bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Hours of Paid Work with Dietary Intake and Quality in Japanese Married Women: A Cross-Sectional Study
Authors: Oono Fumi , Matsuura Nozomi , Saito Aki , Fujiwara Aya , Takahashi Osamu , Sasaki Satoshi , Iida Kaoruko
Published: August 2021

This study investigated the association of hours of paid work with dietary intake and diet quality among Japanese married women. This cross-sectional study was a secondary analysis of a nationwide population survey in 2013. The analytic sample included 644 married women aged 20–59 years. The participants were categorized into five groups according to hours of paid work per week: 0 (housewives), 1–14, 15–34, 35–42, and ≥43 h. Dietary intake was assessed by a self-administered diet history questionnaire. The Nutrient-Rich Food Index 9.3 (NRF9.3) was used to measure the dietary quality. The association of hours of paid work with dietary intake and NRF9.3 score was assessed using a multivariable general linear regression analysis with adjustments for confounders. Hours of paid work were associated with a higher intake of rice and lower intake of vegetables, potatoes, soy products, and seaweeds and nutrients including protein, dietary fiber, and most vitamins and minerals. Hours of paid work were negatively associated with the NRF9.3 score. This study showed that Japanese married women engaging in paid work, especially those who work long hours, have less healthy diets. Efforts to improve the dietary intake of married women with paid work might be needed.
Enabling Better Nutrition and Physical Activity for Adolescents from Middle Eastern Backgrounds: Focus Groups
Authors: Hayba Nematullah , Khalil Claudia , Allman-Farinelli Margaret
Published: August 2021

The obesity epidemic in adolescents from Middle Eastern (ME) backgrounds necessitates co-designed and culturally-responsive interventions. This study’s objective was to gather the opinions, attitudes, capabilities, opportunities and motivations of ME adolescents residing in Australia on healthy eating and physical activity (PA) behaviours to inform a future prevention program. Five focus groups were conducted, with 32 ME participants, aged 13–18 years, recruited via purposive and snowball sampling. More participants were female (n = 19) and from lower socioeconomic areas (n = 25). A reflexive thematic analysis was performed using the Capability, Opportunity, Motivation-Behaviour (COM-B) model as the coding framework. Limited nutritional knowledge and cooking skills accompanied by a desire to make dietary changes were reported. Local and school facilities provided adolescents with PA opportunities, but participants declared safety concerns and limited opportunities for females and older grade students. Social support from family and friends were enablers for both healthy eating and PA. Cravings and desire for cultural foods influenced food choices. Individual and/or group approaches using social media and face-to-face format were recommended for future programs. To enable PA and dietary behaviour changes, interventions should be specifically tailored for ME adolescents to improve their nutrition literacy and skills, along with providing safe environments for sport in conjunction with social support.
Oxidized LDL Downregulates ABCA1 Expression via MEK/ERK/LXR Pathway in INS-1 Cells
Authors: Lyu Jingya , Fukunaga Kensaku , Imachi Hitomi , Sato Seisuke , Kobayashi Toshihiro , Saheki Takanobu , Ibata Tomohiro , Yoshimura Takafumi , Iwama Hisakazu , Murao Koji
Published: August 2021

Impaired insulin secretion is one of the main causes of type 2 diabetes. Cholesterol accumulation-induced lipotoxicity contributes to impaired insulin secretion in pancreatic beta cells. However, the detailed mechanism in this process remains unclear. In this study, we proved that oxidized low-density lipoprotein (OxLDL) reduced insulin content, decreased PDX-1 expression, and impaired glucose-stimulated insulin secretion (GSIS) in INS-1 cells, which were rescued by addition of high-density lipoprotein (HDL). OxLDL receptors and cholesterol content were increased by OxLDL. Consistently, OxLDL suppressed cholesterol transporter ABCA1 expression and transcription in a dose-dependent and time-dependent manner. Inhibition of MEK by its specific inhibitor, PD98059, altered the effect of OxLDL on ABCA1 transcription and activation of ERK. Next, chromatin immunoprecipitation assay demonstrated that liver X receptor (LXR) could directly bind to ABCA1 promoter and this binding was inhibited by OxLDL. Furthermore, OxLDL decreased the nuclear LXR expression, which was prevented by HDL. LXR-enhanced ABCA1 transcription was suppressed by OxLDL, and the effect was cancelled by mutation of the LXR-binding sites. In summary, our study shows that OxLDL down-regulates ABCA1 expression by MEK/ERK/LXR pathway, leading to cholesterol accumulation in INS-1 cells, which may result in impaired insulin synthesis and GSIS.
Validity and Reproducibility of a Food Frequency Questionnaire to Assess Nutrients Intake of Pregnant Women in the South-East of Spain
Authors: Hinojosa-Nogueira Daniel , Romero-Molina Desirée , Giménez-Asensio María José , Gonzalez-Alzaga Beatriz , Lopéz-Flores Inmaculada , Cueva Silvia Pastoriza de la , Rufián-Henares José Ángel , Hernández Antonio F. , Lacasaña Marina
Published: August 2021

Proper nutrition during pregnancy is pivotal to maintain good health for the child and the mother. This study evaluates the reproducibility and validity of a food frequency questionnaire (FFQ) designed to assess nutrient intake during pregnancy in the GENEIDA (Genetics, Early life Environmental Exposures and Infant Development in Andalusia) prospective birth cohort study. In addition, the nutrient intake was estimated and then compared with European guidelines and other studies. Diet information was collected from 690 pregnant women using a FFQ administered at two periods of pregnancy (used for the reproducibility study) and 24-h dietary recall (for the validity study). Statistical approaches included Spearman’s correlation coefficient and percentage agreement, classifying women into the same or adjacent quintiles to assess reproducibility, and limits of agreement (LoA) to evaluate validity. In the study of reproducibility, significant correlations for nutrients adjusted for total energy had an average of 0.417. Moreover, the percentage of subjects classified in the same quintile for nutrient intakes were above 66%. In the validation study, the significant correlation for nutrients adjusted for total energy had an average of 0.272. Nevertheless, the percentage of results in the LoA was above 94%. Our results were similar to other studies suggesting that the FFQ used is a valid tool of collect dietary intakes for South-East Spanish pregnant women.
Affordability of Different Isocaloric Healthy Diets in Germany—An Assessment of Food Prices for Seven Distinct Food Patterns
Authors: Kabisch Stefan , Wenschuh Sören , Buccellato Palina , Spranger Joachim , Pfeiffer Andreas F.H.
Published: August 2021

Affordability of different isocaloric healthy diets in Germany—an assessment of food prices for seven distinct food patterns Background: For decades, low-fat diets were recommended as the ideal food pattern to prevent obesity, type 2 diabetes and their long-term complications. Nowadays, several alternatives considering sources and quantity of protein, fat and carbohydrates have arisen and clinical evidence supports all of them for at least some metabolic outcomes. Given this variety in diets and the lack of a single ideal diet, one must evaluate if patients at risk, many of which having a lower income, can actually afford these diets. Aim: We modelled four-week food plans for a typical family of two adults and two school children based on seven different dietary patterns: highly processed standard omnivore diet (HPSD), freshly cooked standard omnivore diet (FCSD), both with German average dietary composition, low-protein vegan diet (VeganD), low-fat vegetarian diet (VegetD), low-fat omnivore diet (LFD), Mediterranean diet (MedD) and high-fat moderate-carb diet (MCD). The isocaloric diets were designed with typical menu variation for all meal times. We then assessed the lowest possible prices for all necessary grocery items in 12 different supermarket chains, avoiding organic foods, special offers, advertised exotic super foods and luxury articles. Prices for dietary patterns were compared in total, stratified by meal time and by food groups. Results: Among all seven dietary patterns, price dispersion by supermarket chains was 12–16%. Lowest average costs were calculated for the VegetD and the FCSD, followed by HPSD, LFD, VeganD, MedD and—on top—MCD. VeganD, MedD and MCD were about 16%, 23% and 67% more expensive compared to the FCSD. Major food groups determining prices for all diets are vegetables, salads and animal-derived products. Calculations for social welfare severely underestimate expenses for any kind of diet. Conclusions: Food prices are a relevant factor for healthy food choices. Food purchasing is financially challenging for persons with very low income in Germany. Fresh-cooked plant-based diets are less pricy than the unhealthy HPSD. Diets with reduced carbohydrate content are considerably more expensive, limiting their use for people with low income. Minimum wage and financial support for long-term unemployed people in Germany are insufficient to assure a healthy lifestyle.
Maternal 3,3-Dimethyl-1-Butanol Therapy Protects Adult Male Rat Offspring against Hypertension Programmed by Perinatal TCDD Exposure
Authors: Hsu Chien-Ning , Hou Chih-Yao , Lee Chien-Te , Chang-Chien Guo-Ping , Lin Sufan , Tain You-Lin
Published: August 2021

Maternal exposure to environmental pollutants affects fetal development, which can result in hypertension in adulthood. Gut microbiota-derived metabolite trimethylamine (TMA), trimethylamine-N-oxide (TMAO), and short chain fatty acids (SCFAs) have been associated with hypertension. We tested a hypothesis that maternal 3,3-Dimethyl-1-butanol (DMB, a TMA inhibitor) therapy prevents 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure-induced hypertension in adult offspring relevant to alterations of gut microbiota-derived metabolites, the mediation of aryl hydrocarbon receptor (AHR) signaling, and the renin-angiotensin system (RAS). Pregnant Sprague-Dawley rats were given weekly oral dose of TCDD 200 ng/kg for four doses (T), 1% DMB in drinking water (D), TCDD + DMB (TD), or vehicle (C) in pregnancy and lactation periods. Male progeny (n = 8/group) were sacrificed at the age of 12 weeks. Perinatal TCDD exposure caused hypertension in adult male offspring coinciding with reduced α-diversity, increased the Firmicutes to Bacteroidetes ratio, less abundant beneficial bacteria, impaired SCFA receptors’ expression, the activation of AHR signaling, and the aberrant activation of the RAS. Treatment with DMB during pregnancy and lactation rescued hypertension induced by perinatal TCDD exposure. This was accompanied by reshaping gut microbiota, mediating TMA-TMAO metabolic pathway, increasing acetic acid and its receptors, and restoring the AHR and RAS pathway. Our data provide new insights into the therapeutic potential of DMB, a microbiome-based metabolite treatment, for the prevention of hypertension of developmental origins.
The Pro-Health Benefits of Morusin Administration—An Update Review
Authors: Panek-Krzyśko Anita , Stompor-Gorący Monika
Published: August 2021

Prenylflavonoids are widespread in nature. Plants are valuable sources of natural polyphenolic compounds with isoprenyl groups, which include flavones, flavanones, chalcones and aurones. They can be found in flowers, bark and stems. One of the most important compounds found in the bark of white mulberry (Morus alba) is morusin, a prenylated flavone with interesting pro-health properties. The research carried out so far revealed that morusin has antioxidant, antitumor, anti-inflammatory and anti-allergic activity. Moreover, its neuroprotective and antihyperglycemic properties have also been confirmed. Morusin suppresses the growth of different types of tumors, including breast cancer, glioblastoma, pancreatic cancer, hepatocarcinoma, prostate cancer, and gastric cancer. It also inhibits the inflammatory response by suppressing COX activity and iNOS expression. Moreover, an antimicrobial effect against Gram-positive bacteria was observed after treatment with morusin. The objective of this review is to summarize the current knowledge about the positive effects of morusin on human health in order to facilitate future study on the development of plant polyphenolic drugs and nutraceutics in the group of prenylflavones.
Association between Dietary Intake of Flavonoids and Cancer Recurrence among Breast Cancer Survivors
Authors: Cheon Minjung , Chung Minsung , Park Yongsoon
Published: August 2021

Intake of flavonoids is associated with the incidence of breast cancer, but the association between the intake of flavonoids and cancer recurrence is unclear. This study aimed to investigate the hypothesis that intake of flavonoids and flavonoid-rich foods is negatively associated with cancer recurrence. Among 572 women who underwent breast cancer surgery, 66 patients had a cancer recurrence. Dietary data were collected using a structured 24-h dietary recall, and intake of flavonoids was calculated based on the Korea Rural Development Administration flavonoid database. Among overweight and obese patients, disease-free survival was associated with intake of flavonoids (p = 0.004) and flavonoid-rich foods (p = 0.003). Intake of flavonoids (hazard ratio (HR) = 0.249, 95% confidence interval (CI): 0.09–0.64) and flavonoid-rich foods (HR = 0.244, 95% CI: 0.09–0.66) was negatively associated with cancer recurrence after adjusting for confounding factors in overweight and obese patients. Consumption of flavonoids and flavonoid-rich foods was lower in overweight and obese patients with cancer recurrence than those without recurrence and in normal-weight patients. This study suggests that intake of flavonoids and flavonoid-rich foods could have beneficial effects on cancer recurrence in overweight and obese breast cancer survivors.
Low Iodine Intake May Decrease Women’s Fecundity: A Population-Based Cross-Sectional Study
Authors: Xing Mingluan , Gu Simeng , Wang Xiaofeng , Mao Guangming , Mo Zhe , Lou Xiaoming , Li Xueqing , Huang Xuemin , Wang Yuanyang , Wang Zhifang
Published: August 2021

Salt iodization is one of the most cost-effective strategies to eliminate iodine deficiency disorders (IDD). However, China’s dismantling of salt monopoly has reduced the availability of iodized salt in the susceptible population in pregnancy, which might cause IDD and have adverse health effects on both themselves and their offspring. The aim of our study was therefore to explore the association between IDD and women’s reproductive health. This is a population-based cross-sectional study conducted in 2018 in Zhejiang Province, China. A total of 1653 pregnant women participated in this study. Median urinary iodine concentration (UIC) in the population was used to assess iodine intake. Cox regression analyses were used to estimate the association between iodine intake and time to pregnancy, which was indicated with fecundability ratio (FR) and 95% confidence interval (CI). The percentage of participants with iodine deficiency who had been waiting longer than 13 months to get pregnant (20%; median UIC 119.6 μg/L) was significantly higher than those with iodine sufficiency (14%; median UIC 147.1 μg/L). A significant decrease in fecundity was observed in participants with iodine deficiency (FR, 0.820; 95% CI, 0.725−0.929) than those with iodine sufficiency. These findings indicate the importance of ongoing monitoring of iodine nutrition in women of reproductive age. Keeping a safe and optimal level of iodine nutrition during pregnancy should be emphasized.
Approaching In Vivo Models of Pneumococcus–Host Interaction: Insights into Surface Proteins, Capsule Production, and Extracellular Vesicles
Authors: Olaya-Abril Alfonso , González-Reyes José A. , Rodríguez-Ortega Manuel J.
Published: August 2021

Infections caused by the Gram-positive bacterium Streptococcus pneumoniae have become a major health problem worldwide because of their high morbidity and mortality rates, especially in developing countries. This microorganism colonizes the human upper respiratory tract and becomes pathogenic under certain circumstances, which are not well known. In the interaction with the host, bacterial surface structures and proteins play major roles. To gain knowledge into gradual changes and adaptive mechanisms that this pathogen undergoes from when it enters the host, we mimicked several in vivo situations representing interaction with epithelial and macrophage cells, as well as a condition of presence in blood. Then, we analyzed, in four pneumococcal strains, two major surface structures, the capsule and extracellular vesicles produced by the pneumococci, as well as surface proteins by proteomics, using the “shaving” approach, followed by LC-MS/MS. We found important differences in both surface ultrastructures and proteins among the culture conditions and strains used. Thus, this work provides insights into physiological adaptations of the pneumococcus when it interacts with the host, which may be useful for the design of strategies to combat infections caused by this pathogen.
Helicobacter pylori-Induced Inflammation: Possible Factors Modulating the Risk of Gastric Cancer
Authors: Kumar Sushil , Patel Girijesh Kumar , Ghoshal Uday C.
Published: August 2021

Chronic inflammation and long-term tissue injury are related to many malignancies, including gastric cancer (GC). Helicobacter pylori (H. pylori), classified as a class I carcinogen, induces chronic superficial gastritis followed by gastric carcinogenesis. Despite a high prevalence of H. pylori infection, only about 1–3% of people infected with this bacterium develop GC worldwide. Furthermore, the development of chronic gastritis in some, but not all, H. pylori-infected subjects remains unexplained. These conflicting findings indicate that clinical outcomes of aggressive inflammation (atrophic gastritis) to gastric carcinogenesis are influenced by several other factors (in addition to H. pylori infection), such as gut microbiota, co-existence of intestinal helminths, dietary habits, and host genetic factors. This review has five goals: (1) to assess our current understanding of the process of H. pylori-triggered inflammation and gastric precursor lesions; (2) to present a hypothesis on risk modulation by the gut microbiota and infestation with intestinal helminths; (3) to identify the dietary behavior of the people at risk of GC; (4) to check the inflammation-related genetic polymorphisms and role of exosomes together with other factors as initiators of precancerous lesions and gastric carcinoma; and (5) finally, to conclude and suggest a new direction for future research.
A Rapid Method for Performing a Multivariate Optimization of Phage Production Using the RCCD Approach
Authors: Silva Jessica , Dias Roberto , Junior José Ivo , Marcelino Maraísa , Silva Mirelly , Carmo Adriele , Sousa Maira , Silva Cynthia , de Paula Sergio
Published: August 2021

Bacteriophages can be used in various applications, from the classical approach as substitutes for antibiotics (phage therapy) to new biotechnological uses, i.e., as a protein delivery vehicle, a diagnostic tool for specific strains of bacteria (phage typing), or environmental bioremediation. The demand for bacteriophage production increases daily, and studies that improve these production processes are necessary. This study evaluated the production of a T4-like bacteriophage vB_EcoM-UFV09 (an E. coli-infecting phage with high potential for reducing environmental biofilms) in seven types of culture media (Luria–Bertani broth and the M9 minimal medium with six different carbon sources) employing four cultivation variables (temperature, incubation time, agitation, and multiplicity of infection). For this purpose, the rotatable central composite design (RCCD) methodology was used, combining and comparing all parameters to determine the ideal conditions for starting to scale up the production process. We used the RCCD to set up the experimental design by combining the cultivation parameters in a specific and systematic way. Despite the high number of conditions evaluated, the results showed that when specific conditions were utilized, viral production was effective even when using a minimal medium, such as M9/glucose, which is less expensive and can significantly reduce costs during large-scale phage production.
Examining the Relationship between Toxoplasma gondii and Seropositivity and Serointensity and Depression in Adults from the United Kingdom and the United States: A Cross-Sectional Study
Authors: Gale Shawn D. , Erickson Lance D. , Brown Bruce L. , Hedges Dawson W.
Published: August 2021

Infecting approximately one-third of the world’s population, the neurotropic protozoan Toxoplasma gondii has been associated with cognition and several neuropsychiatric diseases including schizophrenia and bipolar disorder. Findings have been mixed, however, about the relationship between Toxoplasma gondii and depression, with some studies reporting positive associations and others finding no associations. To further investigate the association between Toxoplasma gondii and depression, we used data from the UK Biobank and the National Health and Examination Survey (NHANES). Results from adjusted multiple-regression modeling showed no significant associations between Toxoplasma gondii and depression in either the UK Biobank or NHANES datasets. Further, we found no significant interactions between Toxoplasma gondii and age, sex, educational attainment, and income in either dataset that affected the association between Toxoplasma gondii and depression. These results from two community-based datasets suggest that in these samples, Toxoplasma gondii is not associated with depression. Differences between our findings and other findings showing an association between Toxoplasma gondii and depression could be due to several factors including differences in socioeconomic variables, differences in Toxoplasma gondii strain, and use of different covariates in statistical modeling.
Detrimental Effect of Cannabidiol on the Early Onset of Diabetic Nephropathy in Male Mice
Authors: Carmona-Hidalgo Beatriz , García-Martín Adela , Muñoz Eduardo , González-Mariscal Isabel
Published: August 2021

Anti-inflammatory and antidiabetogenic properties have been ascribed to cannabidiol (CBD). CBD-based medicinal drugs have been approved for over a lustrum, and a boom in the commercialization of CBD products started in parallel. Herein, we explored the efficacy of CBD in streptozotocin (STZ)-induced diabetic mice to prevent diabetic nephropathy at onset. Eight-to-ten-week-old C57BL6J male mice were treated daily intraperitoneally with 10 mg/kg of CBD or vehicle for 14 days. After 8 days of treatment, mice were challenged with STZ or vehicle (healthy-control). At the end of the study, non-fasting blood glucose (FBG) level was 276 ± 42 mg/dL in vehicle-STZ-treated compared to 147 ± 9 mg/dL (p ≤ 0.01) in healthy-control mice. FBG was 114 ± 8 mg/dL in vehicle-STZ-treated compared to 89 ± 4 mg/dL in healthy-control mice (p ≤ 0.05). CBD treatment did not prevent STZ-induced hyperglycemia, and non-FBG and FBG levels were 341 ± 40 and 133 ± 26 mg/dL, respectively. Additionally, treatment with CBD did not avert STZ-induced glucose intolerance or pancreatic beta cell mass loss compared to vehicle-STZ-treated mice. Anatomopathological examination showed that kidneys from vehicle-STZ-treated mice had a 35% increase of glomerular size compared to healthy-control mice (p ≤ 0.001) and presented lesions with a 43% increase in fibrosis and T cell infiltration (p ≤ 0.001). Although treatment with CBD prevented glomerular hypertrophy and reduced T cell infiltration, it significantly worsened overall renal damage (p ≤ 0.05 compared to vehicle-STZ mice), leading to a more severe renal dysfunction than STZ alone. In conclusion, we showed that CBD could be detrimental for patients with type 1 diabetes, particularly those undergoing complications such as diabetic nephropathy.
Lactoferrin and Its Potential Impact for the Relief of Pain: A Preclinical Approach
Authors: Godínez-Chaparro Beatriz , Guzmán-Mejía Fabiola , Drago-Serrano Maria Elisa
Published: August 2021

Pain is one of the most disabling symptoms of several clinical conditions. Neurobiologically, it is classified as nociceptive, inflammatory, neuropathic and dysfunctional. Opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are conventionally prescribed for the treatment of pain. Long-term administration of opioids results in the loss of analgesic efficacy, leading to increased dosage, tolerance, and addiction as the main drawbacks of their use, while the adverse effects of NSAIDs include gastric ulcer formation, intestinal bleeding, acute kidney injury, and hepatotoxicity. Lactoferrin is an iron-binding, anti-inflammatory glycoprotein that displays analgesic activities associated, in part, by interacting with the low-density lipoprotein receptor-related protein (LRP), which may result in the regulation of the DAMP–TRAF6–NFκB, NO–cGMP–ATP K+-sensitive channel and opioid receptor signaling pathways. This review summarizes and discusses for the first time the analgesic effects of lactoferrin and its presumable mechanisms based on pre-clinical trials. Given its anti-nociceptive and anti-inflammatory properties, lactoferrin may be used as an adjunct to enhance the efficacy and to decrease the tolerogenic effects of canonical therapeutic drugs prescribed for pain treatment.
Combined Treatment with Acalabrutinib and Rapamycin Inhibits Glioma Stem Cells and Promotes Vascular Normalization by Downregulating BTK/mTOR/VEGF Signaling
Authors: Su Yu-Kai , Bamodu Oluwaseun Adebayo , Su I-Chang , Pikatan Narpati Wesa , Fong Iat-Hang , Lee Wei-Hwa , Yeh Chi-Tai , Chiu Hsiao-Yean , Lin Chien-Min
Published: August 2021

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median duration of survival of approximately 14 months after diagnosis. High resistance to chemotherapy remains a major problem. Previously, BTK has been shown to be involved in the intracellular signal transduction including Akt/mTOR signaling and be critical for tumorigenesis. Thus, we aim to evaluate the effect of BTK and mTOR inhibition in GBM. We evaluated the viability of GBM cell lines after treatment with acalabrutinib and/or rapamycin through a SRB staining assay. We then evaluated the effect of both drugs on GBM stem cell-like phenotypes through various in vitro assay. Furthermore, we incubated HUVEC cells with tumorsphere conditioned media and observed their angiogenesis potential, with or without treatment. Finally, we conducted an in vivo study to confirm our in vitro findings and analyzed the effect of this combination on xenograft mice models. Drug combination assay demonstrated a synergistic relationship between acalabrutinib and rapamycin. CSCs phenotypes, including tumorsphere and colony formation with the associated expression of markers of pluripotency are inhibited by either acalabrutinib or rapamycin singly and these effects are enhanced upon combining acalabrutinib and rapamycin. We showed that the angiogenesis capabilities of HUVEC cells are significantly reduced after treatment with acalabrutinib and/or rapamycin. Xenograft tumors treated with both drugs showed significant volume reduction with minimal toxicity. Samples taken from the combined treatment group demonstrated an increased Desmin/CD31 and col IV/vessel ratio, suggesting an increased rate of vascular normalization. Our results demonstrate that BTK-mTOR inhibition disrupts the population of GBM-CSCs and contributes to normalizing GBM vascularization and thus, may serve as a basis for developing therapeutic strategies for chemoresistant/radioresistant GBM.
Tackling Stereochemistry in Drug Molecules with Vibrational Optical Activity
Authors: Bogaerts Jonathan , Aerts Roy , Vermeyen Tom , Johannessen Christian , Herrebout Wouter , Batista Joao
Published: August 2021

Chirality plays a crucial role in drug discovery and development. As a result, a significant number of commercially available drugs are structurally dissymmetric and enantiomerically pure. The determination of the exact 3D structure of drug candidates is, consequently, of paramount importance for the pharmaceutical industry in different stages of the discovery pipeline. Traditionally the assignment of the absolute configuration of druggable molecules has been carried out by means of X-ray crystallography. Nevertheless, not all molecules are suitable for single-crystal growing. Additionally, valuable information about the conformational dynamics of drug candidates is lost in the solid state. As an alternative, vibrational optical activity (VOA) methods have emerged as powerful tools to assess the stereochemistry of drug molecules directly in solution. These methods include vibrational circular dichroism (VCD) and Raman optical activity (ROA). Despite their potential, VCD and ROA are still unheard of to many organic and medicinal chemists. Therefore, the present review aims at highlighting the recent use of VOA methods for the assignment of the absolute configuration of chiral small-molecule drugs, as well as for the structural analysis of biologics of pharmaceutical interest. A brief introduction on VCD and ROA theory and the best experimental practices for using these methods will be provided along with selected representative examples over the last five years. As VCD and ROA are commonly used in combination with quantum calculations, some guidelines will also be presented for the reliable simulation of chiroptical spectra. Special attention will be paid to the complementarity of VCD and ROA to unambiguously assess the stereochemical properties of pharmaceuticals.
Elucidating the Effects of Curcumin against Influenza Using In Silico and In Vitro Approaches
Authors: Kim Minjee , Choi Hanul , Kim Sumin , Kang Lin Woo , Kim Young Bong
Published: August 2021

The influenza virus is a constantly evolving pathogen that challenges medical and public health systems. Traditionally, curcumin has been used to treat airway inflammatory diseases, such as bronchitis and pneumonia. To elucidate common targets of curcumin and influenza infection and underlying mechanisms, we employed network pharmacology and molecular docking approaches and confirmed results using in vitro experiments. Biological targets of curcumin and influenza were collected, and potential targets were identified by constructing compound–disease target (C-D) and protein–protein interaction (PPI) networks. The ligand–target interaction was determined using the molecular docking method, and in vitro antiviral experiments and target confirmation were conducted to evaluate curcumin’s effects on influenza. Our network and pathway analyses implicated the four targets of AKT1, RELA, MAPK1, and TP53 that could be involved in the inhibitory effects of curcumin on influenza. The binding energy calculations of each ligand–target interaction in the molecular docking showed that curcumin bound to AKT1 with the highest affinity among the four targets. In vitro experiments, in which influenza virus-infected MDCK cells were pre-, co-, or post-treated with curcumin, confirmed curcumin’s prophylactic and therapeutic effects. Influenza virus induction increased the level of mRNA expression of AKT in MDCK cells, and the level was attenuated by curcumin treatment. Collectively, our findings identified potential targets of curcumin against influenza and suggest curcumin as a potential therapy for influenza infection.
Solid and Semisolid Innovative Formulations Containing Miconazole-Loaded Solid Lipid Microparticles to Promote Drug Entrapment into the Buccal Mucosa
Authors: De Caro Viviana , Giannola Libero Italo , Di Prima Giulia
Published: August 2021

The currently available antifungal therapy for oral candidiasis (OC) has various limitations restricting its clinical use, such as short retention time, suboptimal drug concentration and low patients compliance. These issues could be overcome using micro or nanotechnology. In particular, solid lipid microparticles (SLMs) resulted as a particularly promising penetration enhancer carrier for lipophilic drugs, such as the antifungal miconazole (MCZ). Based on these considerations, cetyl decanoate (here synthesized without the use of metal catalysis) was employed together with 1-hexadecanol to prepare MCZ-loaded SLMs. These resulted in a powder composed of 45–300 µm diameter solid spherical particles, able to load a high amount of MCZ in the amorphous form and characterized by a melting temperature range perfectly compatible with oromucosal administration (35–37 °C). Moreover, when compared to Daktarin® 2% oral gel in ex vivo experiments, SLMs were able to increase up to three-fold MCZ accumulation into the porcine buccal mucosa. The prepared SLMs were then loaded into a buccal gel or a microcomposite mucoadhesive buccal film and evaluated in terms of MCZ permeation and/or accumulation into porcine buccal mucosa by using lower doses than the conventional dosage form. The promising results obtained highlighted an enhancement in terms of MCZ accumulation even at low doses. Furthermore, the prepared buccal film was eligible as stable, reproducible and also highly mucoadhesive. Therefore, the formulated SLMs represent a penetration enhancer vehicle suitable to reduce the dose of lipophilic drugs to be administered to achieve the desired therapeutic effects, as well as being able to be effectively embedded into easily administrable solid or semisolid dosage forms.
External Model Performance Evaluation of Twelve Infliximab Population Pharmacokinetic Models in Patients with Inflammatory Bowel Disease
Authors: Schräpel Christina , Kovar Lukas , Selzer Dominik , Hofmann Ute , Tran Florian , Reinisch Walter , Schwab Matthias , Lehr Thorsten
Published: August 2021

Infliximab is approved for treatment of various chronic inflammatory diseases including inflammatory bowel disease (IBD). However, high variability in infliximab trough levels has been associated with diverse response rates. Model-informed precision dosing (MIPD) with population pharmacokinetic models could help to individualize infliximab dosing regimens and improve therapy. The aim of this study was to evaluate the predictive performance of published infliximab population pharmacokinetic models for IBD patients with an external data set. The data set consisted of 105 IBD patients with 336 infliximab concentrations. Literature review identified 12 published models eligible for external evaluation. Model performance was evaluated with goodness-of-fit plots, prediction- and variability-corrected visual predictive checks (pvcVPCs) and quantitative measures. For anti-drug antibody (ADA)-negative patients, model accuracy decreased for predictions > 6 months, while bias did not increase. In general, predictions for patients developing ADA were less accurate for all models investigated. Two models with the highest classification accuracy identified necessary dose escalations (for trough concentrations < 5 µg/mL) in 88% of cases. In summary, population pharmacokinetic modeling can be used to individualize infliximab dosing and thereby help to prevent infliximab trough concentrations dropping below the target trough concentration. However, predictions of infliximab concentrations for patients developing ADA remain challenging.
Suppression of Bottom Porosity in Fiber Laser Butt Welding of Stainless Steel
Authors: Pang Xiaobing , Dai Jiahui , Zhang Mingjun , Zhang Yan
Published: August 2021

The application bottleneck of laser welding is being gradually highlighted due to a high prevalence of porosity. Although laser welding technology has been well applied in fields such as vehicle body manufacturing, the suppression of weld porosity in the laser welding of stainless steel containers in the pharmaceutical industry is still challenging. The suppression of bottom porosity was investigated by applying ultrasonic vibration, changing welding positions and optimizing shielding gas in this paper. The results indicate that bottom porosities can be suppressed through application of ultrasonic vibration at an appropriate power. The keyhole in ultrasound-assisted laser welding is easier to penetrate, with better stability. No obvious bulge at the keyhole rear wall is found in vertical down welding, and the keyhole is much more stable than that in flat welding, thus eliminating bottom porosity. The top and bottom shielding gases achieve the minimal total porosities, without bottom porosity.
Phase-Shifting Projected Fringe Profilometry Using Binary-Encoded Patterns
Authors: Cheng Nai-Jen , Su Wei-Hung
Published: August 2021

A phase unwrapping method for phase-shifting projected fringe profilometry is presented. It did not require additional projections to identify the fringe orders. The pattern used for the phase extraction could be used for phase unwrapping directly. By spatially encoding the fringe patterns that were used to perform the phase-shifting technique with binary contrasts, fringe orders could be discerned. For spatially isolated objects or surfaces with large depth discontinuities, unwrapping could be identified without ambiguity. Even though the surface color or reflectivity varied periodically with position, it distinguished the fringe order very well.
Implementation of Pruned Backpropagation Neural Network Based on Photonic Integrated Circuits
Authors: Zhang Qi , Xing Zhuangzhuang , Huang Duan
Published: August 2021

We demonstrate a pruned high-speed and energy-efficient optical backpropagation (BP) neural network. The micro-ring resonator (MRR) banks, as the core of the weight matrix operation, are used for large-scale weighted summation. We find that tuning a pruned MRR weight banks model gives an equivalent performance in training with the model of random initialization. Results show that the overall accuracy of the optical neural network on the MNIST dataset is 93.49% after pruning six-layer MRR weight banks on the condition of low insertion loss. This work is scalable to much more complex networks, such as convolutional neural networks and recurrent neural networks, and provides a potential guide for truly large-scale optical neural networks.
Limited Phenotypic Variation in Vulnerability to Cavitation and Stomatal Sensitivity to Vapor Pressure Deficit among Clones of Aristotelia chilensis from Different Climatic Origins
Authors: Yáñez Marco A. , Urzua Javier I. , Espinoza Sergio E. , Peña Victor L.
Published: August 2021

Aristotelia chilensis (Molina) Stuntz is a promising species in the food industry as it provides ‘super fruits’ with remarkable antioxidant activity. However, under the predicted climate change scenario, the ongoing domestication of the species must consider selecting the most productive genotypes and be based on traits conferring drought tolerance. We assessed the vulnerability to cavitation and stomatal sensitivity to vapor pressure deficit (VPD) in A. chilensis clones originated from provenances with contrasting climates. A nursery experiment was carried out for one growing season on 2-year-old potted plants. Measurements of stomatal conductance (gs) responses to VPD were taken in spring, summer, and autumn, whereas vulnerability to cavitation was evaluated at the end of spring. Overall, the vulnerability to cavitation of the species was moderate (mean P50 of −2.2 MPa). Parameters of the vulnerability curves (Kmax, P50, P88, and S50) showed no differences among clones or when northern and southern clones were compared. Moreover, there were no differences in stomatal sensitivity to VPD at the provenance or the clonal level. However, compared with other studies, the stomatal sensitivity was considered moderately low, especially in the range of 1 to 3 kPa of VPD. The comparable performance of genotypes from contrasting provenance origins suggests low genetic variation for these traits. Further research must consider testing on diverse environmental conditions to assess the phenotypic plasticity of these types of traits.
Roots of Apium graveolens and Petroselinum crispum—Insight into Phenolic Status against Toxicity Level of Trace Elements
Authors: Arsenov Danijela , Župunski Milan , Pajević Slobodanka , Nemeš Ivana , Simin Nataša , Alnuqaydan Abdullah M. , Watson Malcolm , Aloliqi Abdulaziz A. , Mimica-Dukić Neda
Published: August 2021

Celery (Appium graveolens L.) and parsley (Petroselinum crispum (Mill.) Fuss) are herbs utilized in the everyday diet as spices and culinary flavorings, often used in the chemical and medicinal industries. Despite the knowing benefits of different plants from the Apiaceae family, their chemical composition is closely associated with various extrinsic factors. Environmental loading with trace elements (TEs) can modify a plant’s metabolic pathways, change bioactive compounds production, cause plant pollution, and consequently provoke human health issues. Therefore, we established this research aiming to unravel the linkage between TEs accumulation and phenolic status in celery and parsley. Higher As, Cd, and Ni levels were observed in celery, which was followed by greater DPPH∙ radical scavenging activity and higher coumarins content. Contrary, parsley accumulated chromium to a greater extent, was richer in flavonoids, apigenin, and its glucosides. No significant difference between species was found in total phenolic contents, where ferulic and chlorogenic acid dominated in both species. A direct relationship between TEs and selected secondary metabolites was proven by the standardized major axis model. Besides abundant bioactive compounds, analyzed plant species showed a moderate hazard index in the children population, since the hazard index was higher than 1. Therefore, future perspectives should be turned towards the production of genotypes with a lower potential for toxic elements accumulation, so the health benefits of plant food will be more prominent.
Calcium Oxalate Crystals in Leaves of the Extremophile Plant Colobanthus quitensis (Kunth) Bartl. (Caryophyllaceae)
Authors: Gómez-Espinoza Olman , González-Ramírez Daniel , Méndez-Gómez Jairo , Guillén-Watson Rossy , Medaglia-Mata Alejandro , Bravo León A.
Published: August 2021

The presence of calcium oxalate (CaOx) crystals has been widely reported in the plant kingdom. These structures play a central role in various physiological functions, including calcium regulation, metal detoxification, and photosynthesis. However, precise knowledge about their possible roles and functions in plants is still limited. Therefore, the present work aims to study the ecotypic variability of Colobanthus quitensis, an extremophile species, concerning CaOx crystal accumulation. The CaOx crystals were studied in leaves of C. quitensis collected from different provenances within a latitudinal gradient (From Andes mountains in central Chile to Antarctica) and grown under common garden conditions. Polarized light microscopy, digital image analysis, and electron microscopy were used to characterize CaOx crystals. The presence of CaOx crystals was confirmed in the four provenances of C. quitensis, with significant differences in the accumulation among them. The Andean populations presented the highest accumulation of crystals and the Antarctic population the lowest. Electron microscopy showed that CaOx crystals in C. quitensis are classified as druses based on their morphology. The differences found could be linked to processes of ecotypic differentiation and plant adaptation to harsh environments.
Biosynthetic Pathway of Proanthocyanidins in Major Cash Crops
Authors: Lim Insu , Ha Jungmin
Published: August 2021

Proanthocyanidins (PAs) are a group of oligomers or polymers composed of monomeric flavanols. They offer many benefits for human fitness, such as antioxidant, anticancer, and anti-inflammatory activities. To date, three types of PA have been observed in nature: procyanidins, propelargonidins, and prodelphinidins. These are synthesized as some of the end-products of the flavonoid pathway by different consecutive enzymatic activities, from the same precursor—naringenin. Although the general biosynthetic pathways of PAs have been reported in a few model plant species, little is known about the species-specific pathways in major crops containing different types of PA. In the present study, we identified the species-specific pathways in 10 major crops, based on the presence/absence of flavanol-based intermediates in the metabolic pathway, and found 202 orthologous genes in the reference genomic database of each species, which may encode for key enzymes involved in the biosynthetic pathways of PAs. Parallel enzymatic reactions in the pathway are responsible for the ratio between PAs and anthocyanins, as well as among the three types of PAs. Our study suggests a promising strategy for molecular breeding, to regulate the content of PAs and anthocyanins and improve the nutritional quality of food sources globally.
Effects of Microelements on Downy Mildew (Peronospora belbahrii) of Sweet Basil
Authors: Elad Yigal , Nisan Ziv , Kleinman Ziv , Rav-David Dalia , Yermiyahu Uri
Published: August 2021

We recently demonstrated that spraying or irrigating with Ca, Mg and K reduces the severity of sweet basil downy mildew (SBDM). Here, the effects of Mn, Zn, Cu and Fe on SBDM were tested in potted plants. The effects of Mn and Zn were also tested under semi-commercial and commercial-like field conditions. Spray applications of a mixture of EDTA-chelated microelements (i.e., Fe-EDTA, Mn-EDTA, Zn-EDTA, Cu-EDTA and Mo) reduces SBDM severity. The application of EDTA chelates of individual microelements (i.e., Fe-EDTA, Mn-EDTA and Zn-EDTA) significantly reduces SBDM in potted plants. Foliar applications of Mn-EDTA and Zn-EDTA are found to be effective under semi-commercial conditions and were, thus, further tested under commercial-like conditions. Under commercial-like conditions, foliar-applied Mn-EDTA and Zn-EDTA decreased SBDM severity by 46–71%. When applied through the irrigation solution, those two microelements reduce SBDM by more than 50%. Combining Mg with Mn-EDTA and Zn-EDTA in the irrigation solution does not provide any additional disease reduction. In the commercial-like field experiment, the microelement-mixture treatment, applied as a spray or via the irrigation solution, was combined with fungicides spray treatments. This combination provides synergistic disease control. The mode of action in this plant–pathogen system may involve features of altered host resistance.