bluuebunny/crossref_metadata_2025 huggingface dataset:
Pesticide Toxicity Footprints of Australian Dietary Choices
Authors: Ridoutt Bradley , Baird Danielle , Navarro Javier , Hendrie Gilly A.
Published: December 2021

Pesticides are widely used in food production, yet the potential harm associated with their emission into the environment is rarely considered in the context of sustainable diets. In this study, a life cycle assessment was used to quantify the freshwater ecotoxicity, human toxicity carcinogenic effects, and human toxicity noncarcinogenic effects associated with pesticide use in relation to 9341 individual Australian adult daily diets. The three environmental indicators were also combined into a pesticide toxicity footprint, and a diet quality score was applied to each diet. Energy-dense and nutrient-poor discretionary foods, fruits, and protein-rich foods were the sources of most of the dietary pesticide impacts. Problematically, a dietary shift toward recommended diets was found to increase the pesticide toxicity footprint compared to the current average diet. Using a quadrant analysis, a recommended diet was identified with a 38% lower pesticide toxicity footprint. This was achieved mainly through a reduction in the discretionary food intake and by limiting the choice of fresh fruits. As the latter contradicts dietary recommendations to eat a variety of fruits of different types and colors, we concluded that dietary change may not be the best approach to lowering the environmental impacts of pesticides in the food system. Instead, targeted action in the horticultural industry may be more effective. Consumers might encourage this transition by supporting growers that reduce pesticide use and apply less environmentally harmful active ingredients.
Concentrations of Insulin-like Growth Factors and Insulin-like Growth Factor-Binding Proteins and Respective Gene Expressions in Children before and after Hematopoietic Stem Cell Transplantation
Authors: Strojny Wojciech , Czogała Wojciech , Tomasik Przemysław , Bik-Multanowski Mirosław , Wójcik Małgorzata , Miklusiak Klaudia , Miklusiak Karol , Hałubiec Przemysław , Skoczeń Szymon
Published: December 2021

Insulin-like growth factors (IGF-1 and IGF-2) and insulin-like growth factor-binding proteins (IGFBP-1 to -7) are involved in the regulation of cell proliferation and differentiation and may be associated with various metabolic parameters. The aim of our study was to compare levels of IGFs and IGFBPs and the expressions of their genes in children before and after hematopoietic stem cell transplantation (HSCT) to assess their potential as markers of late metabolic complications of HSCT. We also conducted additional comparisons with healthy controls and of correlations of IGF and IGFBP levels with anthropometric and biochemical parameters. We analyzed 19 children treated with HSCT and 21 healthy controls. We found no significant differences in the levels of IGFs and IGFBPs and expressions of their genes before and after HSCT, while IGF and IGFBP levels were significantly lower in children treated with HSCT compared with controls. We conclude that our results did not reveal significant differences between the levels of IGFs and IGFBPs before and after HSCT, which would make them obvious candidates for markers of late complications of the procedure in children. However, due to the very low number of patients this conclusion must be taken with caution and may be altered by further research.
Cytotoxic Lactalbumin-Oleic Acid Complexes in the Human Milk Diet of Preterm Infants
Authors: Chetta Katherine E. , Alcorn Joseph L. , Baatz John E. , Wagner Carol L.
Published: December 2021

Frozen storage is necessary to preserve expressed human milk for critically ill and very preterm infants. Milk pasteurization is essential for donor milk given to this special population. Due to these storage and processing conditions, subtle changes occur in milk nutrients. These changes may have clinical implications. Potentially, bioactive complexes of unknown significance could be found in human milk given to preterm infants. One such complex, a cytotoxic α-lactalbumin-oleic acid complex named “HAMLET,” (Human Alpha-Lactalbumin Made Lethal to Tumor cells) is a folding variant of alpha-lactalbumin that is bound to oleic acid. This complex, isolated from human milk casein, has specific toxicity to both carcinogenic cell lines and immature non-transformed cells. Both HAMLET and free oleic acid trigger similar apoptotic mechanisms in tissue and stimulate inflammation via the NF-κB and MAPK p38 signaling pathways. This protein-lipid complex could potentially trigger various inflammatory pathways with unknown consequences, especially in immature intestinal tissues. The very preterm population is dependent on human milk as a medicinal and broadly bioactive nutriment. Therefore, HAMLET’s possible presence and bioactive role in milk should be addressed in neonatal research. Through a pediatric lens, HAMLET’s discovery, formation and bioactive benefits will be reviewed.
Epithelial Ablation of Miro1/Rhot1 GTPase Augments Lung Inflammation by Cigarette Smoke
Authors: Sharma Shikha , Wang Qixin , Muthumalage Thivanka , Rahman Irfan
Published: December 2021

Mitochondrial quality control is sustained by Miro1 (Rhot1), a calcium-binding membrane-anchored GTPase during mitophagy. The exact mechanism that operates the interaction of Miro1 with mitophagy machinery and their role in cigarette smoke (CS)-induced mitochondrial dysfunction that often results in lung inflammation is unclear. We hypothesized that Miro1 plays an important role in regulating mitophagy machinery and the resulting lung inflammation by CS exposure to mice. The lung epithelial Rhot1fl/fl (WT) and Rhot1CreCC10 mice were exposed to mainstream CS for 3 days (acute) and 4 months (chronic). Acute CS exposure showed a notable increase in the total inflammatory cells, macrophages, and neutrophils that are associated with inflammatory mediators. Chronic exposure showed increased infiltration of neutrophils versus air controls. The effects of acute and chronic CS exposure were augmented in the Rhot1CreCC10 group, indicating that epithelial Miro1 ablation led to the augmentation of inflammatory cell infiltration with alteration in the inflammatory mediators. Thus, Rhot1/Miro1 plays an important role in regulating CS-induced lung inflammatory responses with implications in mitochondrial quality control.
Ivabradine–Flecainide as Breakthrough Drug Combination for Congenital Junctional Ectopic Tachycardia: A Case Report and Literature Review
Authors: Di Marco Giovanni Maria , De Nigris Angelica , Pepe Angela , Pagano Annamaria , Di Nardo Giangiacomo , Tipo Vincenzo
Published: December 2021

Congenital junctional ectopic tachycardia (CJET) is a rare tachyarrhythmia that remains difficult to manage, with suboptimal control in most cases. Here, we report literature research on the use of ivabradine in the treatment of pediatric junctional ectopic tachycardia (JET), both congenital and postoperative, and describe the successful use of ivabradine–flecainide association for CJET therapy resistant to other antiarrhythmic agents. This new drug combination was effective in completely suppressing JET. Ivabradine–flecainide combination may be considered a new therapeutic strategy of CJET with a satisfactory efficacy/tolerability ratio in patients resistant to conventional drug combinations.
Unmasking of Gitelman Syndrome during Pregnancy in an Adolescent with Thyrotoxic Crisis
Authors: Acharya Ratna , Upadhyay Kiran
Published: December 2021

Background. Gitelman syndrome (GS) is an inherited salt-losing renal tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. Patients can be asymptomatic until late adolescence or adulthood, and hence may be discovered incidentally during presentation with other illnesses. GS has been described in association with thyroid disorders and should be considered in patients with hyperthyroidism and persistent hypokalemia, especially in those with associated hypomagnesemia and hypocalciuria. Case summary. In this report, we describe an 18-year-old female who presented with hyperemesis gravidarum and thyrotoxicosis, and was incidentally found to have GS, confirmed by the sequence analysis of SLC12A3. Conclusions. Thyroid dysfunctions, such as hypothyroidism, thyrotoxicosis, and thyroid nodules, may develop during pregnancy. A structural homology between the beta-human chorionic gonadotropin and thyroid stimulating hormone molecules, as well as their receptors is probably the basis for the transient thyrotoxicosis crisis during pregnancy. Since hyperemesis in pregnancy can also lead to hypokalemia and alkalosis, a high index of suspicion for GS during pregnancy is required for timely diagnosis and management.
MLR-1023 Treatment in Mice and Humans Induces a Thermogenic Program, and Menthol Potentiates the Effect
Authors: Rebello Candida J. , Coulter Ann A. , Reaume Andrew G. , Cong Weina , Cusimano Luke A. , Greenway Frank L.
Published: December 2021

A glucose-lowering medication that acts by a different mechanism than metformin, or other approved diabetes medications, can supplement monotherapies when patients fail to meet blood glucose goals. We examined the actions underlying the effects of an insulin sensitizer, tolimidone (MLR-1023) and investigated its effects on body weight. Diet-induced obesity (CD1/ICR) and type 2 diabetes (db/db) mouse models were used to study the effect of MLR-1023 on metabolic outcomes and to explore its synergy with menthol. We also examined the efficacy of MLR-1023 alone in a clinical trial (NCT02317796), as well as in combination with menthol in human adipocytes. MLR-1023 produced weight loss in humans in four weeks, and in mice fed a high-fat diet it reduced weight gain and fat mass without affecting food intake. In human adipocytes from obese donors, the upregulation of Uncoupling Protein 1, Glucose (UCP)1, adiponectin, Glucose Transporter Type 4 (GLUT4), Adipose Triglyceride Lipase (ATGL), Carnitine palmitoyltransferase 1 beta (CPT1β), and Transient Receptor Potential Melastin (TRPM8) mRNA expression suggested the induction of thermogenesis. The TRPM8 agonist, menthol, potentiated the effect of MLR-1023 on the upregulation of genes for energy expenditure and insulin sensitivity in human adipocytes, and reduced fasting blood glucose in mice. The amplification of the thermogenic program by MLR-1023 and menthol in the absence of adrenergic activation will likely be well-tolerated, and bears investigation in a clinical trial.
Effects of Ephedrine-Containing Products on Weight Loss and Lipid Profiles: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Yoo Hee-Jeong , Yoon Ha-Young , Yee Jeong , Gwak Hye-Sun
Published: December 2021

Ephedrine, the main active ingredient of mahuang, may lead to weight loss; however, it can also induce cardiovascular side effects. As ephedrine use remains controversial, this study aimed to systematically review previous studies on ephedrine-containing products and perform meta-analysis of the existing evidence on weight, blood pressure (BP), heart rate, and lipid change effects of ephedrine-containing products. We searched for placebo-controlled randomized studies in PubMed, Web of Science, and EMBASE until July 2021 using the following search terms: (ephedr* OR mahuang) AND (“weight loss” OR obes* OR overweight). Mean differences (MDs) and 95% confidence intervals (CIs) were calculated to evaluate the effects of ephedrine-containing products on weight, BP, heart rate, and lipid profiles. A total of 10 articles were included. Compared with the placebo group, the ephedrine-containing product group was associated with greater weight loss, with an MD of −1.97 kg (95% CI: −2.38, −1.57). In the ephedrine-containing product group, the mean heart rate was 5.76 beats/min higher than in the placebo group (95% CI: 3.42, 8.10), whereas intergroup differences in systolic and diastolic BP were not statistically significant. The ephedrine-containing product group had a significantly higher mean high-density lipoprotein cholesterol level (MD: 2.74 mg/dL; 95% CI: 0.94, 4.55), lower mean low-density lipoprotein cholesterol level (MD: −5.98 mg/dL; 95% CI: −10.97, −0.99), and lower mean triglyceride level (MD: −11.25 mg/dL; 95% CI: −21.83, −0.68) than the placebo group. Compared with placebo, the ephedrine-containing products showed better effects on weight loss and lipid profiles, whereas they caused increased heart rate. The ephedrine-containing products may be beneficial to obese or overweight patients; however, close monitoring is needed, especially heart rate monitoring.
Clinical Outcomes of Secondary Prophylactic Granulocyte Colony-Stimulating Factors in Breast Cancer Patients at a Risk of Neutropenia with Doxorubicin and Cyclophosphamide-Based Chemotherapy
Authors: Choi Jae Hee , Geum Min Jung , Kang Ji Eun , Park Nam Gi , Oh Yun Kyoung , Rhie Sandy Jeong
Published: December 2021

Doxorubicin and cyclophosphamide (AC)-based chemotherapy has been a standard regimen for early-stage breast cancer (ESBC) with an intermediate risk (10–20%) of febrile neutropenia (FN). Secondary prophylaxis of granulocyte colony-stimulating factor (G-CSF) is considered in patients receiving AC-based chemotherapy; however, relevant studies are limited. Here, we retrospectively reviewed the electronic medical records of 320 patients who completed adjuvant AC-based chemotherapy from September 2016 to September 2020. Approximately 46.6% of the patients developed severe neutropenic events (SNE) during AC-based chemotherapy. Secondary prophylaxis of G-CSF reduced the risk of recurrent SNE (p < 0.01) and the relative dose intensity (RDI) < 85% (p = 0.03) in patients who had experienced SNE during AC-based chemotherapy. Age ≥ 65 years (p = 0.02) and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 60 IU/L (p = 0.04) were significant risk factors for RDI < 85%. The incidences of FN, grade 4 neutropenia, unscheduled hospitalization, and interruption to the dosing regimen were reduced in patients administered secondary prophylaxis with G-CSF (before vs. after administration: FN, 19.4% vs. 4.6%; grade 4 neutropenia, 86.1% vs. 14.8%; unscheduled hospitalization, 75.9% vs. 11.1%; interruption to the dosing regimen, 18.5% vs. 8.3%). This study indicated the importance of active intervention of G-CSF use to prevent recurrent SNE and improve clinical outcomes in patients with breast cancer who receive AC-based chemotherapy.
Design and Development of Autotaxin Inhibitors
Authors: Jia Yi , Li Yan , Xu Xu-Dong , Tian Yu , Shang Hai
Published: December 2021

Autotaxin (ATX) is the only enzyme of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP2) family with lysophospholipase D (lysoPLD) activity, which is mainly responsible for the hydrolysis of extracellular lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA can induce various responses, such as cell proliferation, migration, and cytokine production, through six G protein-coupled receptors (LPA1-6). This signaling pathway is associated with metabolic and inflammatory disorder, and inhibiting this pathway has a positive effect on the treatment of related diseases, while ATX, as an important role in the production of LPA, has been shown to be associated with the occurrence and metastasis of tumors, fibrosis and cardiovascular diseases. From mimics of ATX natural lipid substrates to the rational design of small molecule inhibitors, ATX inhibitors have made rapid progress in structural diversity and design over the past 20 years, and three drugs, GLPG1690, BBT-877, and BLD-0409, have entered clinical trials. In this paper, we will review the structure of ATX inhibitors from the perspective of the transformation of design ideas, discuss the advantages and disadvantages of each inhibitor type, and put forward prospects for the development of ATX inhibitors in the future.
Tetrahydroimidazo[4,5-c]pyridine-Based Inhibitors of Porphyromonas gingivalis Glutaminyl Cyclase
Authors: Ramsbeck Daniel , Taudte Nadine , Jänckel Nadine , Strich Stefanie , Rahfeld Jens-Ulrich , Buchholz Mirko
Published: December 2021

Periodontitis is a severe yet underestimated oral disease. Since it is linked to several systemic diseases, such as diabetes, artheriosclerosis, and even Alzheimer’s disease, growing interest in treating periodontitis has emerged recently. The major cause of periodontitis is a shift in the oral microbiome. A keystone pathogen that is associated with this shift is Porphyromonas gingivalis. Hence, targeting P. gingivalis came into focus of drug discovery for the development of novel antiinfective compounds. Among others, glutaminyl cyclases (QCs) of oral pathogens might be promising drug targets. Here, we report the discovery and structure–activity relationship of a novel class of P. gingivalis QC inhibitors according to a tetrahydroimidazo[4,5-c]pyridine scaffold. Some compounds exhibited activity in the lower nanomolar range and thus were further characterized with regard to their selectivity and toxicity.
Exploiting the Metabolism of the Gut Microbiome as a Vehicle for Targeted Drug Delivery to the Colon
Authors: Bakshi Hamid A. , Quinn Gerry A. , Aljabali Alaa A. A. , Hakkim Faruck L. , Farzand Rabia , Nasef Mohamed M. , Abuglela Naji , Ansari Prawej , Mishra Vijay , Serrano-Aroca Ángel , Tambuwala Murtaza M.
Published: December 2021

The prevalence of colon-associated diseases has increased significantly over the past several decades, as evidenced by accumulated literature on conditions such as Crohn’s disease, irritable bowel syndrome, colorectal cancer, and ulcerative colitis. Developing therapeutics for these diseases is challenging due to physiological barriers of the colon, systemic side effects, and the intestinal environment. Therefore, in a search for novel methods to overcome some of these problems, researchers discovered that microbial metabolism by gut microbiotia offers a potential method for targeted drug delivery This overview highlights several drug delivery systems used to modulate the microbiota and improve colon-targeted drug delivery. This technology will be important in developing a new generation of therapies which harness the metabolism of the human gut microflora.
Discovery of New Chemical Tools against Leishmania amazonensis via the MMV Pathogen Box
Authors: López-Arencibia Atteneri , Sifaoui Ines , Reyes-Batlle María , Bethencourt-Estrella Carlos J. , San Nicolás-Hernández Desirée , Lorenzo-Morales Jacob , Piñero José E.
Published: December 2021

The protozoan parasite Leishmania causes a spectrum of diseases and there are over 1 million infections each year. Current treatments are toxic, expensive, and difficult to administer, and resistance to them is emerging. In this study, we screened the antileishmanial activity of the Pathogen Box compounds from the Medicine for Malaria Venture against Leishmania amazonensis, and compared their structures and cytotoxicity. The compounds MMV676388 (3), MMV690103 (5), MMV022029 (7), MMV022478 (9) and MMV021013 (10) exerted a significant dose-dependent inhibition effect on the proliferation of L. amazonensis promastigotes and intracellular amastigotes. Moreover, studies on the mechanism of cell death showed that compounds 3 and 5 induced an apoptotic process while the compounds 7, 9 and 10 seem to induce an autophagic mechanism. The present findings underline the potential of these five molecules as novel therapeutic leishmanicidal agents.
Monitoring of Cardiorespiratory Parameters in Rats—Validation Based on Pharmacological Stimulation
Authors: Miklosz Joanna , Kalaska Bartlomiej , Zajaczkowski Stanislaw , Pawlak Dariusz , Mogielnicki Andrzej
Published: December 2021

The methods used in preclinical studies should minimize the suffering and the number of animals but still provide precise and consistent results enabling the introduction of drug candidates into the phase of clinical trials. Thus, we aimed to develop a method allowing us to perform preliminary safety and toxicity studies of candidates for human medicines, while reducing the number of animals. We have devised a method based on a combination of two devices: Plugsys (Transonics System Inc., Ithaca, NY, USA) and PhysioSuite (Kent Scientific Corporation, Torrington, CT, USA), which allow simultaneous registration of nine circulatory and respiratory parameters, and body temperature. Vehicle and adrenaline, or nitroglycerin, as reference substances were administered into the right femoral vein of Wistar rats. Physiological conditions were registered over 60 min after drug administration by measuring systolic, diastolic and mean blood pressure, heart rate (HR), blood perfusion of paw vessels, blood oxygen saturation, respiratory rate, average and peak exhaled CO2, and body temperature. Blood pressure was measured by cannula placed in the left common carotid artery and connected to the pressure transducer (Plugsys). The other parameters were measured by the PhysioSuite. Adrenaline-induced immediate dose-related hypertension and nitroglycerin hypotension were correlated with the change in blood perfusion. They both increased HR. Adrenaline decreased blood oxygen saturation and slightly affected respiratory parameters, while nitroglycerin caused a progressive increase in respiratory rate and a decrease in the peak of exhaled CO2. Our method may become an inseparable part of the preliminary safety and toxicity studies of tested drugs, while being an important step towards improving animal welfare.
SK Channels Modulation Accelerates Equilibrium Recovery in Unilateral Vestibular Neurectomized Rats
Authors: Tighilet Brahim , Bourdet Audrey , Péricat David , Timon-David Elise , Rastoldo Guillaume , Chabbert Christian
Published: December 2021

We have previously reported in a feline model of acute peripheral vestibulopathy (APV) that the sudden, unilateral, and irreversible loss of vestibular inputs induces selective overexpression of small conductance calcium-activated potassium (SK) channels in the brain stem vestibular nuclei. Pharmacological blockade of these ion channels by the selective antagonist apamin significantly alleviated the evoked vestibular syndrome and accelerated vestibular compensation. In this follow-up study, we aimed at testing, using a behavioral approach, whether the antivertigo (AV) effect resulting from the antagonization of SK channels was species-dependent or whether it could be reproduced in a rodent APV model, whether other SK channel antagonists reproduced similar functional effects on the vestibular syndrome expression, and whether administration of SK agonist could also alter the vestibular syndrome. We also compared the AV effects of apamin and acetyl-DL-leucine, a reference AV compound used in human clinic. We demonstrate that the AV effect of apamin is also found in a rodent model of APV. Other SK antagonists also produce a trend of AV effect when administrated during the acute phase of the vertigo syndrome. Conversely, the vertigo syndrome is worsened upon administration of SK channel agonist. It is noteworthy that the AV effect of apamin is superior to that of acetyl-DL-leucine. Taken together, these data reinforce SK channels as a pharmacological target for modulating the manifestation of the vertigo syndrome during APV.
Enhancement of the Topical Bioavailability and Skin Whitening Effect of Genistein by Using Microemulsions as Drug Delivery Carriers
Authors: Vu Quoc Lam , Fang Chih-Wun , Suhail Muhammad , Wu Pao-Chu
Published: December 2021

Genistein, the most abundant isoflavone of the soy-derived phytoestrogen compounds, is a potent antioxidant and inhibitor of tyrosine kinase, which can inhibit UVB-induced skin carcinogenesis in hairless mice and UVB-induced erythema on human skin. In current study, genistein-loaded microemulsions were developed by using the various compositions of oil, surfactants, and co-surfactants and used as a drug delivery carrier to improve the solubility, peremability, skin whitening, and bioavailbility of genistein. The mean droplet size and polydispersity index of all formulations was less than 100 nm and 0.26 and demonstrated the formation of microemulsions. Similarly, various studies, such as permeation, drug skin deposition, pharmacokinetics, skin whitening test, skin irritation, and stability, were also conducted. The permeability of genistein was significantly affected by the composition of microemulsion formulation, particular surfactnat, and cosurfactant. In-vitro permeation study revealed that both permeation rate and deposition amount in skin were significantly increased from 0.27 μg/cm2·h up to 20.00 μg/cm2·h and 4.90 up to 53.52 μg/cm2, respectively. In in-vivo whitening test, the change in luminosity index (ΔL*), tended to decrease after topical application of genistein-loaded microemulsion. The bioavailability was increased 10-fold by topical administration of drug-loaded microemulsion. Conclusively, the prepared microemulsion has been enhanced the bioavailability of genistein and could be used for clinical purposes.
The Effect of Curcumin Differs on Individual Cognitive Domains across Different Patient Populations: A Systematic Review and Meta-Analysis
Authors: Tsai I-Chen , Hsu Chih-Wei , Chang Chun-Hung , Tseng Ping-Tao , Chang Ke-Vin
Published: December 2021

Curcumin is a polyphenol with strong antioxidant and anti-inflammatory effects that has been shown to be effective in ameliorating cognitive decline in animal studies. However, its clinical effectiveness is inconclusive, and relevant gastrointestinal adverse events (AEs) have been reported. The aim of this meta-analysis was to summarize the existing evidence from randomized controlled trials (RCTs) of effects of curcumin on overall cognitive function, individual cognitive domains, and gastrointestinal AE. The study includes 8 RCTs and 389 participants. A random-effects model was used for the meta-analysis. Compared with the placebo group, the curcumin group was associated with an improvement in working memory (Hedges’ g = 0.396, 95% confidence interval (CI) = 0.078 to 0.714, p = 0.015) and a borderline benefit in processing speed (Hedges’ g = 0.303, 95% CI = −0.013 to 0.619, p = 0.06). In the domains of language, episodic memory/visual learning, verbal memory, cognitive flexibility/problem solving, and overall cognitive function, no significant difference existed for the comparison between the curcumin and placebo groups. The curcumin group had a significantly higher risk of gastrointestinal AEs than the placebo group (odds ratio = 3.019, 95% CI = 1.118 to 8.150, p = 0.029). In the future, the effects of curcumin on working memory, processing speed, and gastrointestinal AE should be further investigated.
Valproic Acid Prodrug Affects Selective Markers, Augments Doxorubicin Anticancer Activity and Attenuates Its Toxicity in a Murine Model of Aggressive Breast Cancer
Authors: Tarasenko Nataly , Wilner Harel Josef , Nudelman Abraham , Kessler-Icekson Gania , Rephaeli Ada
Published: December 2021

We studied the unique inhibitor of the histone deacetylases (HDAC) valproate-valpromide of acyclovir (AN446) that upon metabolic degradation release the HDAC inhibitor (HDACI) valproic acid (VPA). Among the HDAC inhibitors that we have tested, only AN446, and to a lesser extent VPA, synergized with doxorubicin (Dox) anti-cancer activity. Romidepsin (Rom) was additive and the other HDACIs tested were antagonistic. These findings led us to test and compare the anticancer activities of AN446, VPA, and Rom with and without Dox in the 4T1 triple-negative breast cancer murine model. A dose of 4 mg/kg once a week of Dox had no significant effect on tumor growth. Rom was toxic, and when added to Dox the toxicity intensified. AN446, AN446 + Dox, and VPA + Dox suppressed tumor growth. AN446 and AN446 + Dox were the best inhibitory treatments for tumor fibrosis, which promotes tumor growth and metastasis. Dox increased fibrosis in the heart and kidneys, disrupting their function. AN446 most effectively suppressed Dox-induced fibrosis in these organs and protected their function. AN446 and AN446 + Dox treatments were the most effective inhibitors of metastasis to the lungs, as measured by the gap area. Genes that control and regulate tumor growth, DNA damage and repair, reactive oxygen production, and generation of inflammation were examined as potential therapeutic targets. AN446 affected their expression in a tissue-dependent manner, resulting in augmenting the anticancer effect of Dox while reducing its toxicity. The specific therapeutic targets that emerged from this study are discussed.
De Novo Molecular Design of Caspase-6 Inhibitors by a GRU-Based Recurrent Neural Network Combined with a Transfer Learning Approach
Authors: Huang Shuheng , Mei Hu , Lu Laichun , Qiu Minyao , Liang Xiaoqi , Xu Lei , Kuang Zuyin , Heng Yu , Pan Xianchao
Published: December 2021

Due to their potential in the treatment of neurodegenerative diseases, caspase-6 inhibitors have attracted widespread attention. However, the existing caspase-6 inhibitors showed more or less inevitable deficiencies that restrict their clinical development and applications. Therefore, there is an urgent need to develop novel caspase-6 candidate inhibitors. Herein, a gated recurrent unit (GRU)-based recurrent neural network (RNN) combined with transfer learning was used to build a molecular generative model of caspase-6 inhibitors. The results showed that the GRU-based RNN model can accurately learn the SMILES grammars of about 2.4 million chemical molecules including ionic and isomeric compounds and can generate potential caspase-6 inhibitors after transfer learning of the known 433 caspase-6 inhibitors. Based on the novel molecules derived from the molecular generative model, an optimal logistic regression model and Surflex-dock were employed for predicting and ranking the inhibitory activities. According to the prediction results, three potential caspase-6 inhibitors with different scaffolds were selected as the promising candidates for further research. In general, this paper provides an efficient combinational strategy for de novo molecular design of caspase-6 inhibitors.
Humanization, Radiolabeling and Biodistribution Studies of an IgG1-Type Antibody Targeting Uncomplexed PSA for Theranostic Applications
Authors: Strand Joanna , Sjöström Kjell , Lamminmaki Urpo J. , Vilhelmsson Timmermand Oskar , Strand Sven-Erik , Tran Thuy A.
Published: December 2021

Metastatic castration-resistant prostate cancer is today incurable. Conventional imaging methods have limited detection, affecting their ability to give an accurate outcome prognosis, and current therapies for metastatic prostate cancer are insufficient. This inevitably leads to patients relapsing with castration-resistant prostate cancer. Targeting prostate-specific antigens whose expression is closely linked to the activity in the androgen receptor pathway, and thus the pathogenesis of prostate cancer, is a possible way to increase specificity and reduce off-target effects. We have humanized and evaluated radioimmunoconjugates of a previously murine antibody, m5A10, targeting PSA intended for theranostics of hormone-refractory prostate cancer. The humanized antibody h5A10 was expressed in mammalian HEK293 cells transfected with the nucleotide sequences for the heavy and light chains of the antibody. Cell culture medium was filtered and purified by Protein G chromatography, and the buffer was changed to PBS pH 7.4 by dialysis. Murine and humanized 5A10 were conjugated with p-SCN-Bn-CHX-A”-DTPA. Surface plasmon resonance was used to characterize the binding to PSA of the immunoconjugates. Immunoconjugates were labeled with either indium-111 or lutetium-177. Biodistribution studies of murine and humanized 5A10 were performed in mice with LNCaP xenografts. 5A10 was successfully humanized, and in vivo targeting showed specific binding in xenografts. The results thus give an excellent platform for further theranostic development of humanized 5A10 for clinical applications.
A Combination Approach in Inhibiting Type 2 Diabetes-Related Enzymes Using Ecklonia radiata Fucoidan and Acarbose
Authors: Mabate Blessing , Daub Chantal Désirée , Malgas Samkelo , Edkins Adrienne Lesley , Pletschke Brett Ivan
Published: December 2021

Although there are chemotherapeutic efforts in place for Type 2 diabetes mellitus (T2DM), there is a need for novel strategies (including natural products) to manage T2DM. Fucoidan, a sulphated polysaccharide was extracted from Ecklonia radiata. The integrity of the fucoidan was confirmed by structural analysis techniques such as FT-IR, NMR and TGA. In addition, the fucoidan was chemically characterised and tested for cell toxicity. The fucoidan was investigated with regards to its potential to inhibit α-amylase and α-glucosidase. The fucoidan was not cytotoxic and inhibited α-glucosidase (IC50 19 µg/mL) more strongly than the standard commercial drug acarbose (IC50 332 µg/mL). However, the fucoidan lacked potency against α-amylase. On the other hand, acarbose was a more potent inhibitor of α-amylase (IC50 of 109 µg/mL) than α-glucosidase. Due to side effects associated with the use of acarbose, a combination approach using acarbose and fucoidan was investigated. The combination showed synergistic inhibition (>70%) of α-glucosidase compared to when the drugs were used alone. The medicinal implication of this synergism is that a regimen with a reduced acarbose dose may be used, thus minimising side effects to the patient, while achieving the desired therapeutic effect for managing T2DM.
Design of 3D Scaffolds for Hard Tissue Engineering: From Apatites to Silicon Mesoporous Materials
Authors: García Ana , Cabañas María Victoria , Peña Juan , Sánchez-Salcedo Sandra
Published: December 2021

Advanced bioceramics for bone regeneration constitutes one of the pivotal interests in the multidisciplinary and far-sighted scientific trajectory of Prof. Vallet Regí. The different pathologies that affect osseous tissue substitution are considered to be one of the most important challenges from the health, social and economic point of view. 3D scaffolds based on bioceramics that mimic the composition, environment, microstructure and pore architecture of hard tissues is a consolidated response to such concerns. This review describes not only the different types of materials utilized: from apatite-type to silicon mesoporous materials, but also the fabrication techniques employed to design and adequate microstructure, a hierarchical porosity (from nano to macro scale), a cell-friendly surface; the inclusion of different type of biomolecules, drugs or cells within these scaffolds and the influence on their successful performance is thoughtfully reviewed.
Emerging Role of miR-345 and Its Effective Delivery as a Potential Therapeutic Candidate in Pancreatic Cancer and Other Cancers
Authors: Natesh Nagabhishek Sirpu , White Brianna M. , Bennett Maia M. C. , Uz Metin , Kalari Kandy Rakhee Rathnam , Batra Surinder K. , Mallapragada Surya K. , Rachagani Satyanarayana
Published: December 2021

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality, poor prognosis, and palliative treatments, due to the rapid upregulation of alternative compensatory pathways and desmoplastic reaction. miRNAs, small non-coding RNAs, have been recently identified as key players regulating cancer pathogenesis. Dysregulated miRNAs are associated with molecular pathways involved in tumor development, metastasis, and chemoresistance in PDAC, as well as other cancers. Targeted treatment strategies that alter miRNA levels in cancers have promising potential as therapeutic interventions. miRNA-345 (miR-345) plays a critical role in tumor suppression and is differentially expressed in various cancers, including pancreatic cancer (PC). The underlying mechanism(s) and delivery strategies of miR-345 have been investigated by us previously. Here, we summarize the potential therapeutic roles of miR-345 in different cancers, with emphasis on PDAC, for miRNA drug discovery, development, status, and implications. Further, we focus on miRNA nanodelivery system(s), based on different materials and nanoformulations, specifically for the delivery of miR-345.
Excipient-Free Inhalable Microparticles of Azithromycin Produced by Electrospray: A Novel Approach to Direct Pulmonary Delivery of Antibiotics
Authors: Arauzo Beatriz , Lopez-Mendez Tania B. , Lobera Maria Pilar , Calzada-Funes Javier , Pedraz Jose Luis , Santamaria Jesus
Published: December 2021

Inhalation therapy offers several advantages in respiratory disease treatment. Azithromycin is a macrolide antibiotic with poor solubility and bioavailability but with a high potential to be used to fight lung infections. The main objective of this study was to generate a new inhalable dry powder azithromycin formulation. To this end, an electrospray was used, yielding a particle size around 2.5 µm, which is considered suitable to achieve total deposition in the respiratory system. The physicochemical properties and morphology of the obtained microparticles were analysed with a battery of characterization techniques. In vitro deposition assays were evaluated after aerosolization of the powder at constant flow rate (100 L/min) and the consideration of the simulation of two different realistic breathing profiles (healthy and chronic obstructive pulmonary disease (COPD) patients) into a next generation impactor (NGI). The formulation was effective in vitro against two types of bacteria, Staphylococcus aureus and Pseudomonas aeruginosa. Finally, the particles were biocompatible, as evidenced by tests on the alveolar cell line (A549) and bronchial cell line (Calu-3).
Dual Targeting of Cancer Cells and MMPs with Self-Assembly Hybrid Nanoparticles for Combination Therapy in Combating Cancer
Authors: Zhang Kai , Li Jingjing , Xin Xiaofei , Du Xiaoqing , Zhao Di , Qin Chao , Han Xiaopeng , Huo Meirong , Yang Lei , Yin Lifang
Published: December 2021

The co-delivery of chemotherapeutic agents and immune modulators to their targets remains to be a great challenge for nanocarriers. Here, we developed a hybrid thermosensitive nanoparticle (TMNP) which could co-deliver paclitaxel-loaded transferrin (PTX@TF) and marimastat-loaded thermosensitive liposomes (MMST/LTSLs) for the dual targeting of cancer cells and the microenvironment. TMNPs could rapidly release the two payloads triggered by the hyperthermia treatment at the site of tumor. The released PTX@TF entered cancer cells via transferrin-receptor-mediated endocytosis and inhibited the survival of tumor cells. MMST was intelligently employed as an immunomodulator to improve immunotherapy by inhibiting matrix metalloproteinases to reduce chemokine degradation and recruit T cells. The TMNPs promoted the tumor infiltration of CD3+ T cells by 2-fold, including memory/effector CD8+ T cells (4.2-fold) and CD4+ (1.7-fold), but not regulatory T cells. Our in vivo anti-tumor experiment suggested that TMNPs possessed the highest tumor growth inhibitory rate (80.86%) compared with the control group. We demonstrated that the nanoplatform could effectively inhibit the growth of tumors and enhance T cell recruitment through the co-delivery of paclitaxel and marimastat, which could be a promising strategy for the combination of chemotherapy and immunotherapy for cancer treatment.
Recent Advances in Therapeutic Drug Monitoring of Voriconazole, Mycophenolic Acid, and Vancomycin: A Literature Review of Pediatric Studies
Authors: Resztak Matylda , Sobiak Joanna , Czyrski Andrzej
Published: December 2021

The review includes studies dated 2011–2021 presenting the newest information on voriconazole (VCZ), mycophenolic acid (MPA), and vancomycin (VAN) therapeutic drug monitoring (TDM) in children. The need of TDM in pediatric patients has been emphasized by providing the information on the differences in the drugs pharmacokinetics. TDM of VCZ should be mandatory for all pediatric patients with invasive fungal infections (IFIs). Wide inter- and intrapatient variability in VCZ pharmacokinetics cause achieving and maintaining therapeutic concentration during therapy challenging in this population. Demonstrated studies showed, in most cases, VCZ plasma concentrations to be subtherapeutic, despite the updated dosages recommendations. Only repeated TDM can predict drug exposure and individualizing dosing in antifungal therapy in children. In children treated with mycophenolate mofetil (MMF), similarly as in adult patients, the role of TDM for MMF active form, MPA, has not been well established and is undergoing continued debate. Studies on the MPA TDM have been carried out in children after renal transplantation, other organ transplantation such as heart, liver, or intestine, in children after hematopoietic stem cell transplantation or cord blood transplantation, and in children with lupus, nephrotic syndrome, Henoch-Schönlein purpura, and other autoimmune diseases. MPA TDM is based on the area under the concentration–time curve; however, the proposed values differ according to the treatment indication, and other approaches such as pharmacodynamic and pharmacogenetic biomarkers have been proposed. VAN is a bactericidal agent that requires TDM to prevent an acute kidney disease. The particular group of patients is the pediatric one. For this group, the general recommendations of the dosing may not be valid due to the change of the elimination rate and volume of distribution between the subjects. The other factor is the variability among patients that concerns the free fraction of the drug. It may be caused by both the patients’ population and sample preconditioning. Although VCZ, MMF, and VAN have been applied in pediatric patients for many years, there are still few issues to be solve regarding TDM of these drugs to ensure safe and effective treatment. Except for pharmacokinetic approach, pharmacodynamics and pharmacogenetics have been more often proposed for TDM.
Formulation of Genistein-HP β Cyclodextrin-Poloxamer 188 Ternary Inclusion Complex: Solubility to Cytotoxicity Assessment
Authors: Zafar Ameeduzzafar , Alruwaili Nabil K. , Imam Syed Sarim , Alsaidan Omar Awad , Alkholifi Faisal K. , Alharbi Khalid Saad , Mostafa Ehab M. , Alanazi Abdullah S. , Gilani Sadaf Jamal , Musa Arafa , Alshehri Sultan , Rawaf Alenazy , Alquraini Ali
Published: December 2021

The current study was designed to prepare the inclusion complex Genistein (GS) using Hydroxypropyl β cyclodextrin (HP β CD) and poloxamer 188 (PL 188). The binary inclusion complex (GS BC) and ternary inclusion complex (GS TC) were developed by microwave irradiation technique and evaluated for a comparative dissolution study. Further, the samples were assessed for FTIR, DSC, XRD, and NMR for the confirmation of complex formation. Finally, antioxidant and antimicrobial studies and cytotoxicity studies on a breast cancer (MCF-7) cell line were conducted. The dissolution study result showed a marked increment in GS dissolution/release after incorporation in binary (GS: HP β CD, 1:1) and ternary (GS: HP β CD: PL 188; 1:1:0.5) inclusion complexes. Moreover, the ternary complex exhibited a significant enhancement (p < 0.05) in dissolution than did the binary complexes. This might be due to the presence of PL 188, which helps in solubility enhancement of GS. DSC, XRD and SEM evaluation confirmed the modification in the structure of GS. FTIR and NMR results indicated the formation of an inclusion complex. The antioxidant and antimicrobial activity results revealed that GS TC has shown significant (p < 0.05) higher activity than pure GS. The cytotoxicity study results also depicted concentration-dependent cytotoxicity. GS TC exhibited significantly (p < 0.05) high cytotoxicity to cancer cells (IC50 = 225 µg/mL) than pure GS (IC50 = 480 µg/mL). Finally, it was concluded that a remarkable enhancement in the dissolution was observed after the inclusion of GS in the ternary complex and it therefore has significant potential for the treatment of breast cancer.
Machine Learning Predicts Drug Metabolism and Bioaccumulation by Intestinal Microbiota
Authors: McCoubrey Laura E. , Thomaidou Stavriani , Elbadawi Moe , Gaisford Simon , Orlu Mine , Basit Abdul W.
Published: December 2021

Over 150 drugs are currently recognised as being susceptible to metabolism or bioaccumulation (together described as depletion) by gastrointestinal microorganisms; however, the true number is likely higher. Microbial drug depletion is often variable between and within individuals, depending on their unique composition of gut microbiota. Such variability can lead to significant differences in pharmacokinetics, which may be associated with dosing difficulties and lack of medication response. In this study, literature mining and unsupervised learning were used to curate a dataset of 455 drug–microbiota interactions. From this, 11 supervised learning models were developed that could predict drugs’ susceptibility to depletion by gut microbiota. The best model, a tuned extremely randomised trees classifier, achieved performance metrics of AUROC: 75.1% ± 6.8; weighted recall: 79.2% ± 3.9; balanced accuracy: 69.0% ± 4.6; and weighted precision: 80.2% ± 3.7 when validated on 91 drugs. This machine learning model is the first of its kind and provides a rapid, reliable, and resource-friendly tool for researchers and industry professionals to screen drugs for susceptibility to depletion by gut microbiota. The recognition of drug–microbiome interactions can support successful drug development and promote better formulations and dosage regimens for patients.
Colonic Delivery of Celastrol-Loaded Layer-by-Layer Liposomes with Pectin/Trimethylated Chitosan Coating to Enhance Its Anti-Ulcerative Colitis Effects
Authors: Xian Jing , Zhong Xuemei , Gu Huan , Wang Xiao , Li Jiaxin , Li Jingjing , Wu Yihan , Zhang Chen , Zhang Jinming
Published: December 2021

Herein, a flexible oral colon-targeting delivery system, mediated by electrostatic layer-by-layer alternate deposition with pectin-trimethyl chitosan (TMC) onto liposomes-loading celastrol (Cel/PT-LbL Lipo), was fabricated to enhance anti-UC efficacy. Along with layer-by-layer coating, Cel/Lipo exhibited surface charge reversal, a slight increase in particle size, and a sustained drug release profile in a simulative gastrointestinal tract medium. Based on its bilayer coating of polysaccharides, Cel/PT-LbL Lipo alleviated cytotoxicity of celastrol in colon epithelial NCM460 cells. Due to the strong mucoadhesion of TMC with mucin, PT-LbL Lipo benefited colon localization and prolonged retention ability of its payloads. Ultimately, Cel/PT-LbL Lipo significantly mitigated colitis symptoms and accelerated colitis repair in DSS-treated mice by regulating the levels of pro-inflammatory factors related to the TLR4/MyD88/NF-κB signaling pathway. Collectively, this study demonstrates that the pectin/trimethylated chitosan coating may allow for Cel/PT-LbL Lipo to function as a more beneficial therapeutic strategy for UC treatment.