bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatic and Vascular Vitamin K Status in Patients with High Cardiovascular Risk
Authors: Rapp Nikolas , Brandenburg Vincent M. , Kaesler Nadine , Bakker Stephan J. L. , Stöhr Robert , Schuh Alexander , Evenepoel Pieter , Schurgers Leon J.
Published: October 2021

Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk factors for cardiovascular morbidity and mortality. In this study we investigated how two vitamin K surrogate markers, dephosphorylated-undercarboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolopathy (CUA) and patients with atrial fibrillation or aortic valve stenosis. Through inter- and intra-cohort comparisons, we assessed the influence of vitamin K antagonist (VKA) use, vitamin K supplementation and disease etiology on vitamin K status, as well as the correlation between both markers. Overall, VKA therapy was associated with 8.5-fold higher PIVKA-II (0.25 to 2.03 AU/mL) and 3-fold higher dp-ucMGP (843 to 2642 pM) levels. In the absence of VKA use, non-renal patients with established VC have dp-ucMGP levels similar to controls (460 vs. 380 pM), while in HD and CUA patients, levels were strongly elevated (977 pM). Vitamin K supplementation significantly reduced dp-ucMGP levels within 12 months (440 to 221 pM). Overall, PIVKA-II and dp-ucMGP showed only weak correlation (r2 ≤ 0.26) and distinct distribution pattern in renal and non-renal patients. In conclusion, VKA use exacerbated vitamin K deficiency across all etiologies, while vitamin K supplementation resulted in a vascular VKDP status better than that of the general population. Weak correlation of vitamin K biomarkers calls for thoughtful selection lead by the research question. Vitamin K status in non-renal deficient patients was not anomalous and may question the role of vitamin K deficiency in the pathogenesis of VC in these patients.
Mechanisms Involved in the Relationship between Vitamin D and Insulin Resistance: Impact on Clinical Practice
Authors: Contreras-Bolívar Victoria , García-Fontana Beatriz , García-Fontana Cristina , Muñoz-Torres Manuel
Published: October 2021

Recent evidence has revealed anti-inflammatory properties of vitamin D as well as extra-skeletal activity. In this context, vitamin D seems to be involved in infections, autoimmune diseases, cardiometabolic diseases, and cancer development. In recent years, the relationship between vitamin D and insulin resistance has been a topic of growing interest. Low 25-hydroxyvitamin D (25(OH)D) levels appear to be associated with most of the insulin resistance disorders described to date. In fact, vitamin D deficiency may be one of the factors accelerating the development of insulin resistance. Vitamin D deficiency is a common problem in the population and may be associated with the pathogenesis of diseases related to insulin resistance, such as obesity, diabetes, metabolic syndrome (MS) and polycystic ovary syndrome (PCOS). An important question is the identification of 25(OH)D levels capable of generating an effect on insulin resistance, glucose metabolism and to decrease the risk of developing insulin resistance related disorders. The benefits of 25(OH)D supplementation/repletion on bone health are well known, and although there is a biological plausibility linking the status of vitamin D and insulin resistance supported by basic and clinical research findings, well-designed randomized clinical trials as well as basic research are necessary to know the molecular pathways involved in this association.
Dietary Interventions with or without Omega-3 Supplementation for the Management of Rheumatoid Arthritis: A Systematic Review
Authors: Raad Tala , Griffin Anne , George Elena S. , Larkin Louise , Fraser Alexander , Kennedy Norelee , Tierney Audrey C.
Published: October 2021

Rheumatoid Arthritis (RA) is a chronic autoimmune condition characterized by symptoms of inflammation and pain in the joints. RA is estimated to have a worldwide prevalence of 0.5–1%, with a predominance in females. Diet may play an important role in the symptoms of RA; however, little is known about the effects of various diets. The aim of this systematic review is to explore the effect of dietary interventions, with or without omega-3 supplementation for the management of RA. The electronic databases MEDLINE, EMBASE, CINAHL, and the Cochrane Library were systematically searched for clinical trials investigating dietary interventions, with or without omega-3 supplementation to retrieve papers from inception to April 2021. Randomized and non-randomized controlled trials of dietary interventions in adults with RA were eligible for inclusion. Twenty studies with a total of 1063 participants were included. The most frequently reported outcomes were pain, duration of morning stiffness, joint tenderness, grip strength and inflammatory markers. Dietary interventions with an anti-inflammatory basis may be an effective way for adults with RA seeking complementary treatments, potentially leading to improvements in certain parameters. However, there is a need for longer duration studies that are well-designed and sufficiently powered to investigate the influence of diet on RA.
What Is the Impact of Energy Expenditure on Energy Intake?
Authors: Bosy-Westphal Anja , Hägele Franziska A. , Müller Manfred J.
Published: October 2021

Coupling energy intake (EI) to increases in energy expenditure (EE) may be adaptively, compensatorily, or maladaptively leading to weight gain. This narrative review examines if functioning of the homeostatic responses depends on the type of physiological perturbations in EE (e.g., due to exercise, sleep, temperature, or growth), or if it is influenced by protein intake, or the extent, duration, timing, and frequency of EE. As different measures to increase EE could convey discrepant neuronal or humoral signals that help to control food intake, the coupling of EI to EE could be tight or loose, which implies that some ways to increase EE may have advantages for body weight regulation. Exercise, physical activity, heat exposure, and a high protein intake favor weight loss, whereas an increase in EE due to cold exposure or sleep loss likely contributes to an overcompensation of EI, especially in vulnerable thrifty phenotypes, as well as under obesogenic environmental conditions, such as energy dense high fat—high carbohydrate diets. Irrespective of the type of EE, transient elevations in the metabolic rate seem to be general risk factors for weight gain, because a subsequent decrease in energy requirement is not compensated by an adequate adaptation of appetite and EI.
Anti-Inflammatory Properties of Fructo-Oligosaccharides in a Calf Lung Infection Model and in Mannheimia haemolytica-Infected Airway Epithelial Cells
Authors: Cai Yang , Gilbert Myrthe S. , Gerrits Walter J. J. , Folkerts Gert , Braber Saskia
Published: October 2021

Emerging antimicrobial-resistant pathogens highlight the importance of developing novel interventions. Here, we investigated the anti-inflammatory properties of Fructo-oligosaccharides (FOS) in calf lung infections and in airway epithelial cells stimulated with pathogens, and/or bacterial components. During a natural exposure, 100 male calves were fed milk replacer with or without FOS for 8 weeks. Then, immune parameters and cytokine/chemokine levels in the bronchoalveolar lavage fluid (BALF) and blood were measured, and clinical scores were investigated. Calf primary bronchial epithelial cells (PBECs) and human airway epithelial cells (A549) were treated with Mannheimia haemolytica, lipopolysaccharides (LPS), and/or flagellin, with or without FOS pretreatment. Thereafter, the cytokine/chemokine levels and epithelial barrier function were examined. Relative to the control (naturally occurring lung infections), FOS-fed calves had greater macrophage numbers in BALF and lower interleukin (IL)-8, IL-6, and IL-1β concentrations in the BALF and blood. However, FOS did not affect the clinical scores. At slaughter, FOS-fed calves had a lower severity of lung lesions compared to the control. Ex vivo, FOS prevented M. haemolytica-induced epithelial barrier dysfunction. Moreover, FOS reduced M. haemolytica- and flagellin-induced (but not LPS-induced) IL-8, TNF-α, and IL-6 release in PBECs and A549 cells. Overall, FOS had anti-inflammatory properties during the natural incidence of lung infections but had no effects on clinical symptoms.
Short-Term Intake of Yellowstripe Scad versus Salmon Did Not Induce Similar Effects on Lipid Profile and Inflammatory Markers among Healthy Overweight Adults despite Their Comparable EPA+DHA Content
Authors: Chang Wei Lin , Azlan Azrina , Noor Sabariah Md , Ismail Irmi Zarina , Loh Su Peng
Published: October 2021

Yellowstripe scad (YSS) have comparable eicosapentaenoic acid and docosahexaenoic acid (EPA+DHA) content to salmon. We aimed to compare the effects of YSS and salmon on lipid profile and inflammatory markers. A randomized crossover trial with two diet periods was conducted among healthy overweight (with BMI 23.0–27.4 kg/m2) Malaysian adults aged 21–55 years. Steamed whole YSS fish (≈385 g whole fish/day) or salmon fillets (≈246 g fillet/day) were given for eight weeks (3 days per week), retaining approximately 1000 mg EPA+DHA per day. Diets were switched after an 8-week washout period. Fasting blood samples were collected before and after each diet period. A total of 49 subjects participated in the intervention (35% male and 65% female; mean age 29 (7) years). YSS did not induce any significant changes in outcome measures. However, the consumption of salmon as compared with YSS was associated with reduction in triglycerides (between-group difference: −0.09 mmol/1, p = 0.01), VLDL-cholesterol (between-group difference: −0.04 mmol/1, p = 0.01), atherogenic index of plasma (between-group difference: −0.05 mmol/1, p = 0.006), and IL-6 (between-group difference: −0.01 pg/mL, p = 0.03). Despite their comparable EPA+DHA content, short-term consumption of salmon but not YSS induced significant changes in lipid profile and inflammatory markers. Larger clinical trials are needed to confirm the findings.
Lifestyle, WCRF/AICR Recommendations, and Esophageal Adenocarcinoma Risk: A Systematic Review of the Literature
Authors: Nucci Daniele , Marino Alessio , Realdon Stefano , Nardi Mariateresa , Fatigoni Cristina , Gianfredi Vincenza
Published: October 2021

One of the most notable changes in the epidemiology of esophageal cancer (EC) is the rising incidence and prevalence of esophageal adenocarcinoma (EAC) in developed countries. The aim of this systematic review was to collect and summarize all the available evidence regarding lifestyle, diet, and EAC risk. We searched the PubMed and Scopus databases in January 2021 for studies providing information about lifestyle, diet, WCRF/AICR recommendations, and EAC risk; published in English; without a time filter. The Newcastle–Ottawa Scale was used to assess risk of bias. The results are stratified by risk factor. A total of 106 publications were included. Half of the case-control studies were judged as high quality, whilst practically all cohort studies were judged as high quality. Body mass index and waist circumference were associated with increased EAC risk. Physical activity did not appear to have a significant direct role in EAC risk. A diet rich in fruit, vegetables, and whole grains appeared to be more protective than a Western diet. Alcohol does not seem to be related to EAC, whereas smokers, particularly heavy smokers, have an increased risk of EAC. Prevention remains the best option to avert EAC. Comprehensible and easy to follow recommendations should be provided to all subjects. Protocol ID number: CRD-42021228762, no funds received.
Dietary Intake, Eating Behavior, Physical Activity, and Quality of Life in Infertile Women with PCOS and Obesity Compared with Non-PCOS Obese Controls
Authors: Wang Zheng , Groen Henk , Cantineau Astrid E. P. , van Elten Tessa M. , Karsten Matty D. A. , van Oers Anne M. , Mol Ben W. J. , Roseboom Tessa J. , Hoek Annemieke
Published: October 2021

To personalize lifestyle advice for women with polycystic ovary syndrome (PCOS) and obesity, detailed information regarding dietary intake, eating behavior, physical activity levels, and quality of life (QoL) may be useful. We aimed to investigate in a post-hoc cross-sectional analysis within a large multicenter randomized controlled trial in women with infertility whether there are significant differences in dietary intake (vegetables, fruits, sugary drinks, alcoholic beverages, savory snacks, and sweet snacks); eating behavior (emotional eating, external eating, and restricted eating); physical activity; and QoL between women with PCOS and obesity and non-PCOS obese controls. Participants were asked to complete the food frequency questionnaire (FFQ), the Dutch Eating Behavior Questionnaire (DEBQ), the Short QUestionnaire to ASsess Health-enhancing physical activity (SQUASH), and the 36-item Short Form Health Survey (SF-36) at study entry (PCOS: n = 170; non-PCOS: n = 321, mean BMI: 36). Linear and binary (multinomial) logistic regressions were used, and the analyses were adjusted for age, waist–hip circumference ratio, and homeostasis model assessment of insulin resistance (HOMA-IR). No statistically significant differences in dietary intake or physical activity were observed between the two groups. The overall score of emotional eating was 34.6 ± 11.2 in the PCOS group and 34.1 ± 11.3 in the non-PCOS group (p = 0.11). QoL scores (physical and mental) did not differ between PCOS and non-PCOS women. These findings suggest that infertile women with PCOS and obesity and infertile non-PCOS obese controls do not have different dietary habits and have similar mental and physical QoL.
Vitamin D Intake in Slovenian Adolescents, Adults, and the Elderly Population
Authors: Hribar Maša , Hristov Hristo , Lavriša Živa , Koroušić Seljak Barbara , Gregorič Matej , Blaznik Urška , Žmitek Katja , Pravst Igor
Published: October 2021

Vitamin D is involved in calcium and phosphorus metabolism, and is vital for numerous bodily functions. In the absence of sufficient UV-B light-induced skin biosynthesis, dietary intake becomes the most important source of vitamin D. In the absence of biosynthesis, the recommended dietary vitamin D intake is 10–20 µg/day. Major contributors to dietary vitamin D intake are the few foods naturally containing vitamin D (i.e., fish), enriched foods, and supplements. The present study aimed to estimate the vitamin D intake in Slovenia, to identify food groups that notably contribute to vitamin D intake, and to predict the effects of hypothetical mandatory milk fortification. This study was conducted using data collected by the national cross-sectional food consumption survey (SI.Menu) in adolescents (n = 468; 10–17 years), adults (n = 364; 18–64 years), and the elderly (n = 416; 65–74 years). Data collection was carried out between March 2017 and April 2018 using the EU Menu Methodology, which included two 24-h recalls, and a food propensity questionnaire. Very low vitamin D intakes were found; many did not even meet the threshold for very low vitamin D intake (2.5 µg/day). Mean daily vitamin D intake was 2.7, 2.9, and 2.5 µg in adolescents, adults, and the elderly, respectively. Daily energy intake was found to be a significant predictor of vitamin D intake in all population groups. In adolescents and adults, sex was also found to be a significant predictor, with higher vitamin D intake in males. The study results explained the previously reported high prevalence of vitamin D deficiency in Slovenia. An efficient policy approach is required to address the risk of vitamin D deficiency, particularly in vulnerable populations.
Daily Leucine Intake Is Positively Associated with Lower Limb Skeletal Muscle Mass and Strength in the Elderly
Authors: Lixandrão Manoel E. , Longobardi Igor , Leitão Alice E. , Morais João V. M. , Swinton Paul A. , Aihara André Y. , Goes Paola C. K. , Ugrinowitsch Carlos , Candow Darren G. , Gualano Bruno , Roschel Hamilton
Published: October 2021

Higher daily protein intake, with an emphasis on leucine content, is thought to mitigate age-related anabolic resistance, potentially counteracting age-related morphological and functional declines. The present study investigated potential associations between total daily leucine intake and dependent variables, including quadriceps muscle cross-sectional area (CSA) and maximum dynamic muscle strength (1-RM) in a cohort of healthy free-living older individuals of both sexes (n = 67; 34/33 men/women). Participants performed three 24 h dietary recalls and underwent a magnetic resonance imaging exam followed by 1-RM tests. Our results demonstrate moderate associations between total daily leucine and both quadriceps CSA (r = 0.42; p = 0.004) and 1-RM (r = 0.45; p = 0.001). Furthermore, our exploratory biphasic linear regression analyses, adjusted for sex, age, and protein intake relative to body weight, revealed a plateau for daily leucine intake and muscle mass and muscle strength (~7.6–8.0 g·day−1) in older adults. In conclusion, we demonstrated that total daily leucine intake is associated with muscle mass and strength in healthy older individuals and this association remains after controlling for multiple factors, including overall protein intake. Furthermore, our breakpoint analysis revealed non-linearities and a potential threshold for habitual leucine intake, which may help guide future research on the effects of chronic leucine intake in age-related muscle loss.
Anti-Inflammatory Effect of 4,5-Dicaffeoylquinic Acid on RAW264.7 Cells and a Rat Model of Inflammation
Authors: Jang Goeun , Lee Seulah , Hong Joonho , Park Boram , Kim Dokyung , Kim Chunsung
Published: October 2021

Anti-inflammatory agents that are safer and more effective than the currently used non-steroidal anti-inflammatory drugs are urgently needed. The dicaffeoylquinic acid (diCQA) isomer 4,5-diCQA exhibits antioxidant activity and various other health-promoting benefits; however, its anti-inflammatory properties require further investigation. This study was conducted to evaluate the anti-inflammatory properties of 4,5-diCQA in vitro and in vivo using RAW264.7 cells and a carrageenan-induced inflammation model, respectively. In RAW264.7 cells, 4,5-diCQA pretreatment significantly inhibited lipopolysaccharide-induced expression of nitric oxide, prostaglandin E2, nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, interleukin-1β, and interleukin-6, without inducing cytotoxicity. The inhibitory effects of 4,5-diCQA were mediated by the suppression of nuclear factor-κB nuclear translocation and mitogen-activated protein kinase (MAPK) phosphorylation. Oral administration of 4,5-diCQA at doses of 5, 10, and 20 mg/kg of the body weight suppressed carrageenan-induced edema and the expression of nitric oxide synthase, cyclooxygenase-2, and tumor necrosis factor-α in a dose-dependent manner. Collectively, our results suggest that 4,5-diCQA exerts anti-inflammatory effects by suppressing activation of the nuclear factor-κB and MAPK pathways in vitro and reducing carrageenan-induced edema in vivo. Therefore, 4,5-diCQA shows potential as a natural alternative to non-steroidal anti-inflammatory drugs.
Changes in Fitness of Rural Primary School Students from Southwest China after Two-Year’s Nutrition Intervention
Authors: Zhao Ran , Gan Qian , Hu Zhuolun , Xu Peipei , Li Li , Yang Titi , Pan Hui , Hu Xiaoqi , Zhang Qian
Published: October 2021

Children in China’s poor rural areas often have insufficient protein and micronutrient intake. There is little research about the effect of milk and egg supplementation published on these children. A prospective randomized controlled trial was applied to evaluate the effect of milk and egg supplementation on the growth and fitness of poor rural primary school students in southwest China whose physical development was below national averages. A total of 955 healthy students aged 6–13 years old were recruited. The intervention group (538) received 200 g milk and 50 g braised egg at each school day, while the control group (417) kept their normal diet and received no extra supplementation. Serum vitamin D levels were measured by an enzyme-linked immunosorbent assay. A mixed linear model with repeated measures was performed to analyze the efficacy of the supplementation. Statistically significant interactions between groups and time were seen in weight in boys, but not in girls. Significant improvement in vitamin D levels, the broad jump, and the 8 × 50 m shuttle run were observed in both genders. Therefore, the supplementation of egg and milk for two years might have a positive effect on growth and physical fitness and decreasing vitamin D deficiency in poor rural Chinese children.
Total Fat and Fatty Acid Intake among 1–7-Year-Old Children from 33 Countries: Comparison with International Recommendations
Authors: Monnard Cathriona , Fleith Mathilde
Published: October 2021

This work reviews available data on dietary intakes of total fat, saturated fatty acids (SFA) and individual polyunsaturated fatty acids (PUFA) in children in different countries worldwide and for the first time, compares them with recent international recommendations. Studies published before June 2021 reporting total fat, total SFA and individual PUFA intakes in children aged 1–7 y were included. Observed intakes were evaluated against FAO/WHO and EFSA recommendations. 65 studies from 33 countries were included. Fat intake was too low in 88% of studies in young children (1–3 y). SFA intake was >10%E in 69–73% of children, especially in Europe. Linoleic acid intake was <3%E in 24% of studies in 1–2 y olds and within FAO/WHO recommendations among all other ages. Alpha-linolenic acid intake was <0.5%E in almost half of studies. Docosahexaenoic acid (DHA) or eicosapentaenoic acid + DHA intakes were below recommendations in most studies. In summary, while total fat intake was too low among younger children, SFA intake was above, especially in Europe and n-3 PUFA intake, especially DHA, were below recommendations for all ages. Intake of n-3 PUFA, especially DHA, is generally suboptimal. More data, particularly from developing countries, are required to refine these findings and guide implementation of adapted nutrition policies.
Dietary Patterns, Eating Behavior, and Nutrient Intakes of Spanish Preschool Children with Autism Spectrum Disorders
Authors: Plaza-Diaz Julio , Flores-Rojas Katherine , Torre-Aguilar María José de la , Gomez-Fernández Antonio Rafael , Martín-Borreguero Pilar , Perez-Navero Juan Luis , Gil Angel , Gil-Campos Mercedes
Published: October 2021

Eating behavior problems are characteristic of children with autism spectrum disorders (ASD) with a highly restricted range of food choices, which may pose an associated risk of nutritional problems. Hence, detailed knowledge of the dietary patterns (DPs) and nutrient intakes of ASD patients is necessary to carry out intervention strategies if required. The present study aimed to determine the DPs and macro-and micronutrient intakes in a sample of Spanish preschool children with ASD compared to typically developing control children. Fifty-four children with ASD (two to six years of age) diagnosed with ASD according to the Diagnostic Manual-5 criteria), and a control group of 57 typically developing children of similar ages were recruited. A validated food frequency questionnaire was used, and the intake of energy and nutrients was estimated through three non-consecutive 24-h dietary registrations. DPs were assessed using principal component analysis and hierarchical clustering analysis. Children with ASD exhibited a DP characterized by high energy and fat intakes and a low intake of vegetables and fruits. Likewise, meat intake of any type, both lean and fatty, was associated with higher consumption of fish and dietary fat. Furthermore, the increased consumption of dairy products was associated with increased consumption of cereals and pasta. In addition, they had frequent consumption of manufactured products with poor nutritional quality, e.g., beverages, sweets, snacks and bakery products. The percentages of children with ASD complying with the adequacy of nutrient intakes were higher for energy, saturated fat, calcium, and vitamin C, and lower for iron, iodine, and vitamins of group B when compared with control children. In conclusion, this study emphasizes the need to assess the DPs and nutrient intakes of children with ASD to correct their alterations and discard some potential nutritional diseases.
Host–Pathogen Interactions of Chlamydia trachomatis in Porcine Oviduct Epithelial Cells
Authors: Amaral Amanda F. , McQueen Bryan E. , Bellingham-Johnstun Kimberly , Poston Taylor B. , Darville Toni , Nagarajan Uma M. , Laplante Caroline , Käser Tobias
Published: October 2021

Chlamydia trachomatis (Ct) causes the most prevalent bacterial sexually transmitted disease leading to ectopic pregnancy and infertility. Swine not only have many similarities to humans, but they are also susceptible to Ct. Despite these benefits and the ease of access to primary tissue from this food animal, in vitro research in swine has been underutilized. This study will provide basic understanding of the Ct host–pathogen interactions in porcine oviduct epithelial cells (pOECs)—the counterparts of human Fallopian tube epithelial cells. Using NanoString technology, flow cytometry, and confocal and transmission-electron microscopy, we studied the Ct developmental cycle in pOECs, the cellular immune response, and the expression and location of the tight junction protein claudin-4. We show that Ct productively completes its developmental cycle in pOECs and induces an immune response to Ct similar to human cells: Ct mainly induced the upregulation of interferon regulated genes and T-cell attracting chemokines. Furthermore, Ct infection induced an accumulation of claudin-4 in the Ct inclusion with a coinciding reduction of membrane-bound claudin-4. Downstream effects of the reduced membrane-bound claudin-4 expression could potentially include a reduction in tight-junction expression, impaired epithelial barrier function as well as increased susceptibility to co-infections. Thereby, this study justifies the investigation of the effect of Ct on tight junctions and the mucosal epithelial barrier function. Taken together, this study demonstrates that primary pOECs represent an excellent in vitro model for research into Ct pathogenesis, cell biology and immunity.
Immunosuppression in Malaria: Do Plasmodium falciparum Parasites Hijack the Host?
Authors: Calle Carlos Lamsfus , Mordmüller Benjamin , Singh Anurag
Published: October 2021

Malaria reflects not only a state of immune activation, but also a state of general immune defect or immunosuppression, of complex etiology that can last longer than the actual episode. Inhabitants of malaria-endemic regions with lifelong exposure to the parasite show an exhausted or immune regulatory profile compared to non- or minimally exposed subjects. Several studies and experiments to identify and characterize the cause of this malaria-related immunosuppression have shown that malaria suppresses humoral and cellular responses to both homologous (Plasmodium) and heterologous antigens (e.g., vaccines). However, neither the underlying mechanisms nor the relative involvement of different types of immune cells in immunosuppression during malaria is well understood. Moreover, the implication of the parasite during the different stages of the modulation of immunity has not been addressed in detail. There is growing evidence of a role of immune regulators and cellular components in malaria that may lead to immunosuppression that needs further research. In this review, we summarize the current evidence on how malaria parasites may directly and indirectly induce immunosuppression and investigate the potential role of specific cell types, effector molecules and other immunoregulatory factors.
Combination Therapies with PRRT
Authors: Yordanova Anna , Ahmadzadehfar Hojjat
Published: October 2021

Peptide receptor radionuclide therapy (PRRT) is a successful targeted radionuclide therapy in neuroendocrine tumors (NETs). However, complete responses remain elusive. Combined treatments anticipate synergistic effects and thus better responses by combining ionizing radiation with other anti-tumor treatments. Furthermore, multimodal therapies often have a balanced toxicity profile. To date, few studies have evaluated the effect of combination therapies with PRRT, some of them phase I/II trials. This review will focus on several clinically tested, tailored approaches to improving the effects of PRRT. The aim is to help clinicians in the treatment planning of NETs to choose the most effective and safe treatment for each patient in the sense of personalized medicine. Current promising combination partners of PRRT are somatostatin analogues (SSAs), chemotherapy, molecular targeted treatment, liver radioembolization, and dual radionuclide PRRT (Lutetium-177-PRRT combined with Yttrium-90-PRRT).
Withasomniferol D, a New Anti-Adipogenic Withanolide from the Roots of Ashwagandha (Withania somnifera)
Authors: Lee Bum Soo , Yoo Min Jeong , Kang Heesun , Lee Seoung Rak , Kim Sil , Yu Jae Sik , Kim Jin-Chul , Jang Tae Su , Pang Changhyun , Kim Ki Hyun
Published: October 2021

Withania somnifera (Solanaceae), well-known as ‘Indian ginseng’ or ‘Ashwagandha’, is a medicinal plant that is used in Ayurvedic practice to promote good health and longevity. As part of an ongoing investigation for bioactive natural products with novel structures, we performed a phytochemical examination of the roots of W. somnifera employed with liquid chromatography–mass spectrometry (LC/MS)-based analysis. The chemical analysis of the methanol extract of W. somnifera roots using repeated column chromatography and high-performance liquid chromatography under the guidance of an LC/MS-based analysis resulted in a new withanolide, withasomniferol D (1). The structure of the newly isolated compound was elucidated by spectroscopic methods, including one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) and high-resolution (HR) electrospray ionization (ESI) mass spectroscopy, and its absolute configuration was established by electronic circular dichroism (ECD) calculations. The anti-adipogenic activities of withasomniferol D (1) were evaluated using 3T3-L1 preadipocytes with Oil Red O staining and quantitative real-time polymerase chain reaction (qPCR). We found that withasomniferol D (1) inhibited adipogenesis and suppressed the enlargement of lipid droplets compared to the control. Additionally, the mRNA expression levels of adipocyte markers Fabp4 and Adipsin decreased noticeably following treatment with 25 μM of withasomniferol D (1). Taken together, these findings provide experimental evidence that withasomniferol D (1), isolated from W. somnifera, exhibits anti-adipogenic activity, supporting the potential application of this compound in the treatment of obesity and related metabolic diseases.
Phage Cocktail Development for Bacteriophage Therapy: Toward Improving Spectrum of Activity Breadth and Depth
Authors: Abedon Stephen T. , Danis-Wlodarczyk Katarzyna M. , Wozniak Daniel J.
Published: October 2021

Phage therapy is the use of bacterial viruses as antibacterial agents. A primary consideration for commercial development of phages for phage therapy is the number of different bacterial strains that are successfully targeted, as this defines the breadth of a phage cocktail’s spectrum of activity. Alternatively, phage cocktails may be used to reduce the potential for bacteria to evolve phage resistance. This, as we consider here, is in part a function of a cocktail’s ‘depth’ of activity. Improved cocktail depth is achieved through inclusion of at least two phages able to infect a single bacterial strain, especially two phages against which bacterial mutation to cross resistance is relatively rare. Here, we consider the breadth of activity of phage cocktails while taking both depth of activity and bacterial mutation to cross resistance into account. This is done by building on familiar algorithms normally used for determination solely of phage cocktail breadth of activity. We show in particular how phage cocktails for phage therapy may be rationally designed toward enhancing the number of bacteria impacted while also reducing the potential for a subset of those bacteria to evolve phage resistance, all as based on previously determined phage properties.
Repurposing Peroxisome Proliferator-Activated Receptor Agonists in Neurological and Psychiatric Disorders
Authors: Sagheddu Claudia , Melis Miriam , Muntoni Anna Lisa , Pistis Marco
Published: October 2021

Common pathophysiological mechanisms have emerged for different neurological and neuropsychiatric conditions. In particular, mechanisms of oxidative stress, immuno-inflammation, and altered metabolic pathways converge and cause neuronal and non-neuronal maladaptative phenomena, which underlie multifaceted brain disorders. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors modulating, among others, anti-inflammatory and neuroprotective genes in diverse tissues. Both endogenous and synthetic PPAR agonists are approved treatments for metabolic and systemic disorders, such as diabetes, fatty liver disease, and dyslipidemia(s), showing high tolerability and safety profiles. Considering that some PPAR-acting drugs permeate through the blood–brain barrier, the possibility to extend their scope from the periphery to central nervous system has gained interest in recent years. Here, we review preclinical and clinical evidence that PPARs possibly exert a neuroprotective role, thereby providing a rationale for repurposing PPAR-targeting drugs to counteract several diseases affecting the central nervous system.
Modular Synthesis and Antiproliferative Activity of New Dihydro-1H-pyrazolo[1,3-b]pyridine Embelin Derivatives
Authors: Martín-Acosta Pedro , Amesty Ángel , Guerra-Rodríguez Miguel , Guerra Borja , Fernández-Pérez Leandro , Estévez-Braun Ana
Published: October 2021

A set of new dihydro-1H-pyrazolo[1,3-b]pyridine and pyrazolo[1,3-b]pyridine embelin derivatives was synthesized through a multicomponent reaction from natural embelin, 3-substituted-5-aminopyrazoles and aldehydes. The synthesized compounds were evaluated against three hematologic tumor cell lines, HEL (acute erythroid leukemia), K-562 (chronic myeloid leukemia) and HL-60 (acute myeloid leukemia), and five breast cancer cell lines (SKBR3, MCF-7, MDA-MB-231, BT-549, HS-578T). The primate non-malignant kidney Vero cell line was used as the control of cytotoxicity. From the obtained results, some structure–activity relationships were outlined. Furthermore, in silico prediction of physicochemical properties and ADME parameters were determined for the derivatives with the best antiproliferative values.
In Silico Studies of Potential Selective Inhibitors of Thymidylate Kinase from Variola virus
Authors: Garcia Danielle R. , Souza Felipe R. , Guimarães Ana P. , Valis Martin , Pavelek Zbyšek , Kuca Kamil , Ramalho Teodorico C. , França Tanos C. C.
Published: October 2021

Continuing the work developed by our research group, in the present manuscript, we performed a theoretical study of 10 new structures derived from the antivirals cidofovir and ribavirin, as inhibitor prototypes for the enzyme thymidylate kinase from Variola virus (VarTMPK). The proposed structures were subjected to docking calculations, molecular dynamics simulations, and free energy calculations, using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method, inside the active sites of VarTMPK and human TMPK (HssTMPK). The docking and molecular dynamic studies pointed to structures 2, 3, 4, 6, and 9 as more selective towards VarTMPK. In addition, the free energy data calculated through the MM-PBSA method, corroborated these results. This suggests that these compounds are potential selective inhibitors of VarTMPK and, thus, can be considered as template molecules to be synthesized and experimentally evaluated against smallpox.
Bacterial Cellulose as a Potential Bio-Scaffold for Effective Re-Epithelialization Therapy
Authors: Cherng Juin-Hong , Chou Sheng-Chieh , Chen Chin-Li , Wang Yi-Wen , Chang Shu-Jen , Fan Gang-Yi , Leung Fang-Shiuan , Meng En
Published: October 2021

Currently, there are several therapeutic approaches available for wound injury management. However, a better understanding of the underlying mechanisms of how biomaterials affect cell behavior is needed to develop potential repair strategies. Bacterial cellulose (BC) is a bacteria-produced biopolymer with several advantageous qualities for skin tissue engineering. The aim here was to investigate BC-based scaffold on epithelial regeneration and wound healing by examining its effects on the expression of scavenger receptor-A (SR-A) and underlying macrophage behavior. Full-thickness skin wounds were generated on Sprague-Dawley rats and the healing of these wounds, with and without BC scaffolds, was examined over 14 days using Masson’s trichome staining. BC scaffolds displayed excellent in vitro biocompatibility, maintained the stemness function of cells and promoted keratinocyte differentiation of cells, which are vital in maintaining and restoring the injured epidermis. BC scaffolds also exhibited positive in vivo effects on the wound microenvironment, including improved skin extracellular matrix deposition and controlled excessive inflammation by reduction of SR-A expression. Furthermore, BC scaffold significantly enhanced epithelialization by stimulating the balance of M1/M2 macrophage re-programming for beneficial tissue repair relative to that of collagen material. These findings suggest that BC-based materials are promising products for skin injury repair.
Gentamicin Population Pharmacokinetics in Pediatric Patients—A Prospective Study with Data Analysis Using the saemix Package in R
Authors: Paioni Paolo , Jäggi Vera F. , Tilen Romy , Seiler Michelle , Baumann Philipp , Bräm Dominic S. , Jetzer Carole , Haid Robin T. U. , Goetschi Aljoscha N. , Goers Roland , Müller Daniel , Coman Schmid Diana , Meyer zu Schwabedissen Henriette E. , Rinn Bernd , Berger Christoph , Krämer Stefanie D.
Published: October 2021

The aminoglycoside gentamicin is used for the empirical treatment of pediatric infections. It has a narrow therapeutic window. In this prospective study at University Children’s Hospital Zurich, Switzerland, we aimed to characterize the pharmacokinetics of gentamicin in pediatric patients and predict plasma concentrations at typical recommended doses. We recruited 109 patients aged from 1 day to 14 years, receiving gentamicin (7.5 mg/kg at age ≥ 7 d or 5 mg/kg). Plasma levels were determined 30 min, 4 h and 24 h after the infusion was stopped and then transferred, together with patient data, to the secure BioMedIT node Leonhard Med. Population pharmacokinetic modeling was performed with the open-source R package saemix on the SwissPKcdw platform in Leonhard Med. Data followed a two-compartment model. Bodyweight, plasma creatinine and urea were identified as covariates for clearance, with bodyweight as a covariate for central and peripheral volumes of distribution. Simulations with 7.5 mg/kg revealed a 95% CI of 13.0–21.2 mg/L plasma concentration at 30 min after the stopping of a 30-min infusion. At 24 h, 95% of simulated plasma levels were <1.8 mg/L. Our study revealed that the recommended dosing is appropriate. It showed that population pharmacokinetic modeling using R provides high flexibility in a secure environment.
Human Skin Permeation Enhancement Using PLGA Nanoparticles Is Mediated by Local pH Changes
Authors: Luengo Javiana , Schneider Marc , Schneider Anna M. , Lehr Claus-Michael , Schaefer Ulrich F.
Published: October 2021

The steady improvement and optimization of transdermal permeation is a constant and challenging pharmaceutical task. In this study the influence of poly(lactide-co-glycolide) (PLGA) nanoparticles on the dermal permeation of the anti-inflammatory drug flufenamic acid (FFA) was investigated. For this aim, different vehicles under non-buffered and buffered conditions and different skin models (human heat separated epidermis and reconstructed human epidermis equivalents) were tested. Permeation experiments were performed using static Franz diffusion cells under infinite dosing conditions. Already the presence of drug-free nanoparticles increased drug permeation across the skin. Drug permeation was even enhanced when applying drug-loaded nanoparticles. In contrast, buffered vehicles with different pH values (pH 5.4–7.4) revealed the influence of the pH on the permeation of FFA. The change of the surrounding pH of the biodegradable nanoparticulate system was demonstrated and visualized using pH-sensitive fluorescent probes. While a potential contribution of hair follicles could be ruled out, our data suggest that the enhanced permeation of FFA through human skin in the presence of PLGA nanoparticles is mediated by a locally decreased pH during hydrolytic degradation of this polymer. This hypothesis is supported by the observation that skin permeation of the weak base caffeine was not affected.
Angiotensin-(1–7) Peptide Hormone Reduces Inflammation and Pathogen Burden during Mycoplasma pneumoniae Infection in Mice
Authors: Collins Katie L. , Younis Usir S. , Tanyaratsrisakul Sasipa , Polt Robin , Hay Meredith , Mansour Heidi M. , Ledford Julie G.
Published: October 2021

The peptide hormone, angiotensin (Ang-(1–7)), produces anti-inflammatory and protective effects by inhibiting production and expression of many cytokines and adhesion molecules that are associated with a cytokine storm. While Ang-(1–7) has been shown to reduce inflammation and airway hyperreactivity in models of asthma, little is known about the effects of Ang-(1–7) during live respiratory infections. Our studies were developed to test if Ang-(1–7) is protective in the lung against overzealous immune responses during an infection with Mycoplasma pneumonia (Mp), a common respiratory pathogen known to provoke exacerbations in asthma and COPD patients. Wild type mice were treated with infectious Mp and a subset of was given either Ang-(1–7) or peptide-free vehicle via oropharyngeal delivery within 2 h of infection. Markers of inflammation in the lung were assessed within 24 h for each set of animals. During Mycoplasma infection, one high dose of Ang-(1–7) delivered to the lungs reduced neutrophilia and Muc5ac, as well as Tnf-α and chemokines (Cxcl1) associated with acute respiratory distress syndrome (ARDS). Despite decreased inflammation, Ang-(1-7)-treated mice also had significantly lower Mp burden in their lung tissue, indicating decreased airway colonization. Ang-(1–7) also had an impact on RAW 264.7 cells, a commonly used macrophage cell line, by dose-dependently inhibiting TNF-α production while promoting Mp killing. These new findings provide additional support to the protective role(s) of Ang1-7 in controlling inflammation, which we found to be highly protective against live Mp-induced lung inflammation.
Safety Evaluation of Nanotechnology Products
Authors: Domb Abraham J. , Sharifzadeh Ghorbanali , Nahum Victoria , Hosseinkhani Hossein
Published: October 2021

Nanomaterials are now being used in a wide variety of biomedical applications. Medical and health-related issues, however, have raised major concerns, in view of the potential risks of these materials against tissue, cells, and/or organs and these are still poorly understood. These particles are able to interact with the body in countless ways, and they can cause unexpected and hazardous toxicities, especially at cellular levels. Therefore, undertaking in vitro and in vivo experiments is vital to establish their toxicity with natural tissues. In this review, we discuss the underlying mechanisms of nanotoxicity and provide an overview on in vitro characterizations and cytotoxicity assays, as well as in vivo studies that emphasize blood circulation and the in vivo fate of nanomaterials. Our focus is on understanding the role that the physicochemical properties of nanomaterials play in determining their toxicity.
Progestins as Anticancer Drugs and Chemosensitizers, New Targets and Applications
Authors: Fedotcheva Tatiana A. , Fedotcheva Nadezhda I. , Shimanovsky Nikolai L.
Published: October 2021

Progesterone and its synthetic analogues, progestins, participate in the regulation of cell differentiation, proliferation and cell cycle progression. Progestins are usually applied for contraception, maintenance of pregnancy, and hormone replacement therapy. Recently, their effectiveness in the treatment of hormone-sensitive tumors was revealed. According to current data, the anticancer activity of progestins is mainly mediated by their cytotoxic and chemosensitizing influence on different cancer cells. In connection with the detection of previously unknown targets of the progestin action, which include the membrane-associated progesterone receptor (PR), non-specific transporters related to the multidrug resistance (MDR) and mitochondrial permeability transition pore (MPTP), and checkpoints of different signaling pathways, new aspects of their application have emerged. It is likely that the favorable influence of progestins is predominantly associated with the modulation of expression and activity of MDR-related proteins, the inhibition of survival signaling pathways, especially TGF-β and Wnt/β-catenin pathways, which activate the proliferation and promote MDR in cancer cells, and the facilitation of mitochondrial-dependent apoptosis. Biological effects of progestins are mediated by the inhibition of these signaling pathways, as well as the direct interaction with the nucleotide-binding domain of ABC-transporters and mitochondrial adenylate translocase as an MPTP component. In these ways, progestins can restore the proliferative balance, the ability for apoptosis, and chemosensitivity to drugs, which is especially important for hormone-dependent tumors associated with estrogen stress, epithelial-to-mesenchymal transition, and drug resistance.
Dextran Sulfate Polymer Wafer Promotes Corneal Wound Healing
Authors: Ammassam Veettil Remya , Marcano Daniela C. , Yuan Xiaoyong , Zaheer Mahira , Adumbumkulath Aparna , Lee Richard , Isenhart Lucas C. , Soriano Nicole , Mhatre Kirti , Joseph Robiya , Mani Sendurai A. , Shin Crystal S. , Acharya Ghanashyam
Published: October 2021

Eye injuries due to corneal abrasions, chemical spills, penetrating wounds, and microbial infections cause corneal scarring and opacification that result in impaired vision or blindness. However, presently available eye drop formulations of anti-inflammatory and antibiotic drugs are not effective due to their rapid clearance from the ocular surface or due to drug-related side effects such as cataract formation or increased intraocular pressure. In this article, we presented the development of a dextran sulfate-based polymer wafer (DS-wafer) for the effective modulation of inflammation and fibrosis and demonstrated its efficacy in two corneal injury models: corneal abrasion mouse model and alkali induced ocular burn mouse model. The DS-wafers were fabricated by the electrospinning method. We assessed the efficacy of the DS-wafer by light microscopy, qPCR, confocal fluorescence imaging, and histopathological analysis. These studies demonstrated that the DS-wafer treatment is significantly effective in modulating corneal inflammation and fibrosis and inhibited corneal scarring and opacification compared to the unsulfated dextran-wafer treated and untreated corneas. Furthermore, these studies have demonstrated the efficacy of dextran sulfate as an anti-inflammatory and antifibrotic polymer therapeutic.