areca nut extracts (ANE), areca nut polyphenols (ANP), and arecoline (ARE) for 12 weeks. The results revealed that ANP significantly reduced WD-induced body weight, liver weight, epididymal fat, and liver total lipid. Serum biomarkers showed that ANP ameliorated WD-enhanced total cholesterol and non-high-density lipoprotein (non-HDL). Moreover, analysis of cellular signaling pathways revealed that sterol regulatory element-binding protein 2 (SREBP2) and enzyme 3-hydroxy-3-methylglutaryld coenzyme A reductase (HMGCR) were significantly downregulated by ANP. The results of gut microbiota analysis revealed that ANP increased the abundance of beneficial bacterium Akkermansias and decreased the abundance of the pathogenic bacterium Ruminococcus while ARE shown the opposite result to ANP. In summary, our data indicated that areca nut polyphenol ameliorated WD-induced dyslipidemia by increasing the abundance of beneficial bacteria in the gut microbiota and reducing the expressions of SREBP2 and HMGCR while areca nut ARE inhibited this improvement potential.
Associations between Knowledge of Health Risks and Sugar-Sweetened Beverage Intake among US Adolescents
Authors: Park Sohyun , Lee Seung Hee , Merlo Caitlin , Blanck Heidi M.
Published: May 2023

Background: Sugar-sweetened beverage (SSB) intake is associated with adverse health outcomes. Objective: We examined associations between the knowledge of health risks related to SSB and SSB intake among adolescents. Design: A cross-sectional study using 2021 YouthStyles survey data. Participants/settings: 831 US adolescents (12–17 years old). Main outcome measures: The outcome variable was SSB intake (none, 1–6 times/week, and ≥1 time/day). Exposure variables were knowledge of seven SSB-related health risks. Statistical analyses performed: Seven multinomial regressions were used to estimate adjusted odds ratios (AOR) for drinking SSB, according to knowledge of SSB-related health risks and after controlling for sociodemographics. Results: Overall, 29% of adolescents consumed SSB ≥1 time/day. Although most adolescents identified cavities (75.4%), weight gain (74.6%), and diabetes (69.7%) as being related to drinking SSB, fewer adolescents identified related conditions such as high blood pressure (31.7%), high cholesterol (25.8%), heart disease (24.6%), and some cancers (18.0%). Compared to non-SSB consumers, drinking SSB ≥1 time/day was significantly higher among adolescents who lacked knowledge of associations between SSB intake and weight gain (AOR = 2.0), heart disease (AOR = 1.9), or some cancers (AOR = 2.3) after controlling for covariates. Conclusions: Among US adolescents, knowledge of SSB-related health risks varied by condition, ranging from 18% (some cancers) to 75% (cavities and weight gain). There were increased odds of drinking SSB among those unaware that weight gain, heart disease, and some cancers are associated with SSB intake. Intervention could evaluate whether increasing certain types of knowledge may influence youth SSB intake.
Crosstalk between Gut Microbiota and Bile Acids in Cholestatic Liver Disease
Authors: Shi Qingmiao , Yuan Xin , Zeng Yifan , Wang Jinzhi , Zhang Yaqi , Xue Chen , Li Lanjuan
Published: May 2023

Emerging evidence suggests the complex interactions between gut microbiota and bile acids, which are crucial end products of cholesterol metabolism. Cholestatic liver disease is characterized by dysfunction of bile production, secretion, and excretion, as well as excessive accumulation of potentially toxic bile acids. Given the importance of bile acid homeostasis, the complex mechanism of the bile acid–microbial network in cholestatic liver disease requires a thorough understanding. It is urgent to summarize the recent research progress in this field. In this review, we highlight how gut microbiota regulates bile acid metabolism, how bile acid pool shapes the bacterial community, and how their interactions contribute to the pathogenesis of cholestatic liver disease. These advances might provide a novel perspective for the development of potential therapeutic strategies that target the bile acid pathway.
A Three-Step Process to Isolate Large Quantities of Bioactive Sesquiterpene Lactones from Cichorium intybus L. Roots and Semisynthesis of Chicory STLs Standards
Authors: Ruggieri Francesca , Hance Philippe , Gioia Bruna , Biela Alexandre , Roussel Pascal , Hilbert Jean-Louis , Willand Nicolas
Published: May 2023

Sesquiterpene lactones (STLs) are a large group of terpenoids most commonly found in plants of the Asteraceae family, e.g., in chicory plants, displaying a wide range of interesting biological activities. However, further studies on the biological potential of chicory-derived STLs and analogues are challenging as only four of these molecules are commercially available (as analytical standards), and to date, there are no published or patented simple extraction–purification processes capable of large-scale STLs isolation. In this work, we describe a novel three-step large-scale extraction and purification method for the simultaneous purification of 11,13-dihydrolactucin (DHLc) and lactucin (Lc) starting from a chicory genotype rich in these STLs and the corresponding glucosyl and oxalyl conjugated forms. After a small-scale screening on 100 mg of freeze-dried chicory root powder, the best results were achieved with a 17 h water maceration at 30 °C. With these conditions, we managed to increase the content of DHLc and Lc, at the same time favoring the hydrolysis of their conjugated forms. On a larger scale, the extraction of 750 g of freeze-dried chicory root powder, followed by a liquid–liquid extraction step and a reversed-phase chromatography, allowed the recovery of 642.3 ± 76.3 mg of DHLc and 175.3 ± 32.9 mg of Lc. The two pure STLs were subsequently used in the context of semisynthesis to generate analogues for biological evaluation as antibacterial agents. In addition, other described chicory STLs that are not commercially available were also synthesized or extracted to serve as analytical standards for the study. In particular, lactucin-oxalate and 11,13-dihydrolactucin-oxalate were synthesized in two steps starting from Lc and DHLc, respectively. On the other hand, 11β,13-dihydrolactucin-glucoside was obtained after a MeOH/H2O (70/30) extraction, followed by a liquid–liquid extraction step and a reversed-phase chromatography. Together, this work will help facilitate the evaluation of the biological potential of chicory-derived STLs and their semisynthetic analogues.
Catestatin: Antimicrobial Functions and Potential Therapeutics
Authors: Jati Suborno , Mahata Sumana , Das Soumita , Chatterjee Saurabh , Mahata Sushil K.
Published: May 2023

The rapid increase in drug-resistant and multidrug-resistant infections poses a serious challenge to antimicrobial therapies, and has created a global health crisis. Since antimicrobial peptides (AMPs) have escaped bacterial resistance throughout evolution, AMPs are a category of potential alternatives for antibiotic-resistant “superbugs”. The Chromogranin A (CgA)-derived peptide Catestatin (CST: hCgA352–372; bCgA344–364) was initially identified in 1997 as an acute nicotinic-cholinergic antagonist. Subsequently, CST was established as a pleiotropic hormone. In 2005, it was reported that N-terminal 15 amino acids of bovine CST (bCST1–15 aka cateslytin) exert antibacterial, antifungal, and antiyeast effects without showing any hemolytic effects. In 2017, D-bCST1–15 (where L-amino acids were changed to D-amino acids) was shown to exert very effective antimicrobial effects against various bacterial strains. Beyond antimicrobial effects, D-bCST1–15 potentiated (additive/synergistic) antibacterial effects of cefotaxime, amoxicillin, and methicillin. Furthermore, D-bCST1–15 neither triggered bacterial resistance nor elicited cytokine release. The present review will highlight the antimicrobial effects of CST, bCST1–15 (aka cateslytin), D-bCST1–15, and human variants of CST (Gly364Ser-CST and Pro370Leu-CST); evolutionary conservation of CST in mammals; and their potential as a therapy for antibiotic-resistant “superbugs”.
Preparation of Nanoparticle-Loaded Extracellular Vesicles Using Direct Flow Filtration
Authors: Mansur Shomit , Habib Shahriar , Hawkins Mikayla , Brown Spenser R. , Weinman Steven T. , Bao Yuping
Published: May 2023

Extracellular vesicles (EVs) have shown great potential as cell-free therapeutics and biomimetic nanocarriers for drug delivery. However, the potential of EVs is limited by scalable, reproducible production and in vivo tracking after delivery. Here, we report the preparation of quercetin-iron complex nanoparticle-loaded EVs derived from a breast cancer cell line, MDA-MB-231br, using direct flow filtration. The morphology and size of the nanoparticle-loaded EVs were characterized using transmission electron microscopy and dynamic light scattering. The SDS-PAGE gel electrophoresis of those EVs showed several protein bands in the range of 20–100 kDa. The analysis of EV protein markers by a semi-quantitative antibody array confirmed the presence of several typical EV markers, such as ALIX, TSG101, CD63, and CD81. Our EV yield quantification suggested a significant yield increase in direct flow filtration compared with ultracentrifugation. Subsequently, we compared the cellular uptake behaviors of nanoparticle-loaded EVs with free nanoparticles using MDA-MB-231br cell line. Iron staining studies indicated that free nanoparticles were taken up by cells via endocytosis and localized at a certain area within the cells while uniform iron staining across cells was observed for cells treated with nanoparticle-loaded EVs. Our studies demonstrate the feasibility of using direct flow filtration for the production of nanoparticle-loaded EVs from cancer cells. The cellular uptake studies suggested the possibility of deeper penetration of the nanocarriers because the cancer cells readily took up the quercetin-iron complex nanoparticles, and then released nanoparticle-loaded EVs, which can be further delivered to regional cells.
Application of Modelling and Simulation Approaches to Predict Pharmacokinetics of Therapeutic Monoclonal Antibodies in Pediatric Population
Authors: Lim Andrew , Sharma Pradeep , Stepanov Oleg , Reddy Venkatesh Pilla
Published: May 2023

Ethical regulations and limited paediatric participants are key challenges that contribute to a median delay of 6 years in paediatric mAb approval. To overcome these barriers, modelling and simulation methodologies have been adopted to design optimized paediatric clinical studies and reduce patient burden. The classical modelling approach in paediatric pharmacokinetic studies for regulatory submissions is to apply body weight-based or body surface area-based allometric scaling to adult PK parameters derived from a popPK model to inform the paediatric dosing regimen. However, this approach is limited in its ability to account for the rapidly changing physiology in paediatrics, especially in younger infants. To overcome this limitation, PBPK modelling, which accounts for the ontogeny of key physiological processes in paediatrics, is emerging as an alternative modelling strategy. While only a few mAb PBPK models have been published, PBPK modelling shows great promise demonstrating a similar prediction accuracy to popPK modelling in an Infliximab paediatric case study. To facilitate future PBPK studies, this review consolidated comprehensive data on the ontogeny of key physiological processes in paediatric mAb disposition. To conclude, this review discussed different use-cases for pop-PK and PBPK modelling and how they can complement each other to increase confidence in pharmacokinetic predictions.
Development of Lyophilised Eudragit® Retard Nanoparticles for the Sustained Release of Clozapine via Intranasal Administration
Authors: Lombardo Rosamaria , Ruponen Marika , Rautio Jarkko , Ghelardini Carla , Di Cesare Mannelli Lorenzo , Calosi Laura , Bani Daniele , Lampinen Riikka , Kanninen Katja M. , Koivisto Anne M. , Penttilä Elina , Löppönen Heikki , Pignatello Rosario
Published: May 2023

Clozapine (CZP) is the only effective drug in schizophrenia resistant to typical antipsychotics. However, existing dosage forms (oral or orodispersible tablets, suspensions or intramuscular injection) show challenging limitations. After oral administration, CZP has low bioavailability due to a large first-pass effect, while the i.m. route is often painful, with low patient compliance and requiring specialised personnel. Moreover, CZP has a very low aqueous solubility. This study proposes the intranasal route as an alternative route of administration for CZP, through its encapsulation in polymeric nanoparticles (NPs) based on Eudragit® RS100 and RL100 copolymers. Slow-release polymeric NPs with dimensions around 400–500 nm were formulated to reside and release CZP in the nasal cavity, where it can be absorbed through the nasal mucosa and reach the systemic circulation. CZP-EUD-NPs showed a controlled release of CZP for up to 8 h. Furthermore, to reduce mucociliary clearance and increase the residence time of NPs in the nasal cavity to improve drug bioavailability, mucoadhesive NPs were formulated. This study shows that the NPs already exhibited strong electrostatic interactions with mucin at time zero due to the presence of the positive charge of the used copolymers. Furthermore, to improve the solubility, diffusion and adsorption of CZPs and the storage stability of the formulation, it was lyophilised using 5% (w/v) HP-β-CD as a cryoprotectant. It ensured the preservation of the NPs’ size, PDI and charge upon reconstitution. Moreover, physicochemical characterisation studies of solid-state NPs were performed. Finally, toxicity studies were performed in vitro on MDCKII cells and primary human olfactory mucosa cells and in vivo on the nasal mucosa of CD-1 mice. The latter showed non-toxicity of B-EUD-NPs and mild CZP-EUD-NP-induced tissue abnormalities.