bluuebunny/crossref_metadata_2025 huggingface dataset:
Unhealthy Lifestyle, Genetics and Risk of Cardiovascular Disease and Mortality in 76,958 Individuals from the UK Biobank Cohort Study
Authors: Livingstone Katherine M. , Abbott Gavin , Ward Joey , Bowe Steven J.
Published: December 2021

To examine associations of unhealthy lifestyle and genetics with risk of all-cause mortality, cardiovascular disease (CVD) mortality, myocardial infarction (MI) and stroke. We used data on 76,958 adults from the UK Biobank prospective cohort study. Favourable lifestyle included no overweight/obesity, not smoking, physical activity, not sedentary, healthy diet and adequate sleep. A Polygenic Risk Score (PRS) was derived using 300 CVD-related single nucleotide polymorphisms. Cox proportional hazard ratios (HR) were used to model effects of lifestyle and PRS on risk of CVD and all-cause mortality, stroke and MI. New CVD (n = 364) and all-cause (n = 2408) deaths, and stroke (n = 748) and MI (n = 1140) events were observed during a 7.8 year mean follow-up. An unfavourable lifestyle (0–1 healthy behaviours) was associated with higher risk of all-cause mortality (HR: 2.06; 95% CI: 1.73, 2.45), CVD mortality (HR: 2.48; 95% CI: 1.64, 3.76), MI (HR: 2.12; 95% CI: 1.65, 2.72) and stroke (HR:1.74; 95% CI: 1.25, 2.43) compared to a favourable lifestyle (≥4 healthy behaviours). PRS was associated with MI (HR: 1.35; 95% CI: 1.27, 1.43). There was evidence of a lifestyle-genetics interaction for stroke (p = 0.017). Unfavourable lifestyle behaviours predicted higher risk of all-cause mortality, CVD mortality, MI and stroke, independent of genetic risk.
Lactate Threshold Training Program on Patients with Multiple Sclerosis: A Multidisciplinary Approach
Authors: Amato Alessandra , Ragonese Paolo , Ingoglia Sonia , Schiera Gabriella , Schirò Giuseppe , Di Liegro Carlo Maria , Salemi Giuseppe , Di Liegro Italia , Proia Patrizia
Published: December 2021

Physical activity could play a key role in improving the quality of life, particularly in patients with nervous system diseases such as multiple sclerosis (MS). Through lactacid anaerobic training, this study aims to investigate the effects at a bio-psycho-physical level to counteract the chronic fatigue associated with the pathology, and to improve mental health at a psychological and neurotrophic level. Eight subjects (age: 34.88 ± 4.45 years) affected by multiple sclerosis were involved. A lactate threshold training program was administered biweekly for 12 weeks at the beginning of the study (T0), at the end of the study (T1) and at 9 months after the end of the study (T2), with physical, psychological and hematochemicals parameters, and dietary habits being tested. The results obtained confirmed that lactacid exercise can influence brain-derived neurotrophic factor (BDNF) levels as well as dehydroepiandrosterone sulfate (DHEAS) levels. In addition, levels of baseline lactate, which could be best used as an energy substrate, showed a decrease after the protocol training. Self-efficacy regarding worries and concerns management significantly increased from T0 to T1. The eating attitudes test (EAT-26) did not highlight any eating disease in the patients with a normal diet enrolled in our study. Physical exercise also greatly influenced the patients psychologically and emotionally, increasing their self-esteem. Lactate threshold training, together with dietary habits, appears to exert synergic positive effects on inflammation, neural plasticity and neuroprotection, producing preventive effects on MS symptoms and progression.
Urolithins: Diet-Derived Bioavailable Metabolites to Tackle Diabetes
Authors: Raimundo Ana F. , Ferreira Sofia , Tomás-Barberán Francisco A. , Santos Claudia N. , Menezes Regina
Published: December 2021

Diabetes remains one of the leading causes of deaths and co-morbidities in the world, with tremendous human, social and economic costs. Therefore, despite therapeutics and technological advancements, improved strategies to tackle diabetes management are still needed. One of the suggested strategies is the consumption of (poly)phenols. Positive outcomes of dietary (poly)phenols have been pointed out towards different features in diabetes. This is the case of ellagitannins, which are present in numerous foodstuffs such as pomegranate, berries, and nuts. Ellagitannins have been reported to have a multitude of effects on metabolic diseases. However, these compounds have high molecular weight and do not reach circulation at effective concentrations, being metabolized in smaller compounds. After being metabolized into ellagic acid in the small intestine, the colonic microbiota hydrolyzes and metabolizes ellagic acid into dibenzopyran-6-one derivatives, known as urolithins. These low molecular weight compounds reach circulation in considerable concentrations ranging until micromolar levels, capable of reaching target tissues. Different urolithins are formed throughout the metabolization process, but urolithin A, isourolithin A, and urolithin B, and their phase-II metabolites are the most frequent ones. In recent years, urolithins have been the focus of attention in regard to their effects on a multiplicity of chronic diseases, including cancer and diabetes. In this review, we will discuss the latest advances about the protective effects of urolithins on diabetes.
Changes in Circulating Metabolites during Weight Loss and Weight Loss Maintenance in Relation to Cardiometabolic Risk
Authors: Papandreou Christopher , Harrold Joanne A. , Hansen Thea T. , Halford Jason C. G. , Sjödin Anders , Bulló Mònica
Published: December 2021

(1) Background: There is a substantial lack of knowledge of the biochemical mechanisms by which weight loss and weight regain exert their beneficial and adverse effects, respectively, on cardiometabolic outcomes. We examined associations between changes in circulating metabolites and changes in cardiometabolic risk factors during diet-induced weight loss and weight loss maintenance. (2) Methods: This prospective analysis of data from the Satiety Innovation (SATIN) study involved adults living with overweight and obesity (mean age=47.5). One hundred sixty-two subjects achieving ≥8% weight loss during an initial 8-week low-calorie diet (LCD) were included in a 12-week weight loss maintenance period. Circulating metabolites (m=123) were profiled using a targeted multiplatform approach. Data were analyzed using multivariate linear regression models. (3) Results: Decreases in the concentrations of several phosphatidylcholines (PCs), sphingomyelins (SMs), and valine were consistently associated with decreases in total (TChol) and low-density lipoprotein cholesterol (LDL-C) levels during the LCD. Increases in PCs and SMs were significantly associated with increases in TChol and LDL-C during the weight loss maintenance period. Decreases and increases in PCs during LCD and maintenance period, respectively, were associated with decreases in the levels of triglycerides. (4) Conclusions: The results of this study suggest that decreases in circulating PCs and SMs during weight loss and the subsequent weight loss maintenance period may decrease the cardiovascular risk through impacting TChol and LDL-C.
Associated Factors of Sarcopenia in Community-Dwelling Older Adults: A Systematic Review and Meta-Analysis
Authors: Gao Qianqian , Hu Kaiyan , Yan Chunjuan , Zhao Bing , Mei Fan , Chen Fei , Zhao Li , Shang Yi , Ma Yuxia , Ma Bin
Published: December 2021

(1) Background: To review the associated factors of sarcopenia in community-dwelling older adults. (2) Methods: PubMed, Embase, Web of Science, and four Chinese electronic databases were searched for observational studies that reported the associated factors of sarcopenia from inception to August 2021. Two researchers independently selected the literature, evaluated their quality, and extracted relevant data. The pooled odds ratio (OR) and its 95% confidence interval (CI) were calculated for each associated factors of sarcopenia using random-effects/fixed-effects models. Publication bias was assessed using funnel plot and the Eggers test. We performed statistical analysis using Stata 15.0 software. (3) Results: A total of 68 studies comprising 98,502 cases were included. Sociodemographic associated factors of sarcopenia among community-dwelling older adults included age (OR = 1.12, 95% CI: 1.10–1.13), marital status (singled, divorced, or widowed) (OR = 1.57, 95% CI: 1.08–2.28), disability for activities of daily living (ADL) (OR = 1.49, 95% CI: 1.15–1.92), and underweight (OR = 3.78, 95% CI: 2.55–5.60). Behavioral associated factors included smoking (OR = 1.20, 95% CI: 1.10–1.21), physical inactivity (OR = 1.73, 95% CI: 1.48–2.01), malnutrition/malnutrition risk (OR = 2.99, 95% CI: 2.40–3.72), long (OR = 2.30, 95% CI: 1.37–3.86) and short (OR = 3.32, 95% CI: 1.86–5.93) sleeping time, and living alone (OR = 1.55, 95% CI: 1.00–2.40). Disease-related associated factors included diabetes (OR = 1.40, 95% CI: 1.18–1.66), cognitive impairment (OR = 1.62, 95% CI: 1.05–2.51), heart diseases (OR = 1.14, 95% CI: 1.00–1.30), respiratory diseases (OR = 1.22, 95% CI: 1.09–1.36), osteopenia/osteoporosis (OR = 2.73, 95% CI: 1.63–4.57), osteoarthritis (OR = 1.33, 95% CI: 1.23–1.44), depression (OR = 1.46, 95% CI: 1.17–1.83), falls (OR = 1.28, 95% CI: 1.14–1.44), anorexia (OR = 1.50, 95% CI: 1.14–1.96), and anemia (OR = 1.39, 95% CI: 1.06–1.82). However, it remained unknown whether gender (female: OR = 1.10, 95% CI: 0.80–1.51; male: OR = 1.50, 95% CI: 0.96–2.34), overweight/obesity (OR = 0.27, 95% CI: 0.17–0.44), drinking (OR = 0.92, 95% CI: 0.84–1.01), hypertension (OR = 0.98, 95% CI: 0.84–1.14), hyperlipidemia (OR = 1.14, 95% CI: 0.89–1.47), stroke (OR = 1.70, 95% CI: 0.69–4.17), cancer (OR = 0.88, 95% CI: 0.85–0.92), pain (OR = 1.08, 95% CI: 0.98–1.20), liver disease (OR = 0.88, 95% CI: 0.85–0.91), and kidney disease (OR = 2.52, 95% CI: 0.19–33.30) were associated with sarcopenia. (4) Conclusions: There are many sociodemographic, behavioral, and disease-related associated factors of sarcopenia in community-dwelling older adults. Our view provides evidence for the early identification of high-risk individuals and the development of relevant interventions to prevent sarcopenia in community-dwelling older adults.
Dietary Animal to Plant Protein Ratio Is Associated with Risk Factors of Metabolic Syndrome in Participants of the AHS-2 Calibration Study
Authors: Azemati Bahar , Rajaram Sujatha , Jaceldo-Siegl Karen , Haddad Ella H. , Shavlik David , Fraser Gary E.
Published: December 2021

Background: Few research studies have focused on the effects of dietary protein on metabolic syndrome and its components. Our objective was to determine the relationship between the type of dietary protein intake and animal to plant (AP) protein ratio with metabolic syndrome and its components. Methods: This population-based study had a cross sectional design and conducted on 518 participants of the Adventist Health Study 2 (AHS-2) Calibration Study. Two sets of three dietary 24-h recalls were obtained six months apart. Anthropometric measures and biochemical tests were performed in clinics. Regression calibration models were used to determine the association of type of dietary protein with metabolic syndrome and its components (raised triglyceride, raised blood pressure, reduced high-density lipoprotein cholesterol (HDL), raised fasting blood glucose and increased waist circumference). Results: The likelihood of metabolic syndrome was lower in those with higher total dietary protein and animal protein intake (p = 0.02).Total protein (β = 0.004, [95%CI: 0.002, 0.007]), animal protein intake (β = 0.004, [95%CI: 0.001, 0.007]) and AP protein intake ratio (β = 0.034, [95%CI: 0.021, 0.047]) were positively associated with waist circumference. Higher AP protein ratio was related to higher fasting blood glucose (β = 0.023, [95%CI: 0.005, 0.041]). Conclusion: Our study suggests that considering a significant amount of plant protein as a part of total dietary protein has beneficial effects on cardiometabolic risk factors.
Sugar Content of Market Beverages and Children’s Sugar Intake from Beverages in Beijing, China
Authors: Wen Jing , Ma Huijuan , Yu Yingjie , Zhang Xiaoxuan , Guo Dandan , Yin Xueqian , Yu Xiaohui , Yin Ning , Wang Junbo , Zhao Yao
Published: December 2021

(1) Background: This study aims to find the sugar content of market beverages and estimate the sugar intake from beverages among students in Beijing. (2) Methods: Using snapshotting, we collected the sugar content of beverages through their packages or nutrition labels. Combined with the statistic of student beverage consumption, we estimated students’ sugar intake. (3) Results: The median sugar content of total beverages was 9.0 g/100 mL, among which the fruits/vegetable juices and beverages had the highest sugar content (10.0 g/100 mL). Sugar content in most beverages in Beijing was generally higher than the recommendations, and fruit/vegetable juices and beverages exceeded the most. The median of sugar intake from beverages among students was 5.3 g/d, and the main sources were fruit/vegetable juices and beverages, protein beverages and carbonated beverages. Sugar intake from beverages differed according to gender, age and living area. Higher sugar intake was found among boys, older students and rural students. (4) Conclusions: Sugar content in market beverages in Beijing were high. Gender, age and residence were the influencing factors of sugar intake. Targeted measures should be taken to decrease the sugar content in beverages, especially the fruit/vegetable juices and beverages and the sugar intake among students.
Vitamin D Deficiency in Patients with Diabetes in French Guiana: Epidemiology and Relation with Microvascular and Macrovascular Complications
Authors: Girard Elise , Nacher Mathieu , Bukasa-Kakamba John , Fahrasmane Aniza , Adenis Antoine , Massicard Mickael , Drak Alsibai Kinan , De Toffol Bertrand , Bekima Raissa , Thelusme Liliane , Okambabelle Diana , Demar Magalie , Aurelus Jean M. , Sabbah Nadia
Published: December 2021

Vitamin D (VD) insufficiency is common among patients with diabetes in French Guiana. The study aimed to evaluate the prevalence of VD deficiency in the different type of diabetes encountered and to analyze the relationship between VD deficiency and diabetes complications. Methods: An observational study was conducted between May 2019 and May 2020 in French Guiana, based on data from the CODIAM study (Diabetes Cohort in French Amazonia), describing the characteristics of patients with diabetes mellitus. Among 600 patients enrolled with diabetes, 361 had an available VD assay. Results: The mean 25(OH)VD (hydroxycalciferol) level was 27.9 ng/mL. The level of VD was inversely proportional to the HbA1c (glycated hemoglobin) level. Patients with angina pectoris had a greater proportion of deficiencies VD < 20 ng/mL than those without angina. By contrast, patients with retinopathy had higher vitamin D concentrations than those without retinopathy. There was no association between vitamin D and arteriopathy, stroke, nephropathy and polyneuropathy. VD deficiency was more frequent in women, and in patients with a high school education. Conclusion: The prevalence of VD deficiency was high in patients with diabetes in French Guiana, emphasizing the importance of VD supplementation.
Examining the Interaction of the Gut Microbiome with Host Metabolism and Cardiometabolic Health in Metabolic Syndrome
Authors: Galié Serena , Papandreou Christopher , Arcelin Pierre , Garcia David , Palau-Galindo Antoni , Gutiérrez-Tordera Laia , Folch Àlex , Bulló Mònica
Published: December 2021

(1) Background: The microbiota-host cross-talk has been previously investigated, while its role in health is not yet clear. This study aimed to unravel the network of microbial-host interactions and correlate it with cardiometabolic risk factors. (2) Methods: A total of 47 adults with overweight/obesity and metabolic syndrome from the METADIET study were included in this cross-sectional analysis. Microbiota composition (151 genera) was assessed by 16S rRNA sequencing, fecal (m = 203) and plasma (m = 373) metabolites were profiled. An unsupervised sparse generalized canonical correlation analysis was used to construct a network of microbiota-metabolite interactions. A multi-omics score was derived for each cluster of the network and associated with cardiometabolic risk factors. (3) Results: Five multi-omics clusters were identified. Thirty-one fecal metabolites formed these clusters and were correlated with plasma sphingomyelins, lysophospholipids and medium to long-chain acylcarnitines. Seven genera from Ruminococcaceae and a member from the Desulfovibrionaceae family were correlated with fecal and plasma metabolites. Positive correlations were found between the multi-omics scores from two clusters with cholesterol and triglycerides levels. (4) Conclusions: We identified a correlated network between specific microbial genera and fecal/plasma metabolites in an adult population with metabolic syndrome, suggesting an interplay between gut microbiota and host lipid metabolism on cardiometabolic health.
Effects of Acute Resistance Exercise with and without Whole-Body Electromyostimulation and Endurance Exercise on the Postprandial Glucose Regulation in Patients with Type 2 Diabetes Mellitus: A Randomized Crossover Study
Authors: Holzer Roman , Schulte-Körne Benedikt , Seidler Jan , Predel Hans-Georg , Brinkmann Christian
Published: December 2021

Background: Long hyperglycemic episodes trigger complications in type 2 diabetes mellitus (T2DM) patients. Postprandial glucose excursions can be reduced by acute physical activity. However, it is not yet clear which type of exercise has the best effect on postprandial glucose levels. Methods: Six T2DM patients participated in three 20-min moderate-intensity exercise sessions after breakfast in a randomized order: resistance exercise with whole-body electromyostimulation (WB-EMS), resistance exercise without electromyostimulation (RES) and cycling endurance exercise (END). A continuous glucose monitoring system recorded glucose dynamics. Results: Postprandially-increased glucose levels decreased in all cases. Time to baseline (initial value prior to meal intake) was quite similar for WB-EMS, RES and END. Neither glucose area under the curve (AUC), nor time in range from the start of the experiment to its end (8 h later) differed significantly. A Friedman analysis of variance, however, revealed an overall significant difference for AUC in the post-exercise recovery phase (END seems to have superior effects, but post-hoc tests failed statistical significance). Conclusions: There are no notable differences between the effects of the different types of exercise on glucose levels, especially when comparing values over a longer period of time.
Nutritional Behaviors, Health Literacy, and Health Locus of Control of Secondary Schoolers in Southern Poland: A Cross-Sectional Study
Authors: Duplaga Mariusz , Grysztar Marcin
Published: December 2021

Nutritional behaviors remain an essential part of a healthy lifestyle. It seems obvious that unfavorable health behaviors adopted in adolescence are maintained late in adulthood and may have a profound effect on health status. The main aim of this study was to assess the association between nutritional behaviors and health literacy (HL), health locus of control (HLC), and socioeconomic variables in secondary school pupils from a voivodship (the main unit of territorial division) in southern Poland. The analysis was based on dataTable from a paper-and-pencil survey taken by 2223 pupils from schools selected as the result of cluster sampling. The survey questionnaire encompassed a set of five items asking about dietary patterns and the consumption of fruit and vegetables as well as fast food, a European Health Literacy Project Questionnaire consisting of 47 items, the Multidimensional Health Locus of Control (MHLC) scale, and items asking about sociodemographic and economic variables. Uni- and multivariate logistic regression models have been developed to assess the predictors of indicator nutrition behaviors. The adjusted models revealed that internal HLC was not significantly associated with any of analyzed nutritional behaviors. “Powerful other HLC” and “Chance HLC” (dimension of external HLC) were significant predictors of the selected dietary patterns. Furthermore, higher HL was associated with higher consumption of fruit and vegetables [odds ratio, 95% confidence interval (OR, 95% CI)]: 1.02 (1.01–1.04) and with lower consumption of fast food (OR, 95% CI, 0.98, 0.95–0.999). There was a significant relationship between gender, the size of the household, self-assessed economic situation, expenditures on mobile phones, and weekly duration of Internet use and selected nutrition behaviors. In conclusion, developed regression models confirmed a significant relationship between HL and the types of consumed food, but not with dieting patterns. Contrary to earlier studies, internal HLC was not associated with nutrition behaviors. In our study, boys showed more favorable nutritional behaviors than girls. More intense use of the Internet was associated with less beneficial nutritional behaviors. This study brings important results that should have an impact on health promotion interventions addressed to adolescents in southern Poland.
A Cross-Sectional Study of the Nutritional Quality of New South Wales High School Student Food and Drink Purchases Made via an Online Canteen Ordering System
Authors: Clinton-McHarg Tara , Delaney Tessa , Lamont Hannah , Lecathelinais Christophe , Yoong Sze Lin , Wolfenden Luke , Sutherland Rachel , Wyse Rebecca
Published: December 2021

Unhealthy dietary patterns in adolescence are associated with an increased risk of future chronic disease. This study aimed to assess online canteen lunch purchases made by high school students to identify: (1) the nutrient composition of purchases (energy, saturated fat, sugar, sodium, percent energy from saturated fat and total sugar); (2) the proportion of items classified as healthier (‘Everyday’) and less healthy (‘Occasional’ or ‘Should not be sold’) according to the New South Wales Healthy Canteen Strategy; (3) the frequency of purchases by product type (e.g., salty snacks), their classification and nutrient composition; and (4) associations between student characteristics and the nutrient composition and classification of purchases. The average order contained 2075 kJ of energy, 6.4 g of saturated fat, 18.4 g of sugar and 795 mg of sodium. Less healthy (‘Occasional’ and ‘Should not be sold’) items combined accounted for 56% of purchases. The most frequently purchased products were burgers and crumbed/coated foods. Students in higher grades purchased a significantly higher mean percent of ‘Everyday’ items, compared to students in grades 7 or 8. The majority of high school student purchases were less healthy (‘Occasional’ or ‘Should not be sold’) items, warranting further investigation of factors influencing online canteen purchasing behaviour in this setting.
Non-Coding RNAs and Wnt/β-Catenin Signaling Pathway in Gastric Cancer: From EMT to Drug Resistance
Authors: Takao Real Karia Bruno , Albuquerque Pinto Camila , Gigek Carolina Oliveira , Wisnieski Fernanda , Arruda Cardoso Smith Marilia
Published: December 2021

Gastric cancer is one of the most common cancers and the third cause of cancer-related death worldwide. The treatment of GC patients improved due to advancements in surgery, radiotherapy and chemotherapy. However, the long-term survival rate of patients with gastric cancer remains around 20%. Thus, development of novel therapeutic approaches is of great interest, in order to reduce the need for mutilating surgeries and morbid adjuvant therapies. For many years, it was believed that the RNA was a mere intermediate molecule in the genetic information flow. However, during the past decades, with the advent of new sequencing technologies, it was revealed that non-coding RNAs play important roles in many different biological processes. The Wnt/β-catenin signaling pathway has been reported to regulate crucial events during neoplasic development, such as cell differentiation, proliferation, invasion, migration, apoptosis, and angiogenesis. In this review, we will focus on microRNAs and long non-coding RNAs that have been implicated in gastric cancer tumorigenesis via modulation of the Wnt/β-catenin signaling pathway, which provided some biomarkers to prognosis, diagnosis, and therapy.
Vitamin D-Related Genetics as Predictive Biomarker of Clinical Remission in Adalimumab-Treated Patients Affected by Crohn’s Disease: A Pilot Study
Authors: Cusato Jessica , Bertani Lorenzo , Antonucci Miriam , Tomasello Cristina , Caviglia Gian Paolo , Dibitetto Simone , Massano Alessandro , Mangia Michela , Mula Jacopo , Ceccarelli Linda , Costa Francesco , Zanzi Federico , Astegiano Marco , Ribaldone Davide Giuseppe , D’Avolio Antonio
Published: December 2021

Adalimumab (ADA) is a human anti-tumor necrosis factor (TNF-α) monoclonal antibody used in inflammatory bowel diseases, such as Crohn’s disease (CD). Vitamin-D (VD) is important for biological functions, such as the modulation of expression of genes encoding enzymes and transporters involved in drug metabolism and transport. ADA trough levels were associated with VD concentrations in patients with IBD, but no data are present in the literature concerning VD pathway-related gene single-nucleotide polymorphisms (SNPs) in affecting clinical outcomes. For this reason, the aim of this study was to evaluate the ability of VD-related genetics to predict clinical remission at 3 and 12 months in patients affected by CD treated with ADA. Patients affected by CD were included in this study. SNPs in CYP27B1, CYP24A1, GC, and VDR genes were analyzed through real-time PCR. A total of 63 patients were enrolled. Calprotectin, hemoglobin, and C-reactive protein levels were influenced by SNPs in VDR, CYP27B1, and GC genes. After 3 months of therapy, clinical remission was predicted by smoke, systemic steroids, and VDR BsmI, whereas at 12 months by GC 1296AA/AC and VD supplementation. This study reports the association between VD pathway-related genetics and ADA treatment. Further studies are needed to confirm these promising data.
Restoring Tumour Selectivity of the Bioreductive Prodrug PR-104 by Developing an Analogue Resistant to Aerobic Metabolism by Human Aldo-Keto Reductase 1C3
Authors: Abbattista Maria R. , Ashoorzadeh Amir , Guise Christopher P. , Mowday Alexandra M. , Mittra Rituparna , Silva Shevan , Hicks Kevin O. , Bull Matthew R. , Jackson-Patel Victoria , Lin Xiaojing , Prosser Gareth A. , Lambie Neil K. , Dachs Gabi U. , Ackerley David F. , Smaill Jeff B. , Patterson Adam V.
Published: December 2021

PR-104 is a phosphate ester pre-prodrug that is converted in vivo to its cognate alcohol, PR-104A, a latent alkylator which forms potent cytotoxins upon bioreduction. Hypoxia selectivity results from one-electron nitro reduction of PR-104A, in which cytochrome P450 oxidoreductase (POR) plays an important role. However, PR-104A also undergoes ‘off-target’ two-electron reduction by human aldo-keto reductase 1C3 (AKR1C3), resulting in activation in oxygenated tissues. AKR1C3 expression in human myeloid progenitor cells probably accounts for the dose-limiting myelotoxicity of PR-104 documented in clinical trials, resulting in human PR-104A plasma exposure levels 3.4- to 9.6-fold lower than can be achieved in murine models. Structure-based design to eliminate AKR1C3 activation thus represents a strategy for restoring the therapeutic window of this class of agent in humans. Here, we identified SN29176, a PR-104A analogue resistant to human AKR1C3 activation. SN29176 retains hypoxia selectivity in vitro with aerobic/hypoxic IC50 ratios of 9 to 145, remains a substrate for POR and triggers γH2AX induction and cell cycle arrest in a comparable manner to PR-104A. SN35141, the soluble phosphate pre-prodrug of SN29176, exhibited superior hypoxic tumour log cell kill (>4.0) to PR-104 (2.5–3.7) in vivo at doses predicted to be achievable in humans. Orthologues of human AKR1C3 from mouse, rat and dog were incapable of reducing PR-104A, thus identifying an underlying cause for the discrepancy in PR-104 tolerance in pre-clinical models versus humans. In contrast, the macaque AKR1C3 gene orthologue was able to metabolise PR-104A, indicating that this species may be suitable for evaluating the toxicokinetics of PR-104 analogues for clinical development. We confirmed that SN29176 was not a substrate for AKR1C3 orthologues across all four pre-clinical species, demonstrating that this prodrug analogue class is suitable for further development. Based on these findings, a prodrug candidate was subsequently identified for clinical trials.
Effect of a Low Dose of Carvedilol on Cyclophosphamide-Induced Urinary Toxicity in Rats—A Comparison with Mesna
Authors: Merwid-Ląd Anna , Ziółkowski Piotr , Szandruk-Bender Marta , Matuszewska Agnieszka , Szeląg Adam , Trocha Małgorzata
Published: December 2021

One of the major side effects of cyclophosphamide (CPX)—an alkylating anticancer drug that is still clinically used—is urotoxicity with hemorrhagic cystitis. The present study was designed to evaluate the ability of carvedilol to protect rats from cyclophosphamide-induced urotoxicity. Rats were injected intraperitoneally (i.p.) with CPX (200 mg/kg) and administered carvedilol (2 mg/kg) intragastrically a day before, at the day and a day after a single i.p. injection of CPX, with or without mesna (40, 80, and 80 mg/kg i.p. 20 min before, 4 h and 8 h after CPX administration, respectively). Pretreatment with carvedilol partly prevented the CPX-induced increase in urinary bladder and kidney index, and completely protects from CPX-evoked alterations in serum potassium and creatinine level, but did not prevent histological alterations in the urinary bladder and hematuria. However, carvedilol administration resulted in significant restoration of kidney glutathione (GSH) level and a decrease in kidney interleukin 1β (IL-1β) and plasma asymmetric dimethylarginine (ADMA) concentrations. Not only did mesna improve kidney function, but it also completely reversed histological abnormalities in bladders and prevented hematuria. In most cases, no significant interaction of carvedilol with mesna was observed, although the effect of both drugs together was better than mesna given alone regarding plasma ADMA level and kidney IL-1β concentration. In conclusion, carvedilol did not counteract the injury caused in the urinary bladders but restored kidney function, presumably via its antioxidant and anti-inflammatory properties.
In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma
Authors: Halatsch Marc-Eric , Dwucet Annika , Schmidt Carl Julius , Mühlnickel Julius , Heiland Tim , Zeiler Katharina , Siegelin Markus D. , Kast Richard Eric , Karpel-Massler Georg
Published: December 2021

Background: Glioblastoma represents the most common primary brain tumor in adults. Despite technological advances, patients with this disease typically die within 1–2 years after diagnosis. In the search for novel therapeutics, drug repurposing has emerged as an alternative to traditional drug development pipelines, potentially facilitating and expediting the transition from drug discovery to clinical application. In a drug repurposing effort, the original CUSP9 and its derivatives CUSP9* and CUSP9v3 were developed as combinations of nine non-oncological drugs combined with metronomic low-dose temozolomide. Methods: In this work, we performed pre-clinical testing of CUSP9v3 in different established, primary cultured and stem-like glioblastoma models. In addition, eight patients with heavily pre-treated recurrent glioblastoma received the CUSP9v3 regime on a compassionate use basis in a last-ditch effort. Results: CUSP9v3 had profound antiproliferative and pro-apoptotic effects across all tested glioblastoma models. Moreover, the cells’ migratory capacity and ability to form tumor spheres was drastically reduced. In vitro, additional treatment with temozolomide did not significantly enhance the antineoplastic activity of CUSP9v3. CUSP9v3 was well-tolerated with the most frequent grade 3 or 4 adverse events being increased hepatic enzyme levels. Conclusions: CUSP9v3 displays a strong anti-proliferative and anti-migratory activity in vitro and seems to be safe to apply to patients. These data have prompted further investigation of CUSP9v3 in a phase Ib/IIa clinical trial (NCT02770378).
Discovery of SARS-CoV-2 Nsp14 and Nsp16 Methyltransferase Inhibitors by High-Throughput Virtual Screening
Authors: Bobrovs Raitis , Kanepe Iveta , Narvaiss Nauris , Patetko Liene , Kalnins Gints , Sisovs Mihails , Bula Anna L. , Grinberga Solveiga , Boroduskis Martins , Ramata-Stunda Anna , Rostoks Nils , Jirgensons Aigars , Tars Kaspars , Jaudzems Kristaps
Published: December 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses mRNA capping to evade the human immune system. The cap formation is performed by the SARS-CoV-2 mRNA cap methyltransferases (MTases) nsp14 and nsp16, which are emerging targets for the development of broad-spectrum antiviral agents. Here, we report results from high-throughput virtual screening against these two enzymes. The docking of seven million commercially available drug-like compounds and S-adenosylmethionine (SAM) co-substrate analogues against both MTases resulted in 80 virtual screening hits (39 against nsp14 and 41 against nsp16), which were purchased and tested using an enzymatic homogeneous time-resolved fluorescent energy transfer (HTRF) assay. Nine compounds showed micromolar inhibition activity (IC50 < 200 μM). The selectivity of the identified inhibitors was evaluated by cross-checking their activity against human glycine N-methyltransferase. The majority of the compounds showed poor selectivity for a specific MTase, no cytotoxic effects, and rather poor cell permeability. Nevertheless, the identified compounds represent good starting points that have the potential to be developed into efficient viral MTase inhibitors.
Structure and Activity of a Selective Antibiofilm Peptide SK-24 Derived from the NMR Structure of Human Cathelicidin LL-37
Authors: Zhang Yingxia , Lakshmaiah Narayana Jayaram , Wu Qianhui , Dang Xiangli , Wang Guangshun
Published: December 2021

The deployment of the innate immune system in humans is essential to protect us from infection. Human cathelicidin LL-37 is a linear host defense peptide with both antimicrobial and immune modulatory properties. Despite years of studies of numerous peptides, SK-24, corresponding to the long hydrophobic domain (residues 9–32) in the anionic lipid-bound NMR structure of LL-37, has not been investigated. This study reports the structure and activity of SK-24. Interestingly, SK-24 is entirely helical (~100%) in phosphate buffer (PBS), more than LL-37 (84%), GI-20 (75%), and GF-17 (33%), while RI-10 and 17BIPHE2 are essentially randomly coiled (helix%: 7–10%). These results imply an important role for the additional N-terminal amino acids (likely E16) of SK-24 in stabilizing the helical conformation in PBS. It is proposed herein that SK-24 contains the minimal sequence for effective oligomerization of LL-37. Superior to LL-37 and RI-10, SK-24 shows an antimicrobial activity spectrum comparable to the major antimicrobial peptides GF-17 and GI-20 by targeting bacterial membranes and forming a helical conformation. Like the engineered peptide 17BIPHE2, SK-24 has a stronger antibiofilm activity than LL-37, GI-20, and GF-17. Nevertheless, SK-24 is least hemolytic at 200 µM compared with LL-37 and its other peptides investigated herein. Combined, these results enabled us to appreciate the elegance of the long amphipathic helix SK-24 nature deploys within LL-37 for human antimicrobial defense. SK-24 may be a useful template of therapeutic potential.
Hit Identification of a Novel Quinazoline Sulfonamide as a Promising EphB3 Inhibitor: Design, Virtual Combinatorial Library, Synthesis, Biological Evaluation, and Docking Simulation Studies
Authors: Lee Kyeong , Nada Hossam , Byun Hyun Jung , Lee Chang Hoon , Elkamhawy Ahmed
Published: December 2021

EphB3 is a major key player in a variety of cellular activities, including cell migration, proliferation, and apoptosis. However, the exact role of EphB3 in cancer remains ambiguous. Accordingly, new EphB3 inhibitors can increase the understanding of the exact roles of the receptor and may act as promising therapeutic candidates. Herein, a hybrid approach of structure-based design and virtual combinatorial library generated 34 quinazoline sulfonamides as potential selective EphB3 inhibitors. A molecular docking study over EphB3 predicted the binding affinities of the generated library, and the top seven hit compounds (3a and 4a–f), with GlideScore ≥ −6.20 Kcal/mol, were chosen for further MM-GBSA calculations. Out of the seven top hits, compound 4c showed the highest MM-GBSA binding free energy (−74.13 Kcal/mol). To validate these predicted results, compounds 3a and 4a–f were synthesized and characterized using NMR, HRMS, and HPLC. The biological evaluation revealed compound 4c as a potent EphB3 inhibitory lead (IC50 = 1.04 µM). The screening of 4c over a mini-panel of kinases consisting of EGFR, Aurora A, Aurora B, CDK2/cyclin A, EphB1, EphB2, EphB4, ERBB2/HER2, and KDR/VEGFR2, showed a promising selective profile against EphB3 isoform. A dose-dependent assay of compound 4c and a molecular docking study over the different forms of EphB provided insights into the elicited biological activities and highlighted reasonable explanations of the selectivity.
Effect of UV Irradiation (A and C) on Casuarina equisetifolia-Mediated Biosynthesis and Characterization of Antimicrobial and Anticancer Activity of Biocompatible Zinc Oxide Nanoparticles
Authors: Khan Amna Komal , Renouard Sullivan , Drouet Samantha , Blondeau Jean-Philippe , Anjum Iram , Hano Christophe , Abbasi Bilal Haider , Anjum Sumaira
Published: December 2021

The green synthesis of nanoparticles has emerged as a simple, safe, sustainable, reliable and eco-friendly protocol. Among different types of NPs, green-synthesized zinc oxide NPs (ZnONPs) show various promising biological uses due to their interesting magnetic, electrical, optical and chemical characteristics. Keeping in view the dependence of the therapeutic efficacy of NPs on their physico-chemical characteristics, the green synthesis of ZnONPs using Casuarina equisetifolia leaf extract under UV-A and UV-C light was carried out in this study. UV-irradiation helped to control the size and morphology of ZnONPs by exciting the electrons in the photoactive compounds of plant extracts to enhance the bio-reduction of ZnO into ZnONPs. C. equisetifolia leaf extract was found enriched with phenolic (2.47 ± 0.12 mg GAE/g DW) and flavonoid content (0.88 ± 0.28 mg QE/g DW) contributing to its 74.33% free-radical scavenging activity. FTIR spectra showed the involvement of polyphenols in the bio-reduction, stabilization and capping of ZnONPs. Moreover, SEM-EDX and XRD analyses showed great potential of UV-C light in yielding smaller (34–39 nm) oval-shaped ZnONPs, whereas UV-A irradiation resulted in the formation of fairly spherical 67–71 nm ZnONPs and control ZnONPs were of mixed shape and even larger size (84–89 nm). Green-synthesized ZnONPs, notably CE-UV-C-ZnONPs, showed promising anti-bacterial activities against Bacillus subtilis, Pseudomonas fluorescens and Pseudomonas aeruginosa. Moreover, ZnONPs also enhanced ROS production which led to a significant loss of mitochondrial membrane potential and activated caspase-3 gene expression and caspase-3/7 activity in human hepatocellular carcinoma (HepG2) cells. CE-UV-C-ZnONP treatment reduced HepG2 cell viability to as low as 36.97% owing to their unique shape and smaller size. Lastly, ZnONPs were found to be highly biocompatible towards brine shrimp and human red blood cells suggesting their bio-safe nature. This research study sheds light on the plausible role of UV radiation in the green synthesis of ZnONPs with reasonable control over their size and morphology, thus improving their biological efficacy.
Promising Strategies of Colloidal Drug Delivery-Based Approaches in Psoriasis Management
Authors: Singh Sukhbir , Sharma Neelam , Behl Tapan , Sarkar Bidhan Chandra , Saha Hasi Rani , Garg Kanika , Singh Supriya Kamari , Arora Sandeep , Amran Md. Shah , Abdellatif Ahmed A. H. , Bilgrami Anwar L. , Ashraf Ghulam Md , Rahman Md. Sohanur
Published: December 2021

Psoriasis is a chronic inflammatory autoimmune disorder that moderately affects social and interpersonal relationships. Conventional treatments for psoriasis have certain problems, such as poor drug penetration through the skin, hyper-pigmentation, and a burning sensation on normal and diseased skin. Colloidal drug delivery systems overcome the pitfalls of conventional approaches for psoriasis therapeutics and have improved patient safety parameters, compliance, and superior effectiveness. They also entail reduced toxicity. This comprehensive review’s topics include the pathogenesis of psoriasis, causes and types of psoriasis, conventional treatment alternatives for psoriasis, the need for colloidal drug delivery systems, and recent studies in colloidal drug delivery systems for the treatment of psoriasis. This review briefly describes colloidal drug delivery approaches, such as emulsion systems—i.e., multiple emulsion, microemulsion, and nano-emulsion; vesicular systems—i.e., liposomes, ethosomes, noisomes, and transferosomes; and particulate systems—i.e., solid lipid nanoparticles, solid lipid microparticles, nano-structured lipid carriers, dendrimers, nanocrystals, polymeric nanoparticles, and gold nanoparticles. The review was compiled through an extensive search of the literature through the PubMed, Google Scholar, and ScienceDirect databases. A survey of literature revealed seven formulations based upon emulsion systems, six vesicular drug delivery systems, and fourteen particulate systems reported for antipsoriatic drugs. Based on the literature studies of colloidal approaches for psoriasis management carried out in recent years, it has been concluded that colloidal pharmaceutical formulations could be investigated broadly and have a broad scope for effective management of many skin disorders in the coming decades.
Formulation and In Vitro Evaluation of Pellets Containing Sulfasalazine and Caffeine to Verify Ileo-Colonic Drug Delivery
Authors: Broesder Annemarie , Bircan Said Y. , de Waard Anneko B. , Eissens Anko C. , Frijlink Henderik W. , Hinrichs Wouter L. J.
Published: December 2021

The ColoPulse coating is a pH-dependent coating that can be used to target drug release to the ileo-colonic region. ColoPulse coated tablets and capsules have demonstrated their targeting capabilities in vivo in more than 100 volunteers and patients. However, so far the ColoPulse coating has not been used for multi-particulate pellet formulations. The sulfasalazine–caffeine method can be used to confirm ileo-colonic drug delivery in vivo. Caffeine serves as a release marker in this method, while sulfasalazine serves as a marker for colonic arrival. In this study, extrusion–spheronization was used to produce microcrystalline cellulose based pellets containing both caffeine and sulfasalazine. Dissolution tests revealed that a superdisintegrant, i.e., croscarmellose sodium or sodium starch glycolate, should be incorporated in the formulation to achieve acceptable release profiles for both sulfasalazine and caffeine. However, acceptable release profiles were only obtained when the pelletizing liquid consisted of ethanol/water 1/1 (v/v) but not with pure water. This phenomenon was ascribed to the differences in the degree of swelling of the superdisintegrant in the pelletizing liquid during the granulation process. The pellets were coated with the ColoPulse coating and showed the desired pH-dependent pulsatile release profile in vitro. In future clinical studies, ileo-colonic targeting should be verified.
Advances in Use of Nanomaterials for Musculoskeletal Regeneration
Authors: Jampilek Josef , Placha Daniela
Published: December 2021

Since the worldwide incidence of bone disorders and cartilage damage has been increasing and traditional therapy has reached its limits, nanomaterials can provide a new strategy in the regeneration of bones and cartilage. The nanoscale modifies the properties of materials, and many of the recently prepared nanocomposites can be used in tissue engineering as scaffolds for the development of biomimetic materials involved in the repair and healing of damaged tissues and organs. In addition, some nanomaterials represent a noteworthy alternative for treatment and alleviating inflammation or infections caused by microbial pathogens. On the other hand, some nanomaterials induce inflammation processes, especially by the generation of reactive oxygen species. Therefore, it is necessary to know and understand their effects in living systems and use surface modifications to prevent these negative effects. This contribution is focused on nanostructured scaffolds, providing a closer structural support approximation to native tissue architecture for cells and regulating cell proliferation, differentiation, and migration, which results in cartilage and bone healing and regeneration.
Recent Advances in Chronotherapy Targeting Respiratory Diseases
Authors: Paudel Keshav Raj , Jha Saurav Kumar , Allam Venkata Sita Rama Raju , Prasher Parteek , Gupta Piyush Kumar , Bhattacharjee Rahul , Jha Niraj Kumar , Vishwas Sukriti , Singh Sachin K. , Shrestha Jesus , Imran Mohammad , Panth Nisha , Chellappan Dinesh Kumar , Ebrahimi Warkiani Majid , Hansbro Philip M. , Dua Kamal
Published: December 2021

Respiratory diseases contribute to a significant percentage of mortality and morbidity worldwide. The circadian rhythm is a natural biological process where our bodily functions align with the 24 h oscillation (sleep–wake cycle) process and are controlled by the circadian clock protein/gene. Disruption of the circadian rhythm could alter normal lung function. Chronotherapy is a type of therapy provided at specific time intervals based on an individual’s circadian rhythm. This would allow the drug to show optimum action, and thereby modulate its pharmacokinetics to lessen unwanted or unintended effects. In this review, we deliberated on the recent advances employed in chrono-targeted therapeutics for chronic respiratory diseases.
Internalization and Transport of PEGylated Lipid-Based Mixed Micelles across Caco-2 Cells Mediated by Scavenger Receptor B1
Authors: Su Xiangjie , Ramírez-Escudero Mercedes , Sun Feilong , van den Dikkenberg Joep B. , van Steenbergen Mies J. , Pieters Roland J. , Janssen Bert J. C. , van Hasselt Peter M. , Hennink Wim E. , van Nostrum Cornelus F.
Published: December 2021

The aim of this study was to get insight into the internalization and transport of PEGylat-ed mixed micelles loaded by vitamin K, as mediated by Scavenger Receptor B1 (SR-B1) that is abundantly expressed by intestinal epithelium cells as well as by differentiated Caco-2 cells. Inhibition of SR-B1 reduced endocytosis and transport of vitamin-K-loaded 0%, 30% and 50% PEGylated mixed micelles and decreased colocalization of the micelles with SR-B1. Confocal fluorescence microscopy, fluorescence-activated cell sorting (FACS) analysis, and surface plasmon resonance (SPR) were used to study the interaction between the mixed micelles of different compositions (varying vitamin K loading and PEG content) and SR-B1. Interaction of PEGylated micelles was independent of the vitamin K content, indicating that the PEG shell prevented vitamin K exposure at the surface of the micelles and binding with the receptor and that the PEG took over the micelles’ ability to bind to the receptor. Molecular docking calculations corroborated the dual binding of both vita-min K and PEG with the binding domain of SR-B1. In conclusion, the improved colloidal stability of PEGylated mixed micelles did not compromise their cellular uptake and transport due to the affinity of PEG for SR-B1. SR-B1 is able to interact with PEGylated nanoparticles and mediates their subsequent internalization and transport.