bluuebunny/crossref_metadata_2025 huggingface dataset:
An Approach toward 17-Arylsubstituted Marginatafuran-Type Isospongian Diterpenoids via a Palladium-Catalyzed Heck–Suzuki Cascade Reaction of 16-Bromolambertianic Acid
Authors: Kharitonov Yurii V. , Shults Elvira E.
Published: April 2022

Isospongian diterpenes are a small but growing family of natural tetracyclic secondary metabolites isolated from marine organisms, primarily sponges and nudibranchs. A palladium-catalyzed domino Heck–Suzuki reaction sequence for the synthesis of the tetracyclic skeleton of marginatafuran-type isospongian diterpenoids with a wide variety of substituents in the C-17 position is reported. The proposed approach was based on selective transformations of the accessible plant diterpenoid lambertianic acid and includes an intramolecular Heck reaction of 16-bromolambertianic and arylation of the palladium intermediate with arylboronic acid. The influence of the nature of the substituent both in arylboronic acids and in the furan ring of 16-bromolambertianic acid on the direction and chemoselectivity of the reaction has been studied. The described derivatization of natural furanolabdanoid lambertianic acid produced new functionalized molecules for biological study and gave novel insights into the reactivity of complex molecular structures.
A Strategy for Rapid Discovery of Marker Peptides Associated with Fibrinolytic Efficacy of Pheretima aspergillum Based on Bioinformatics Combined with Parallel Reaction Monitoring
Authors: Feng Ting-Ting , Zhang Jing-Xian , Zhang Yong-Peng , Sun Jian , Yu Hong , Tao Xiang , Mao Xiu-Hong , Hu Qing , Ji Shen
Published: April 2022

Quality control of animal-derived traditional Chinese medicines has improved dramatically as proteomics research advanced in the past few decades. However, it remains challenging to identify quality attributes with routine proteomics approaches since protein with fibrinolytic activity is rarely reported in pheretima, a typical animal-derived traditional medicine. A novel strategy based on bioinformatics combined with parallel reaction monitoring (PRM) was developed here to rapidly discover the marker peptides associated with a fibrinolytic effect. Potential marker peptides were found by lumbrokinase sequences’ alignment and in silico digestion. The fibrinogen zymography was used to visually identify fibrinolytic proteins in pheretima. As a result, it was found that the fibrinolytic activity varied among different portions of pheretima. Fibrinolytic proteins were distributed regionally in the anterior and anterior-mid portion and there was no significant fibrinogenolytic activity observed in the mid-posterior and posterior portion. Finally, PRM experiments were deployed to validate and quantify selected marker peptides and a total of 11 peptides were identified as marker peptides, which could be potentially used in quality control of pheretima. This strategy provides a robust workflow to benefit the quality control of other animal-derived traditional medicines.
Topical Dosage Formulation of Lyophilized Philadelphus coronarius L. Leaf and Flower: Antimicrobial, Antioxidant and Anti-Inflammatory Assessment of the Plant
Authors: Pető Ágota , Kósa Dóra , Haimhoffer Ádám , Nemes Dániel , Fehér Pálma , Ujhelyi Zoltán , Vecsernyés Miklós , Váradi Judit , Fenyvesi Ferenc , Frum Adina , Gligor Felicia Gabriela , Vicaș Laura Grațiela , Marian Eleonora , Jurca Tunde , Pallag Annamaria , Muresan Mariana Eugenia , Tóth Zoltán , Bácskay Ildikó
Published: April 2022

Philadelphus coronarius is a versatile plant and its use in folk medicine has a long tradition; however, scientifically, the medical utilization of the herb is a less explored research field. The aim of our study was to identify and determine the quantity of the bioactive compounds of both the leaf and the flower and prepare a lyophilized product of them, from which medical ointments were formulated, since the topical application of P. coronarius has also not been studied. In vitro drug release, texture analysis and biocompatibility experiments were carried out, as well as the investigation of microbiological, antioxidant and anti-inflammatory properties. According to our results the composition and the selected excipients of the ointments have a great impact on the drug release, texture and bioavailability of the preparation. During the microbiological testing, the P. coronarius leaf was effective against Escherichia coli and Staphylococcus aureus, but it did not significantly decrease IL-4 production when it was tested on HaCaT cells. P. coronarius is a promising herb, and its topical application in antimicrobial therapy can be a useful addition to modern medical therapy.
Molecular Dynamics Approaches Dissect Molecular Mechanisms Underlying Methylene Blue–Glycosaminoglycan Interactions
Authors: Maszota-Zieleniak Martyna , Zsila Ferenc , Samsonov Sergey A.
Published: April 2022

Glycosaminoglycans (GAGs) are a class of periodic anionic linear polysaccharides involved in a number of biologically relevant processes in the extracellular matrix via interactions with various types of molecules including proteins, peptides and small organic molecules. The metachromatic dye methylene blue (MB) is a GAG binding agent. This molecule possesses a tricyclic, monocationic phenothiazine ring system, while the terminal methyl groups attached to the nitrogen atoms bear the most positive charges of the cation and, therefore, represent potential binding sites for negatively charged GAGs. In this study, we rigorously explored molecular mechanisms underlying these interactions for several GAG types: heparin, heparan and chondroitin sulfates. We found that GAG–MB interactions are predominantly electrostatically driven, with the particularly important role of sulfate groups. MB oligomeric stack formation was favored in the presence of GAGs. Furthermore, the impact of MB binding on the conformation of GAGs was also evaluated. The novel results allow for better quantitative analytics of GAG composition in the studied biochemical systems using MB dye as a GAG-specific marker. Our data add to the knowledge on small molecule–GAG interactions and could be potentially useful for novel developments in drug design and putative disease therapies in which GAGs are involved.
Simultaneous Determination of Paracetamol, Ibuprofen, and Caffeine in Tablets by Molecular Absorption Spectroscopy Combined with Classical Least Square Method
Authors: Tran Binh Thuc , Tran Tuyen Ngoc , Tran Ai My Thi , Nguyen Giang Chau Dang , Nguyen Quynh Trang Thi
Published: April 2022

In this paper, the classical least-squares (CLS) method with molecular absorption spectrophotometric measurement was used to determine simultaneously paracetamol (PAR), ibuprofen (IBU), and caffeine (CAF) in tablets. The absorbance spectra of the standard solutions and samples were measured over a wavelength from 220 to 300 nm with a 0.5 nm step. The concentration of PAR, IBU, and CAF in the sample solutions was calculated by using Visual Basic for Applications (VBA) and a program called CLS-Excel written in Microsoft Excel 2016. The method and the CLS-Excel program were tested on mixed standard laboratory samples with different PAR, IBU, and CAF concentration ratios, and they showed only small errors and a satisfying repeatability. An analytical procedure for tablets containing PAR, IBU, and CAF was developed. The reliability of the procedure was proved via the recovery and repeatability of the analysis results with an actual tablet sample and by comparing the mean contents of active substances in the tablets obtained from the analytical procedure with the HPLC method. The procedure is simple with a reduced cost compared with the HPLC standard method.
Structure-Based Bioisosterism Design, Synthesis, Biological Evaluation and In Silico Studies of Benzamide Analogs as Potential Anthelmintics
Authors: Vairoletti Franco , Paulino Margot , Mahler Graciela , Salinas Gustavo , Saiz Cecilia
Published: April 2022

A recent screen of 67,012 compounds identified a new family of compounds with excellent nematicidal activity: the ortho-substituted benzamide families Wact-11 and Wact-12. These compounds are active against Caenorhabditis elegans and parasitic nematodes by selectively inhibiting nematode complex II, and they display low toxicity in mammalian cells and vertebrate organisms. Although a big number of benzamides were tested against C. elegans in high-throughput screens, bioisosteres of the amide moiety were not represented in the chemical space examined. We thus identified an opportunity for the design, synthesis and evaluation of novel compounds, using bioisosteric replacements of the amide group present in benzamides. The compound Wact-11 was used as the reference scaffold to prepare a set of bioisosteres to be evaluated against C. elegans. Eight types of amide replacement were selected, including ester, thioamide, selenoamide, sulfonamide, alkyl thio- and oxo-amides, urea and triazole. The results allowed us to perform a structure–activity relationship, highlighting the relevance of the amide group for nematicide activity. Experimental evidence was complemented with in silico structural studies over a C. elegans complex II model as a molecular target of benzamides. Importantly, compound Wact-11 was active against the flatworm Echinococcus granulosus, suggesting a previously unreported pan-anthelmintic potential for benzamides.
Preparation and Photocatalytic Properties of Anatase TiO2 with Hollow Hexagonal Frame Structure
Authors: Teng Mengyuan , Liu Haixia , Lin Bensheng , Zhou Xiangzhu , Zhou Wei
Published: April 2022

Titanium dioxide (TiO2) has been widely used to solve energy and environmental pollution problems due to its excellent properties. In this study, the precursor (HTiOF3) with a spherical structure composed of hexagonal prisms was prepared via a simple solvothermal method using tetrabutyl titanate, hydrofluoric acid, glacial acetic acid and isopropanol as raw materials. Then, the calcination time and temperature of the precursor were controlled to prepare anatase TiO2 with different morphologies, and the photocatalytic performance of the prepared catalysts was studied. When the precursor was calcined at 600 °C for 7 h, the prepared TiO2 had a unique hexagonal framework structure and exhibited excellent photocatalytic performance. The degradation rate of the RhB solution was 98.58% at 40 min and the rate of hydrogen evolution was 2508.12 μmol g−1 h−1.
How to Improve Health with Biological Agents—Narrative Review
Authors: Zawistowska-Rojek Anna , Tyski Stefan
Published: April 2022

The proper functioning of the human organism is dependent on a number of factors. The health condition of the organism can be often enhanced through appropriate supplementation, as well as the application of certain biological agents. Probiotics, i.e., live microorganisms that exert a beneficial effect on the health of the host when administered in adequate amounts, are often used in commonly available dietary supplements or functional foods, such as yoghurts. Specific strains of microorganisms, administered in appropriate amounts, may find application in the treatment of conditions such as various types of diarrhoea (viral, antibiotic-related, caused by Clostridioides difficile), irritable bowel syndrome, ulcerative colitis, Crohn’s disease, or allergic disorders. In contrast, live microorganisms capable of exerting influence on the nervous system and mental health through interactions with the gut microbiome are referred to as psychobiotics. Live microbes are often used in combination with prebiotics to form synbiotics, which stimulate growth and/or activate the metabolism of the healthy gut microbiome. Prebiotics may serve as a substrate for the growth of probiotic strains or fermentation processes. Compared to prebiotic substances, probiotic microorganisms are more tolerant of environmental conditions, such as oxygenation, pH, or temperature in a given organism. It is also worth emphasizing that the health of the host may be influenced not only by live microorganisms, but also by their metabolites or cell components, which are referred to as postbiotics and paraprobiotics. This work presents the mechanisms of action employed by probiotics, prebiotics, synbiotics, postbiotics, paraprobiotics, and psychobiotics, together with the results of studies confirming their effectiveness and impact on consumer health.
Economic Evaluation of Individualized Nutritional Support for Hospitalized Patients with Chronic Heart Failure
Authors: Schuetz Philipp , Sulo Suela , Walzer Stefan , Krenberger Sebastian , Stagna Zeno , Gomes Filomena , Mueller Beat , Brunton Cory
Published: April 2022

Background Malnutrition is a highly prevalent risk factor in hospitalized patients with chronic heart failure (CHF). A recent randomized trial found lower mortality and improved health outcomes when CHF patients with nutritional risk received individualized nutritional treatment. Objective To estimate the cost-effectiveness of individualized nutritional support in hospitalized patients with CHF. Methods This analysis used data from CHF patients at risk of malnutrition (N = 645) who were part of the Effect of Early Nutritional Therapy on Frailty, Functional Outcomes and Recovery of Undernourished Medical Inpatients Trial (EFFORT). Study patients with CHF were randomized into (i) an intervention group (individualized nutritional support to reach energy, protein, and micronutrient goals) or (ii) a control group (receiving standard hospital food). We used a Markov model with daily cycles (over a 6-month interval) to estimate hospital costs and health outcomes in the comparator groups, thus modeling cost-effectiveness ratios of nutritional interventions. Results With nutritional support, the modeled total additional cost over the 6-month interval was 15,159 Swiss Francs (SF). With an additional 5.77 life days, the overall incremental cost-effectiveness ratio for nutritional support vs. no nutritional support was 2625 SF per life day gained. In terms of complications, patients receiving nutritional support had a cost savings of 6214 SF and an additional 4.11 life days without complications, yielding an incremental cost-effectiveness ratio for avoided complications of 1513 SF per life day gained. Conclusions On the basis of a Markov model, this economic analysis found that in-hospital nutritional support for CHF patients increased life expectancy at an acceptable incremental cost-effectiveness ratio.
Testing the Impact of Familiarity with Health Benefits Information on Dietary Supplement Choice in Pregnancy: An Online Choice Experiment
Authors: Malek Lenka , Umberger Wendy J. , Zhou Shao-Jia , Huynh Elisabeth , Makrides Maria
Published: April 2022

To help meet the increased requirements for critical nutrients during and around pregnancy, supplementation with essential nutrients is recommended. This study aims to determine how the previous awareness of nutrient health benefits and/or the provision of this information influences the importance placed on nutrients (folate, iodine, omega-3 fatty acids, and vitamin D) when choosing between dietary supplement products for pregnancy. Discrete choice experiment data were collected as part of a cross-sectional online survey administered to 857 pregnant women living in Australia. Four segments of women were identified that differ in their preference criteria when choosing among dietary supplement products for pregnancy. When choosing between products, the reinforcement of perceived health benefits (i.e., showing information on health benefits to those already aware of the benefits) was most effective at increasing the importance of folate (in all segments) and iodine (in two segments, 63% of the sample). Neither prior awareness of health benefits alone nor information provided at the point-of-purchase without prior awareness were enough to increase the importance of folate. Our findings suggest a need for simultaneous strategies that (1) provide information on health benefits before purchase and (2) ensure that information on health benefits is available at the point-of-purchase.
Plasma Kynurenine to Tryptophan Ratio Is Not Associated with Undernutrition in Adults but Reduced after Nutrition Intervention: Results from a Community-Based Study in Bangladesh
Authors: Gazi Md. Amran , Siddique Md. Abdullah , Alam Md. Ashraful , Hossaini Farzana , Hasan Md. Mehedi , Fahim Shah Mohammad , Wahid Barbie Zaman , Kabir Md. Mamun , Das Subhasish , Mahfuz Mustafa , Ahmed Tahmeed
Published: April 2022

Infections and persistent immunological activation are linked to increased kynurenine (KYN) and the KYN-to-Tryptophan (TRP) or KT ratio and may be critical factors in undernutrition. We sought to determine the association between the KT ratio and adult malnutrition, as well as investigate if nutritional supplementation had any influence on the decrease of the KT ratio. A total of 525 undernourished adults aged 18–45 years were recruited and provided a nutrition intervention for 60 feeding days. TRP and KYN concentrations were determined from plasma samples using LC-MS/MS. At baseline, the median (interquartile range (IQR)) TRP, KYN and KT ratios were 24.1 (17.6, 34.3) µmol/L, 0.76 (0.53, 1.18) µmol/L and 30.9 (24.5, 41.7), respectively. Following intervention, the median (IQR) KYN and KT ratios were significantly reduced to 0.713 (0.46, 1.12) µmol/L and 27.5 (21.3, 35.8). The KT ratio was found to be inversely linked with adult BMI (coefficient: −0.09; 95% CI: −0.18, 0.004; p-value = 0.06) but not statistically significant. Additionally, Plasma CRP was correlated positively, while LRP1 was inversely correlated with the KT ratio. Our data suggest that in Bangladeshi adults, the KT ratio is not related to the pathophysiology of malnutrition but correlated with inflammatory and anti-inflammatory biomarkers, and the ratio can be reduced by a nutrition intervention.
Enhanced Growth Inhibition and Apoptosis Induction in Human Colon Carcinoma HT-29 Cells of Soluble Longan Polysaccharides with a Covalent Chemical Selenylation
Authors: Yu Ya-Hui , Tang Zhi-Mei , Xiong Cen , Wu Fei-Fei , Zhao Jun-Ren , Zhao Xin-Huai
Published: April 2022

The selenylated polysaccharides chemically belong to the organic Se-conjugated macromolecules and have recently been attracting more and more attention due to their potential to promote body health or prevent cancers. Longan (Dimocarpus longan L.), as a subtropical fruit, contains soluble and non-digestible polysaccharides that are regarded with health care functions in the body. In this study, the longan polysaccharides (LP) were obtained via enzyme-assisted water extraction, and then chemically selenylated using a reaction system composed of HNO3–Na2SeO3 to yield two selenylated products, namely, SeLP1 and SeLP2, with Se contents of 1.46 and 4.79 g/kg, respectively. The anti-cancer effects of the three polysaccharide samples (LP, SeLP1, and SeLP2) were thus investigated using the human colon cancer HT-29 cells as the cell model. The results showed that SeLP1 and SeLP2 were more able than LP to inhibit cell growth, alter cell morphology, cause mitochondrial membrane potential loss, increase intracellular reactive oxygen and [Ca2+]i levels, and induce apoptosis via regulating the eight apoptosis-related genes and proteins including Bax, caspases-3/-8/-9, CHOP, cytochrome c, DR5, and Bcl-2. It was thereby proven that the selenylated polysaccharides could induce cell apoptosis via activating the death receptor, mitochondrial-dependent, and ER stress pathways. Collectively, both SeLP1 and SeLP2 showed higher activities than LP in HT-29 cells, while SeLP2 was consistently more active than SeLP1 in exerting these assessed anti-cancer effects on the cells. In conclusion, this chemical selenylation covalently introduced Se into the polysaccharide molecules and caused an enhancement in their anti-cancer functions in the cells, while higher selenylation extent was beneficial to the activity enhancement of the selenylated products.
Greater Adherence to Dietary Guidelines Associated with Reduced Risk of Cardiovascular Diseases in Chinese Patients with Type 2 Diabetes
Authors: Wu Shang-Ling , Peng Long-Yun , Chen Yu-Ming , Zeng Fang-Fang , Zhuo Shu-Yu , Li Yan-Bing , Lu Wei , Chen Pei-Yan , Ye Yan-Bin
Published: April 2022

The evidence regarding the impact of the scores on healthy eating indices on the risk of cardiovascular events among patients with type 2 diabetes (T2D) is limited. As such, in this study, we examined the associations of adherence to the Chinese and American dietary guidelines and the risk of cardiovascular disease (CVD) among Chinese individuals with T2D. We conducted a 1:1 age- and sex-matched case–control study based on a Chinese population. We used a structured questionnaire and a validated 79-item food-frequency questionnaire to collect general information and dietary intake information, and calculated the Chinese Healthy Eating Index (CHEI) and the Healthy Eating Index-2015 (HEI-2015). As participants, we enrolled a total of 419 pairs of hospital-based CVD cases and controls, all of whom had T2D. We found a significant inverse association between diet quality scores on the CHEI and HEI-2015 and the risk of CVD. The adjusted odds ratios (95% confidence interval) per five-score increment were 0.68 (0.61, 0.76) in the CHEI and 0.60 (0.52, 0.70) in the HEI-2015. In stratified analyses, the protective associations remained significant in the subgroups of sex, BMI, smoking status, tea-drinking, hypertension state, dyslipidemia state, T2D duration, and medical nutrition therapy knowledge (all p < 0.05). These findings suggest that a higher CHEI or HEI-2015 score, representing a higher-quality diet relative to the most recent Chinese or American dietary guidelines, was associated with a decreased risk of CVD among Chinese patients with T2D.
Associations between Maternal Selenium Status and Cord Serum Vitamin D Levels: A Birth Cohort Study in Wuhan, China
Authors: Gang Huiqing , Zhang Hongling , Zheng Tongzhang , Xia Wei , Xu Shunqing , Li Yuanyuan
Published: April 2022

Serum selenium (Se) has been reported to be associated with serum 25-hydroxyvitamin D [25(OH)D], but epidemiological findings are limited in pregnant women. We aimed to assess the associations between maternal urinary Se concentrations and cord serum 25(OH)D levels. We measured urinary concentrations of Se in the first, second, and third trimesters and cord serum 25(OH)D of 1695 mother-infant pairs from a prospective cohort study in Wuhan, China. The results showed that each doubling of urinary Se concentrations in the first, second, third trimester, and whole pregnancy (average SG-adjusted concentrations across three trimesters) were associated with 8.76% (95% confidence interval (CI): 4.30%, 13.41%), 15.44% (95% CI: 9.18%, 22.06%), 11.84% (95% CI: 6.09%, 17.89%), and 21.14% (95% CI: 8.69%, 35.02%) increases in 25(OH)D levels. Newborns whose mothers with low (<10 μg/L) or medium (10.92–14.34 μg/L) tertiles of urinary Se concentrations in whole pregnancy were more likely to be vitamin D deficient (<20 ng/mL) compared with those with the highest tertile (>14.34 μg/L). Our study provides evidence that maternal Se levels were positively associated with cord serum vitamin D status.
Meal Timing, Meal Frequency and Metabolic Syndrome
Authors: Alkhulaifi Fatema , Darkoh Charles
Published: April 2022

Individuals with metabolic syndrome have increased risk for developing health conditions, including cardiovascular diseases and stroke. Modifiable risk factors, such as exercise and diet, are key components in the prevention and control of metabolic syndrome. Specifically, dietary patterns and habits are extremely successful in controlling more than one of the metabolic syndrome risk factors. Meal timing and frequency have been associated with type 2 diabetes, cardiovascular diseases, and other chronic conditions. However, there is limited evidence linking metabolic syndrome to meal timing and meal frequency. This review summarizes and discusses how meal timing and frequency impact metabolic outcomes in adults.
Toward the Identification of Natural Antiviral Drug Candidates against Merkel Cell Polyomavirus: Computational Drug Design Approaches
Authors: Asseri Amer H. , Alam Md. Jahidul , Alzahrani Faisal , Khames Ahmed , Pathan Mohammad Turhan , Abourehab Mohammed A. S. , Hosawi Salman , Ahmed Rubaiat , Sultana Sifat Ara , Alam Nazia Fairooz , Alam Nafee-Ul , Alam Rahat , Samad Abdus , Pokhrel Sushil , Kim Jin Kyu , Ahammad Foysal , Kim Bonglee , Tan Shing Cheng
Published: April 2022

Merkel cell carcinoma (MCC) is a rare form of aggressive skin cancer mainly caused by Merkel cell polyomavirus (MCPyV). Most MCC tumors express MCPyV large T (LT) antigens and play an important role in the growth-promoting activities of oncoproteins. Truncated LT promotes tumorigenicity as well as host cell proliferation by activating the viral replication machinery, and inhibition of this protein in humans drastically lowers cellular growth linked to the corresponding cancer. Our study was designed with the aim of identifying small molecular-like natural antiviral candidates that are able to inhibit the proliferation of malignant tumors, especially those that are aggressive, by blocking the activity of viral LT protein. To identify potential compounds against the target protein, a computational drug design including molecular docking, ADME (absorption, distribution, metabolism, and excretion), toxicity, molecular dynamics (MD) simulation, and molecular mechanics generalized Born surface area (MM-GBSA) approaches were applied in this study. Initially, a total of 2190 phytochemicals isolated from 104 medicinal plants were screened using the molecular docking simulation method, resulting in the identification of the top five compounds having the highest binding energy, ranging between −6.5 and −7.6 kcal/mol. The effectiveness and safety of the selected compounds were evaluated based on ADME and toxicity features. A 250 ns MD simulation confirmed the stability of the selected compounds bind to the active site (AS) of the target protein. Additionally, MM-GBSA analysis was used to determine the high values of binding free energy (ΔG bind) of the compounds binding to the target protein. The five compounds identified by computational approaches, Paulownin (CID: 3084131), Actaealactone (CID: 11537736), Epigallocatechin 3-O-cinnamate (CID: 21629801), Cirsilineol (CID: 162464), and Lycoricidine (CID: 73065), can be used in therapy as lead compounds to combat MCPyV-related cancer. However, further wet laboratory investigations are required to evaluate the activity of the drugs against the virus.
Design and Synthesis of a Novel 4-aryl-N-(2-alkoxythieno [2,3-b]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide DGG200064 Showed Therapeutic Effect on Colon Cancer through G2/M Arrest
Authors: Lee Eun-Sil , Kim Nayeon , Kang Joon Hee , Abdildinova Aizhan , Lee Seon-Hyeong , Lee Myung Hwi , Kang Nam Sook , Koo Tae-Sung , Kim Soo-Youl , Gong Young-Dae
Published: April 2022

Cancer cells are characterized by an abnormal cell cycle. Therefore, the cell cycle has been a potential target for cancer therapeutic agents. We developed a new lead compound, DGG200064 (7c) with a 2-alkoxythieno [2,3-b]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide core skeleton. To evaluate its properties, compound DGG200064 was tested in vivo through a xenograft mouse model of colorectal cancer using HCT116 cells. The in vivo results showed high cell growth inhibition efficacy. Our results confirmed that the newly synthesized DGG200064 inhibits the growth of colorectal cancer cells by inducing G2/M arrest. Unlike the known cell cycle inhibitors, DGG200064 (GI50 = 12 nM in an HCT116 cell-based assay) induced G2/M arrest by selectively inhibiting the interaction of FBXW7 and c-Jun proteins. Additionally, the physicochemical properties of the lead compounds were analyzed. Based on the results of the study, we suggested further development of DGG200064 as a novel oral anti-colorectal cancer drug.
The Design and Synthesis of a New Series of 1,2,3-Triazole-Cored Structures Tethering Aryl Urea and Their Highly Selective Cytotoxicity toward HepG2
Authors: Oekchuae Sittisak , Sirirak Jitnapa , Charoensuksai Purin , Wongprayoon Pawaris , Chuaypen Natthaya , Boonsombat Jutatip , Ruchirawat Somsak , Tangkijvanich Pisit , Suksamrarn Apichart , Limpachayaporn Panupun
Published: April 2022

Target cancer drug therapy is an alternative treatment for advanced hepatocellular carcinoma (HCC) patients. However, the treatment using approved targeted drugs has encountered a number of limitations, including the poor pharmacological properties of drugs, therapy efficiency, adverse effects, and drug resistance. As a consequence, the discovery and development of anti-HCC drug structures are therefore still in high demand. Herein, we designed and synthesized a new series of 1,2,3-triazole-cored structures incorporating aryl urea as anti-HepG2 agents. Forty-nine analogs were prepared via nucleophilic addition and copper-catalyzed azide-alkyne cycloaddition (CuAAC) with excellent yields. Significantly, almost all triazole-cored analogs exhibited less cytotoxicity toward normal cells, human embryonal lung fibroblast cell MRC-5, compared to Sorafenib and Doxorubicin. Among them, 2m’ and 2e exhibited the highest selectivity indexes (SI = 14.7 and 12.2), which were ca. 4.4- and 3.7-fold superior to that of Sorafenib (SI = 3.30) and ca. 3.8- and 3.2-fold superior to that of Doxorubicin (SI = 3.83), respectively. Additionally, excellent inhibitory activity against hepatocellular carcinoma HepG2, comparable to Sorafenib, was still maintained. A cell-cycle analysis and apoptosis induction study suggested that 2m’ and 2e likely share a similar mechanism of action to Sorafenib. Furthermore, compounds 2m’ and 2e exhibit appropriate drug-likeness, analyzed by SwissADME. With their excellent anti-HepG2 activity, improved selectivity indexes, and appropriate druggability, the triazole-cored analogs 2m’ and 2e are suggested to be promising candidates for development as targeted cancer agents and drugs used in combination therapy for the treatment of HCC.
Application of CRISPR-Cas9 System to Study Biological Barriers to Drug Delivery
Authors: He Ji , Biswas Riya , Bugde Piyush , Li Jiawei , Liu Dong-Xu , Li Yan
Published: April 2022

In recent years, sequence-specific clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) systems have been widely used in genome editing of various cell types and organisms. The most developed and broadly used CRISPR-Cas system, CRISPR-Cas9, has benefited from the proof-of-principle studies for a better understanding of the function of genes associated with drug absorption and disposition. Genome-scale CRISPR-Cas9 knockout (KO) screen study also facilitates the identification of novel genes in which loss alters drug permeability across biological membranes and thus modulates the efficacy and safety of drugs. Compared with conventional heterogeneous expression models or other genome editing technologies, CRISPR-Cas9 gene manipulation techniques possess significant advantages, including ease of design, cost-effectiveness, greater on-target DNA cleavage activity and multiplexing capabilities, which makes it possible to study the interactions between membrane proteins and drugs more accurately and efficiently. However, many mechanistic questions and challenges regarding CRISPR-Cas9 gene editing are yet to be addressed, ranging from off-target effects to large-scale genetic alterations. In this review, an overview of the mechanisms of CRISPR-Cas9 in mammalian genome editing will be introduced, as well as the application of CRISPR-Cas9 in studying the barriers to drug delivery.
Dry Powder Formulation of Simvastatin Nanoparticles for Potential Application in Pulmonary Arterial Hypertension
Authors: Zendehdel Baher Shalaleh , Yaqoubi Shadi , Asare-Addo Kofi , Hamishehkar Hamed , Nokhodchi Ali
Published: April 2022

It has been hypothesized that simvastatin could be used to treat pulmonary arterial hypertension (PAH). This study is intended to formulate a simvastatin nanoparticle dry powder inhalation (DPI) formulation. Simvastatin nanoparticles were prepared via an emulsification and homogenization-extrusion method, followed by spray drying of the colloidal suspension of simvastatin nanoparticles containing mannitol to get it into a respirable size. Particle size distribution, morphology, and crystallinity of the fabricated nanoparticles of the obtained microparticles for DPI formulation were assessed by dynamic light scattering (DLS), scanning electron microscopy (SEM), and X-ray diffraction pattern (XRPD), respectively. Aerosolization performance of the DPI formulation was assessed by the Next Generation Impactor (NGI) equipped with an Aerolizer®. Simvastatin nanoparticles were around 100 nm with a very narrow size distribution (PDI = 0.105). The X-ray diffraction pattern revealed that the crystallinity of simvastatin was decreased by the spray drying procedure. Microscopic images displayed that gathered nanoparticles were in the suitable inhalable range and had the appropriate shape and surface properties for pulmonary delivery. Aerosolization assessment by the NGI indicated a suitable inhalation performance (fine particle fraction of 20%). In conclusion, the results confirmed that the spray drying technique for simvastatin can be optimized to obtain simvastatin aggregated nanoparticles without any coarse carrier to be used in DPI formulation for better deposition of the drug in the lungs for local treatment of PAH.
Low-Dose Aspirin Augments the Anti-Inflammatory Effects of Low-Dose Lithium in Lipopolysaccharide-Treated Rats
Authors: Shvartsur Rachel , Agam Galila , Uzzan Sarit , Azab Abed N.
Published: April 2022

Mounting evidence suggests that immune-system dysfunction and inflammation play a role in the pathophysiology and treatment of mood-disorders in general and of bipolar disorder in particular. The current study examined the effects of chronic low-dose aspirin and low-dose lithium (Li) treatment on plasma and brain interleukin-6 and tumor necrosis factor-α production in lipopolysaccharide (LPS)-treated rats. Rats were fed regular or Li-containing food (0.1%) for six weeks. Low-dose aspirin (1 mg/kg) was administered alone or together with Li. On days 21 and 42 rats were injected with 1 mg/kg LPS or saline. Two h later body temperature was measured and rats were sacrificed. Blood samples, the frontal-cortex, hippocampus, and the hypothalamus were extracted. To assess the therapeutic potential of the combined treatment, rats were administered the same Li + aspirin protocol without LPS. We found that the chronic combined treatment attenuated LPS-induced hypothermia and significantly reduced plasma and brain cytokine level elevation, implicating the potential neuroinflammatory diminution purportedly present among the mentally ill. The combined treatment also significantly decreased immobility time and increased struggling time in the forced swim test, suggestive of an antidepressant-like effect. This preclinical evidence provides a potential approach for treating inflammation-related mental illness.
The Role of Cryotherapy in Vitreous Concentrations of Topotecan Delivered by Episcleral Hydrogel Implant
Authors: Kodetova Martina , Hobzova Radka , Sirc Jakub , Uhlik Jiri , Dunovska Katerina , Svojgr Karel , Cocarta Ana-Irina , Felsoova Andrea , Slanar Ondrej , Sima Martin , Kozak Igor , Pochop Pavel
Published: April 2022

Transscleral diffusion delivery of chemotherapy is a promising way to reach the vitreal seeds of retinoblastoma, the most common intraocular malignancy in childhood. In this in vivo study, the delivery of topotecan via lens-shaped, bi-layered hydrogel implants was combined with transconjunctival cryotherapy to assess whether cryotherapy leads to higher concentrations of topotecan in the vitreous. The study included 18 New Zealand albino rabbits; nine rabbits received a topotecan-loaded implant episclerally and another nine rabbits received transconjunctival cryotherapy superotemporally 2 weeks before implant administration. Median vitreous total topotecan exposures (area under the curve, AUC) were 455 ng·h/mL for the cryotherapy group and 281 ng·h/mL for the non-cryotherapy group, and were significantly higher in the cryotherapy group, similar to maximum levels. Median plasma AUC were 50 ng·h/mL and 34 ng·h/mL for the cryotherapy and non-cryotherapy groups, respectively, with no statistically significant differences between them. In both groups, AUC values in the vitreous were significantly higher than in plasma, with plasma exposure at only approximately 11–12% of the level of vitreous exposure. The results confirmed the important role of the choroidal vessels in the pharmacokinetics of topotecan during transscleral administration and showed a positive effect of cryotherapy on intravitreal penetration, resulting in a significantly higher total exposure in the vitreous.
Retinal Diseases: The Next Frontier in Pharmacodelivery
Authors: Ben-Arzi Assaf , Ehrlich Rita , Neumann Ron
Published: April 2022

The future continuous growth of the global older population augments the burden of retinal diseases worldwide. Retinal characteristics isolating and protecting the sensitive neuro-retina from the rest of the ocular tissues challenge drug delivery and promote research and development toward new horizons. In this review, we wish to describe the unmet medical needs, discuss the novel modes of delivery, and disclose to the reader a spectrum of older-to-novel drug delivery technologies, innovations, and the frontier of pharmacodelivery to the retina. Treating the main retinal diseases in the everlasting war against blindness and its associated morbidity has been growing steadily over the last two decades. Implants, new angiogenesis inhibitor agents, micro- and nano-carriers, and the anchored port delivery system are becoming new tools in this war. The revolution and evolution of new delivery methods might be just a few steps ahead, yet its assimilation in our daily clinical work may take time, due to medical, economical, and regulatory elements that need to be met in order to allow successful development and market utilization of new technologies. Therefore, further work is warranted, as detailed in this Pharmaceutics Special Issue.
International Human Rights Protections Find Support in Hobbes’ Leviathan
Authors: Finholt Hege Cathrine
Published: April 2022

In her paper “Sovereignty and the International Protection of Human rights”, Cristina Lafont argues that “The obligation of respecting human rights in the sense of not contributing to their violation seems to be a universal obligation and thus one that binds states just as much as non-state actors.” In this paper, I argue that one can find support for this claim in Thomas Hobbes’ Leviathan. This requires a different reading of Leviathan than the one that is typically performed by realist thinkers, such as, for instance, Morgenthau and Mearsheimer, who read Hobbes as someone who has no regard for human rights. Contrary to the realists, I suggest a reading of Leviathan that shows that there is in fact a normative underpinning of Hobbes’ view of sovereignty, to the extent that Hobbes can be taken to be one of the forerunners of international law. I do this by showing how Hobbes’ reasons for establishing sovereign power, and not his conclusions on how to organize sovereign power, may give support to Lafont’s claim that an obligation to respect human rights is not confined to the sovereign state, but also to extra-state institutions.
The Use of Plasmonic Spectroscopy for Detecting Ultra-Low Concentrations of Substances
Authors: Kononov Michael , Molkova Elena , Pustovoy Vladimir , Svetikov Vladimir
Published: April 2022

This paper presents the results of research into the excitation of a surface electromagnetic wave (SEW) in Au/AgI and Au/Ag films contacting aqueous solutions of hydrogen peroxide (H2O2) and sodium chloride (NaCl). The dependences of the SEW excitation angle in the Kretschmann configuration on the interaction time of the solution with the metal film have been obtained. The effect of an aqueous H2O2 solution on the AgI and Ag film under prolonged exposure has been demonstrated. It has been shown that the dynamics of the excitation angle can be used to estimate the concentration of solutions with low and ultra-low concentrations. As an example, the results of using the technique for the analysis of aqueous solutions of NaCl are presented.
Emerging Roles of β-Glucanases in Plant Development and Adaptative Responses
Authors: Perrot Thomas , Pauly Markus , Ramírez Vicente
Published: April 2022

Plant β-glucanases are enzymes involved in the synthesis, remodelling and turnover of cell wall components during multiple physiological processes. Based on the type of the glycoside bond they cleave, plant β-glucanases have been grouped into three categories: (i) β-1,4-glucanases degrade cellulose and other polysaccharides containing 1,4-glycosidic bonds to remodel and disassemble the wall during cell growth. (ii) β-1,3-glucanases are responsible for the mobilization of callose, governing the symplastic trafficking through plasmodesmata. (iii) β-1,3-1,4-glucanases degrade mixed linkage glucan, a transient wall polysaccharide found in cereals, which is broken down to obtain energy during rapid seedling growth. In addition to their roles in the turnover of self-glucan structures, plant β-glucanases are crucial in regulating the outcome in symbiotic and hostile plant–microbe interactions by degrading non-self glucan structures. Plants use these enzymes to hydrolyse β-glucans found in the walls of microbes, not only by contributing to a local antimicrobial defence barrier, but also by generating signalling glucans triggering the activation of global responses. As a counterpart, microbes developed strategies to hijack plant β-glucanases to their advantage to successfully colonize plant tissues. This review outlines our current understanding on plant β-glucanases, with a particular focus on the latest advances on their roles in adaptative responses.
PH Responsive Polyurethane for the Advancement of Biomedical and Drug Delivery
Authors: Tan Rachel Yie Hang , Lee Choy Sin , Pichika Mallikarjuna Rao , Cheng Sit Foon , Lam Ki Yan
Published: April 2022

Due to the specific physiological pH throughout the human body, pH-responsive polymers have been considered for aiding drug delivery systems. Depending on the surrounding pH conditions, the polymers can undergo swelling or contraction behaviors, and a degradation mechanism can release incorporated substances. Additionally, polyurethane, a highly versatile polymer, has been reported for its biocompatibility properties, in which it demonstrates good biological response and sustainability in biomedical applications. In this review, we focus on summarizing the applications of pH-responsive polyurethane in the biomedical and drug delivery fields in recent years. In recent studies, there have been great developments in pH-responsive polyurethanes used as controlled drug delivery systems for oral administration, intravaginal administration, and targeted drug delivery systems for chemotherapy treatment. Other applications such as surface biomaterials, sensors, and optical imaging probes are also discussed in this review.
The 3D-Printing-Accelerated Design for a Biodegradable Respirator from Tree Leaves (TRespirator)
Authors: Wang Ziao , Xu Yao , Liu Rulin , Zhu Xi
Published: April 2022

The unpredictable coronavirus pandemic (COVID-19) has led to a sudden and massive demand for face masks, leading to severe plastic pollution. Here, we propose a method for manufacturing biodegradable masks using high-precision 3D printing technology, called “TRespirator”, mainly made of banana leaves and dental floss silk fibers. By adding plastic recycling waste appropriately, TRespirator can achieve similar protection and mechanical properties as N95 masks. In addition, microorganisms attracted during the degradation of plant fibers will accelerate the degradation of microplastics. This respirator provides a new idea for solving the global problem of plastic pollution of masks.
Evaluation of Changes in Polymer Material Properties Due to Aging in Different Environments
Authors: Čubrić Ivana Salopek , Čubrić Goran , Katić Križmančić Ines , Kovačević Monika
Published: April 2022

With the increase in awareness of the importance of engagement in physical activities, high requirements have been placed on polymers intended for use in sports. A number of authors investigated the influence of aging factors on the performance of the polymer. Still, there is a lack of aging protocols that would be product-centered, especially when high performance is imperative. This paper presents a new approach to polymer aging and examines the change of the identified set of properties due to aging under different conditions, and the duration of each (topography, thickness, moisture management, elongation, and bursting force). The results of the testing revealed the increase in thickness due to exposure, especially to the sun-exposed materials. The ability of materials to elongate until the moment of rupture decreases due to exposure to the sun (strong relationship to the time of exposure; R2 reaches 0.99) and the bursting force (up to 6.8%). Furthermore, results indicate the significantly impaired capacity of the polymer material to absorb moisture. The results of measurements indicated (derived) by spectroscopic studies, based on the ATR-FTIR (attenuated total reflectance) method, showed that there was no detectable influence of aging in the sun or shade on the chemical structure of polyester samples.
Mapping Three Decades of Changes in the Tropical Andean Glaciers Using Landsat Data Processed in the Earth Engine
Authors: Turpo Cayo Efrain Yury , Borja Maria Olga , Espinoza-Villar Raul , Moreno Nicole , Camargo Rodney , Almeida Claudia , Hopfgartner Kathrin , Yarleque Christian , Souza Carlos M.
Published: April 2022

The fast retreat of the tropical Andean glaciers (TAGs) is considered an important indicator of climate change impact on the tropics, since the TAGs provide resources to highly vulnerable mountain populations. This study aims to reconstruct the glacier coverage of the TAGs, using Landsat time-series images from 1985 to 2020, by digitally processing and classifying satellite images in the Google Earth Engine platform. We used annual reductions of the Normalized Difference Snow Index (NDSI) and spectral bands to capture the pixels with minimum snow cover. We also implemented temporal and spatial filters to have comparable maps at a multitemporal level and reduce noise and temporal inconsistencies. The results of the multitemporal analysis of this study confirm the recent and dramatic recession of the TAGs in the last three decades, in base to physical and statistical significance. The TAGs reduced from 2429.38 km2 to 1409.11 km2 between 1990 and 2020, representing a loss of 42% of the total glacier area. In addition, the time-series analysis showed more significant losses at altitudes below 5000 masl, and differentiated changes by slope, latitude, and longitude. We found a more significant percentage loss of glacier areas in countries with less coverage. The multiannual validation showed accuracy values of 92.81%, 96.32%, 90.32%, 97.56%, and 88.54% for the metrics F1 score, accuracy, kappa, precision, and recall, respectively. The results are an essential contribution to understanding the TAGs and guiding policies to mitigate climate change and the potential negative impact of freshwater shortage on the inhabitants and food production in the Andean region.