bluuebunny/crossref_metadata_2025 huggingface dataset:
A Randomized Study of Nutritional Supplementation in Patients with Unilateral Wet Age-Related Macular Degeneration
Authors: García-Layana Alfredo , Recalde Sergio , Hernandez Maria , Abraldes Maximino J. , Nascimento João , Hernández-Galilea Emiliano , Olmedilla-Alonso Begoña , Escobar-Barranco Jose Juan , Zapata Miguel Angel , Silva Rufino , Caballero Arredondo Mariana , Lopez-Sabater María Carmen , Mendez-Martínez Silvia , Pardiñas-Barón Nieves , Calvo Pilar , Fernández-Robredo Patricia
Published: April 2021

The purpose of this study is evaluate the efficacy and safety of medicinal products containing the original Age-Related Eye Disease group (AREDS) formulation at doses approved in Europe (EU, control group; n = 59) with a product that adds DHA, lutein, zeaxanthin, resveratrol and hydroxytyrosol to the formula (intervention group; n = 50). This was a multicenter, randomized, observer-blinded trial conducted in patients aged 50 years or older diagnosed with unilateral exudative Age related Macular Degeneration AMD. At month 12, the intervention did not have a significant differential effect on visual acuity compared with the control group, with an estimated treatment difference in Early Treatment Diabetic Retinopathy Study (ETDRS) of −1.63 (95% CI −0.83 to 4.09; p = 0.192). The intervention exhibited a significant and, in most cases, relevant effect in terms of a reduction in some inflammatory cytokines and a greater improvement in the fatty acid profile and serum lutein and zeaxantin concentration. In patients with unilateral wet AMD, the addition of lutein, zeaxanthin, resveratrol, hydroxytyrosol and DHA to the AREDS EU recommended doses in the short-term did not have a differential effect on visual acuity compared to a standard AREDS EU formula but, in addition to improving the fatty acid profile and increasing carotenoid serum levels, may provide a beneficial effect in improving the proinflammatory and proangiogenic profile of patients with AMD.
Sodium Intake and Proteinuria/Albuminuria in the Population—Observational, Cross-Sectional Study
Authors: Cirillo Massimo , Cavallo Pierpaolo , Zulli Enrico , Villa Rachele , Veneziano Rosangela , Costanzo Simona , Magnacca Sara , Di Castelnuovo Augusto , Iacoviello Licia ,   on behalf of Moli-Sani Study Investigators
Published: April 2021

Sodium effects on proteinuria are debated. This observational, cross-sectional, population-based study investigated relationships to proteinuria and albuminuria of sodium intake assessed as urinary sodium/creatinine ratio (NaCR). In 482 men and 454 women aged 35–94 years from the Moli-sani study, data were collected for the following: urinary NaCR (independent variable); urinary total proteins/creatinine ratio (PCR, mg/g), urinary albumin/creatinine ratio (ACR, mg/g), and urinary non-albumin-proteins/creatinine ratio (calculated as PCR minus ACR) (dependent variables). High values were defined as PCR ≥ 150 mg/g, ACR ≥ 30 mg/g, and urinary non-albumin-proteins/creatinine ratio ≥ 120 mg/g. Urinary variables were measured in first-void morning urine. Skewed variables were log-transformed in analyses. The covariates list included sex, age, energy intake, body mass index, waist/hip ratio, estimated urinary creatinine excretion, smoking, systolic pressure, diastolic pressure, diabetes, history of cardiovascular disease, reported treatment with antihypertensive drug, inhibitor or blocker of the renin-angiotensin system, diuretic, and log-transformed data of total physical activity, leisure physical activity, alcohol intake, and urinary ratios of urea nitrogen, potassium, and phosphorus to creatinine. In multivariable linear regression, standardized beta coefficients of urinary NaCR were positive with PCR (women and men = 0.280 and 0.242, 95% confidence interval = 0.17/0.39 and 0.13/0.35, p < 0.001), ACR (0.310 and 0.265, 0.20/0.42 and 0.16/0.38, p < 0.001), and urinary non-albumin-proteins/creatinine ratio (0.247 and 0.209, 0.14/0.36 and 0.09/0.33, p < 0.001). In multivariable logistic regression, higher quintile of urinary NaCR associated with odds ratio of 1.81 for high PCR (1.55/2.12, p < 0.001), 0.51 of 1.62 for high ACR (1.35/1.95, p < 0.001), and of 1.84 for high urinary non-albumin proteins/creatinine ratio (1.58/2.16, p < 0.001). Findings were consistent in subgroups. Data indicate independent positive associations of an index of sodium intake with proteinuria and albuminuria in the population.
Rat Milk and Plasma Immunological Profile throughout Lactation
Authors: Grases-Pintó Blanca , Abril-Gil Mar , Torres-Castro Paulina , Castell Margarida , Rodríguez-Lagunas María J. , Pérez-Cano Francisco J. , Franch Àngels
Published: April 2021

The composition of bioactive factors with immune activity in human breast milk is widely studied. However, the knowledge on rat milk immune factors during the whole lactation period is still scarce. This study aimed to analyze rat breast milk’s immunoglobulin (Ig) content and some critical adipokines and growth factors throughout the lactation period, and to assess relationships with corresponding plasma levels. During lactation, milk concentration of the transforming growth factor (TGF)-β2 and -β3 showed a punctual increase in the first week, whereas adiponectin and leptin remained stable. In the second period of lactation (d14–21), despite the increase in the milk epidermal growth factor (EGF), a decrease in fibroblast growth factor 21 (FGF21) was detected at day 21. Milk IgA concentration had a progressive increase during lactation, while no significant changes were found in IgM and IgG. Regarding plasma levels, a decrease in all studied adipokines was observed in the second period of lactation, with the exception of IgA and TGF-β1, which reached their highest values at the end of the study. A positive correlation in IgM, IgG, and adipokine concentration was detected between milk and plasma compartments. In summary, the changes in the pattern of these bioactive compounds in rat milk and plasma and their relationships during lactation are established.
Evaluation of Clinical Meaningfulness of Red Clover (Trifolium pratense L.) Extract to Relieve Hot Flushes and Menopausal Symptoms in Peri- and Post-Menopausal Women: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Kanadys Wiesław , Barańska Agnieszka , Błaszczuk Agata , Polz-Dacewicz Małgorzata , Drop Bartłomiej , Kanecki Krzysztof , Malm Maria
Published: April 2021

The meta-analysis presented in this article covered the efficacy of red clover isoflavones in relieving hot flushes and menopausal symptoms in perimenopausal and postmenopausal women. Studies were identified by MEDLINE (PubMed), Embase, and the Cochrane Library searches. The quality of the studies was evaluated according to Cochrane criteria. A meta-analysis of eight trials (ten comparisons) demonstrated a statistically significant reduction in the daily incidence of hot flushes in women receiving red clover compared to those receiving placebo: weighted mean difference (WMD—weighted mean difference) −1.73 hot flushes per day, 95% CI (confidence interval) −3.28 to −0.18; p = 0.0292. Due to 87.34% heterogeneity, the performed analysis showed substantive difference in comparisons of postmenopausal women with ≥5 hot flushes per day, when the follow-up period was 12 weeks, with an isoflavone dose of ≥80 mg/day, and when the formulations contained a higher proportion of biochanin A. The meta-analysis of included studies assessing the effect of red clover isoflavone extract on menopausal symptoms showed a statistically moderate relationship with the reduction in the daily frequency of hot flushes. However, further well-designed studies are required to confirm the present findings and to finally determine the effects of red clover on the relief of flushing episodes.
Association between Malnutrition and Quality of Life in Elderly Patients with Rheumatoid Arthritis
Authors: Tański Wojciech , Wójciga Justyna , Jankowska-Polańska Beata
Published: April 2021

Rheumatoid arthritis (RA) is a progressive articular disease. In addition to damaging the joints, it may cause multiple organ complications, and considerably impair the patient’s functioning. Elderly patients with RA report pain, fatigue, mood disorders, sleep disorders and insomnia, accompanied by weakness, poor appetite, and weight loss. All these factors combined have an adverse effect on the patient’s perceived quality of life (QoL). Due to the chronic nature of RA and the high risk of malnutrition in this patient group, the present study investigated QoL, activities of daily living, and frailty syndrome severity in relation to MNA (Mini Nutritional Assessment) questionnaire scores among elderly RA patients. The study included 98 patients (aged over 60) diagnosed with RA per the ARA (American Rheumatism Association) criteria. The following standardized instruments were used: WHOQoL-BREF for QoL, the Edmonton Frail Scale for frailty syndrome severity, MNA for nutritional status assessment, and MMSE (Mini-Mental State Examination) to assess any cognitive impairment. Medical data were obtained from hospital records. Patients with a different nutritional status differed significantly in terms of limitations in activities of daily living (ADL) and instrumental activities of daily living (IADL). Higher levels of malnutrition were associated with greater limitations in activity. An adverse impact of lower body weight on cognitive function was also observed (dementia was identified in 33.33% of malnourished patients vs. 1.79% in patients with a normal body weight). Likewise, frailty was more common in malnourished patients (mild frailty syndrome in 33.3%, moderate in 16.67%, and severe in 16.67%). Malnourished patients had significantly lower QoL scores in all WHOQoL-BREF questionnaire domains than those with a normal body weight, and multiple-factor analysis for the impact of selected variables on QoL in each domain demonstrated that frailty was a significant independent determinant of poorer QoL in all domains: perceived quality of life (β = −0.069), perceived health (β = −0.172), physical domain (β = −0.425), psychological domain (β = −0.432), social domain (β = −0.415), environmental domain (β = −0.317). Malnutrition was a significant independent determinant of QoL in the “perceived health” domain (β = −0.08). In addition, regression analysis demonstrated the positive impact of male sex on QoL scores in the psychological (β = 1.414) and environmental domains (β = 1.123). Malnourished patients have a lower QoL than those with a normal body weight. Malnutrition adversely affects daily functioning, cognitive function, and the severity of frailty syndrome. Frailty syndrome is a significant independent determinant of poorer QoL in all WHOQoL BREF domains.
Does Evidence Exist to Blunt Inflammatory Response by Nutraceutical Supplementation during COVID-19 Pandemic? An Overview of Systematic Reviews of Vitamin D, Vitamin C, Melatonin, and Zinc
Authors: Corrao Salvatore , Mallaci Bocchio Raffaella , Lo Monaco Marika , Natoli Giuseppe , Cavezzi Attilio , Troiani Emidio , Argano Christiano
Published: April 2021

More than one year has passed since the first cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome (SARS)-CoV-2 coronavirus were reported in Wuhan (China), rapidly evolving into a global pandemic. This infectious disease has become a major public health challenge in the world. Unfortunately, to date, no specific antivirals have been proven to be effective against COVID-19, and although a few vaccines are available, the mortality rate is not decreasing but is still increasing. One therapeutic strategy has been focused on infection prevention and control measures. In this regard, the use of nutraceutical supports may play a role against some aspect of the infection, particularly the inflammatory state and the immune system function of patients, thus representing a strategy to control the worst outcomes of this pandemic. For this reason, we performed an overview including meta-analyses and systematic reviews to assess the association among melatonin, vitamin C, vitamin D, zinc supplementation and inflammatory markers using three databases, namely, MEDLINE, PubMed Central and the Cochrane Library of Systematic Reviews. According to the evidence available, an intake of 50,000 IU/month of vitamin D showed efficacy in CRP. An amount of 1 to 2 g per day of vitamin C demonstrated efficacy both in CRP and endothelial function, and a dosage of melatonin ranging from 5 to 25 mg /day showed good evidence of efficacy in CRP, TNF and IL6. A dose of 50 mg/day of elemental zinc supplementation showed positive results in CRP. Based on the data reported in this review, the public health system could consider whether it is possible to supplement the current limited preventive measures through targeted nutraceutical large-scale administration.
Experimental Infection of North American Sheep with Ehrlichia ruminantium
Authors: Nair Arathy , Hove Paidashe , Liu Huitao , Wang Ying , Cino-Ozuna Ada G. , Henningson Jamie , Ganta Charan K. , Ganta Roman R.
Published: April 2021

Ehrlichia ruminantium, a tick-borne rickettsial, causes heartwater in ruminants resulting from vascular damage. Severity of heartwater varies greatly in ruminant species and breeds, age of animals and for diverse geographic E. ruminantium strains. E. ruminantium and a tick vector, Amblyomma variegatum, originating from Africa, are well established in certain Caribbean islands two centuries ago. Besides the possibility of introduction of heartwater through African exotic animal importation, presence of the pathogen, and the tick vector in the Caribbean pose a high risk to ruminants in the USA and other western hemisphere countries. Scientific evidence supporting the heartwater threat to nonendemic regions, however, is lacking. We describe the first infection study in sheep reared in the USA with seven E. ruminantium strains. All infected sheep exhibited clinical signs characteristic of subacute to subclinical disease, which included labored breathing, depression, coughing, and nasal discharges. Gross and microscopic lesions consistent with heartwater disease including edema and hemorrhage were observed in several organs. Pathogen-specific IgG antibody response was detected in animals infected with all seven strains, while molecular analysis confirmed the pathogen presence only when infected with in vitro cultures. This is the first infection study demonstrating severe heartwater in sheep reared in North America.
Assessment of Tumorigenic Potential in Mesenchymal-Stem/Stromal-Cell-Derived Small Extracellular Vesicles (MSC-sEV)
Authors: Tan Thong Teck , Lai Ruenn Chai , Padmanabhan Jayanthi , Sim Wei Kian , Choo Andre Boon Hwa , Lim Sai Kiang
Published: April 2021

Mesenchymal-stem/stromal-cell-derived small extracellular vesicles (MSC-sEV) have been shown to ameliorate many diseases in preclinical studies. However, translating MSC-sEV into clinical use requires the development of scalable manufacturing processes for highly reproducible preparations of safe and potent MSC-sEVs. A major source of variability in MSC-sEV preparations is EV producer cells. To circumvent variability in producer cells, clonal immortalized MSC lines as EV producer lines are increasingly being used for sEV production. The use of sEVs from immortalized producer cells inevitably raises safety concerns regarding the tumorigenicity or tumor promoting potential of the EV products. In this study, cells from E1-MYC line, a MSC cell line immortalized with the MYC gene, were injected subcutaneously into athymic nude mice. At 84 days post-injection, no tumor formation was observed at the injection site, lungs, or lymph nodes. E1-MYC cells pre-and post-sEV production did not exhibit anchorage-independent growth in soft agar. Daily intraperitoneal injections of 1 or 5 μg sEVs from E1-MYC into athymic nude mice with FaDu human head and neck cancer xenografts for 28 days did not promote or inhibit tumor growth relative to the xenograft treated with vehicle control. Therefore, MYC-immortalized MSCs are not tumorigenic and sEVs from these MSCs do not promote tumor growth.
Luminescent Phage-Based Detection of Klebsiella pneumoniae: From Engineering to Diagnostics
Authors: Zelcbuch Lior , Yitzhaki Elad , Nissan Olga , Gidron Eliya , Buchshtab Nufar , Kario Edith , Kredo-Russo Sharon , Zak Naomi B. , Bassan Merav
Published: April 2021

Bacteriophages (“phages”) infect and multiply within specific bacterial strains, causing lysis of their target. Due to the specific nature of these interactions, phages allow a high-precision approach for therapy which can also be exploited for the detection of phage-sensitive pathogens associated with chronic diseases due to gut microbiome imbalance. As rapid phage-mediated detection assays becoming standard-of-care diagnostic tools, they will advance the more widespread application of phage therapy in a precision approach. Using a conventional method and a new cloning approach to develop luminescent phages, we engineered two phages that specifically detect a disease-associated microbial strain. We performed phage sensitivity assays in liquid culture and in fecal matrices and tested the stability of spiked fecal samples stored under different conditions. Different reporter gene structures and genome insertion sites were required to successfully develop the two nluc-reporter phages. The reporter phages detected spiked bacteria in five fecal samples with high specificity. Fecal samples stored under different conditions for up to 30 days did not display major losses in reporter-phage-based detection. Luminescent phage-based diagnostics can provide a rapid co-diagnostic tool to guide the growing field of phage therapy, particularly for a precision-based approach to chronic diseases treatment.
Absence of Association between Methylene Blue Reduced Susceptibility and Polymorphisms in 12 Genes Involved in Antimalarial Drug Resistance in African Plasmodium falciparum
Authors: Gendrot Mathieu , Delandre Océane , Robert Marie , Foguim Francis , Benoit Nicolas , Amalvict Rémy , Fonta Isabelle , Mosnier Joel , Madamet Marylin , Pradines Bruno , Group on
Published: April 2021

Half the human population is exposed to malaria. Plasmodium falciparum antimalarial drug resistance monitoring and development of new drugs are major issues related to the control of malaria. Methylene blue (MB), the oldest synthetic antimalarial, is again a promising drug after the break of its use as an antimalarial drug for more than 80 years and a potential partner for triple combination. Very few data are available on the involvement of polymorphisms on genes known to be associated with standard antimalarial drugs and parasite in vitro susceptibility to MB (cross-resistance). In this context, MB susceptibility was evaluated against 482 isolates of imported malaria from Africa by HRP2-based ELISA chemosusceptibility assay. A total of 12 genes involved in antimalarial drug resistance (Pfcrt, Pfdhfr, Pfmdr1, Pfmdr5, Pfmdr6, PfK13, Pfubq, Pfcarl, Pfugt, Pfact, Pfcoronin, and copy number of Pfpm2) were sequenced by Sanger method and quantitative PCR. On the Pfmdr1 gene, the mutation 86Y combined with 184F led to more susceptible isolates to MB (8.0 nM vs. 11.6 nM, p = 0.03). Concerning Pfmdr6, the isolates bearing 12 Asn repetitions were more susceptible to MB (4.6 nM vs. 11.6 nM, p = 0.005). None of the polymorphisms previously described as involved in antimalarial drug resistance was shown to be associated with reduced susceptibility to MB. Some genes (particularly PfK13, Pfugt, Pfact, Pfpm2) did not present enough genetic variability to draw conclusions about their involvement in reduced susceptibility to MB. None of the polymorphisms analyzed by multiple correspondence analysis (MCA) had an impact on the MB susceptibility of the samples successfully included in the analysis. It seems that there is no in vitro cross-resistance between MB and commonly used antimalarial drugs.
The Off-Patent Biological Market in Belgium: Is the Health System Creating a Hurdle to Fair Market Competition?
Authors: Wilder Philippe Van
Published: April 2021

We investigated the off-patent biological market in Belgium from a policy maker’s perspective, in light of the Belgian pharmaceutical health system. The main barriers relate to a short-term budgetary focus, to the overwhelming innovator’s reach and to a concertation model with assessment and appraisal being mixed which results in poorly effective policy measures.
Relationship between CYP3A5 Polymorphism and Tacrolimus Blood Concentration Changes in Allogeneic Hematopoietic Stem Cell Transplant Recipients during Continuous Infusion
Authors: Yoshikawa Naoki , Takeshima Hidemi , Sekine Masaaki , Akizuki Keiichi , Hidaka Tomonori , Shimoda Kazuya , Ikeda Ryuji
Published: April 2021

A polymorphism in the gene encoding the metabolic enzyme cytochrome P450 family 3 subfamily A member 5 (CYP3A5) is a particularly influential factor in the use of tacrolimus in Japanese patients. Those who are homozygotic for the *3 mutation lack CYP3A5 activity, which results in substantial individual differences in tacrolimus metabolism. The aim of this study was to analyze the relationship between individual differences in tacrolimus blood concentration changes and CYP3A5 polymorphisms in allogeneic hematopoietic stem cell transplantation recipients during the period of increasing blood concentration of the drug following treatment onset. This was a prospective observational cohort study, involving 20 patients administered tacrolimus by continuous infusion. The subjects were divided into the *1/*3 and *3/*3 groups based on CYP3A5 polymorphism analysis. The tacrolimus blood concentration/dose (C/D) ratio increased from day 1 and was largely stable on day 5, and a significant difference was observed between the *1/*3 and *3/*3 groups in the time course of the C/D ratio during this period (p < 0.05). This study reveals the effects of CYP3A5 polymorphism on continuous changes in tacrolimus blood concentration.
Advances in Lipid-Based Nanoparticles for Cancer Chemoimmunotherapy
Authors: Wang Tianqi , Suita Yusuke , Miriyala Saradha , Dean Jordan , Tapinos Nikos , Shen Jie
Published: April 2021

Nanomedicines have shown great potential in cancer therapy; in particular, the combination of chemotherapy and immunotherapy (namely chemoimmunotherapy) that is revolutionizing cancer treatment. Currently, most nanomedicines for chemoimmunotherapy are still in preclinical and clinical trials. Lipid-based nanoparticles, the most widely used nanomedicine platform in cancer therapy, is a promising delivery platform for chemoimmunotherapy. In this review, we introduce the commonly used immunotherapy agents and discuss the opportunities for chemoimmunotherapy mediated by lipid-based nanoparticles. We summarize the clinical trials involving lipid-based nanoparticles for chemoimmunotherapy. We also highlight different chemoimmunotherapy strategies based on lipid-based nanoparticles such as liposomes, nanodiscs, and lipid-based hybrid nanoparticles in preclinical research. Finally, we discuss the challenges that have hindered the clinical translation of lipid-based nanoparticles for chemoimmunotherapy, and their future perspectives.
Urinary Metabolomic Profiling after Administration of Corydalis Tuber and Pharbitis Seed Extract in Healthy Korean Volunteers
Authors: Jeong Hyeon-Cheol , Park Jung Eun , Seo Yohan , Kim Min-Gul , Shin Kwang-Hee
Published: April 2021

Pharmacometabolomics is a useful tool to identify biomarkers that can assess and predict response after drug administration. The primary purpose of pharmacometabolomics is to better understand the mechanisms and pathways of a drug by searching endogenous metabolites that have significantly changed after drug administration. DA-9701, a prokinetic agent, consists of Pharbitis seed and Corydalis tube extract and it is known to improve the gastrointestinal motility. Although the overall mechanism of action of DA-9701 remains unclear, its active ingredients, corydaline and chlorogenic acid, act as a 5-HT3 and D2 receptor antagonist and 5-HT4 receptor agonist. To determine the significant metabolites after the administration of DA-9701, a qualitative analysis was carried out using ultra-high performance liquid chromatography coupled with orbitrap mass spectrometer followed by a multivariate analysis. Seven candidates were selected and a statistical analysis of fold change was performed over time. Our study concluded that all the seven selected metabolites were commonly involved in lipid metabolism and purine metabolism.
Recent Advances to Augment NK Cell Cancer Immunotherapy Using Nanoparticles
Authors: Kim Kwang-Soo , Kim Dong-Hwan , Kim Dong-Hyun
Published: April 2021

Among various immunotherapies, natural killer (NK) cell cancer immunotherapy using adoptive transfer of NK cells takes a unique position by targeting tumor cells that evade the host immune surveillance. As the first-line innate effector cell, it has been revealed that NK cells have distinct mechanisms to both eliminate cancer cells directly and amplify the anticancer immune system. Over the last 40 years, NK cell cancer immunotherapy has shown encouraging reports in pre-clinic and clinic settings. In total, 288 clinical trials are investigating various NK cell immunotherapies to treat hematologic and solid malignancies in 2021. However, the clinical outcomes are unsatisfying, with remained challenges. The major limitation is attributed to the immune-suppressive tumor microenvironment (TME), low activity of NK cells, inadequate homing of NK cells, and limited contact frequency of NK cells with tumor cells. Innovative strategies to promote the cytolytic activity, durable persistence, activation, and tumor-infiltration of NK cells are required to advance NK cell cancer immunotherapy. As maturing nanotechnology and nanomedicine for clinical applications, there is a greater opportunity to augment NK cell therapeutic efficacy for the treatment of cancers. Active molecules/cytokine delivery, imaging, and physicochemical properties of nanoparticles are well equipped to overcome the challenges of NK cell cancer immunotherapy. Here, we discuss recent clinical trials of NK cell cancer immunotherapy, NK cell cancer immunotherapy challenges, and advances of nanoparticle-mediated NK cell therapeutic efficacy augmentation.
Use of Pluronic Surfactants in Gel Formulations of Photosensitive 1,4-Dihydropyridine Derivatives: A Potential Approach in the Treatment of Neuropathic Pain
Authors: Ioele Giuseppina , Muzzalupo Rita , Gündüz Miyase Gözde , De Luca Michele , Mazzotta Elisabetta , Grande Fedora , Occhiuzzi Maria Antonietta , Garofalo Antonio , Ragno Gaetano
Published: April 2021

1,4-Dihydropyridines (DHPs) are the most important class of L-type calcium channel blockers that are employed for the treatment of cardiovascular diseases, particularly hypertension. Various modifications on this scaffold lead to the discovery of new DHPs blocking different types of calcium channels. Among them, the T-type calcium channel has recently attracted great interest due to its role in chronic pain conditions. In this study, we selected three newly synthesized DHPs (HM8, HM10 and MD20) with different selectivity profiles to the T-type calcium channel and formulated them in micellar solutions and micellar-in-gel matrices to be tested for potential topical use in the treatment of neuropathic pain. To prevent the well-known sensitivity to light of the DHPs, the studied compounds were entrapped in colloidal aggregates obtained by using edible Pluronic® surfactants and adding α-tocopherol as an antioxidant. All the prepared formulations were exposed to stressing light, according to international rules. Along with the degradation experiments, the concentrations of the parent compounds and by-products were calculated by multivariate curve resolution—alternating least squares (MCR-ALS) applied to the spectral data. The defined formulations proved suitable as light-stable matrices for the DHP compounds, showing an increase in stability for HM8 and MD20 and an almost complete photoprotection for HM10, compared to ethanol solutions and standard gel formulations.
Excipient-Free Pure Drug Nanoparticles Fabricated by Microfluidic Hydrodynamic Focusing
Authors: Arzi Roni Sverdlov , Kay Asaf , Raychman Yulia , Sosnik Alejandro
Published: April 2021

Nanoprecipitation is one of the most versatile methods to produce pure drug nanoparticles (PDNPs) owing to the ability to optimize the properties of the product. Nevertheless, nanoprecipitation may result in broad particle size distribution, low physical stability, and batch-to-batch variability. Microfluidics has emerged as a powerful tool to produce PDNPs in a simple, reproducible, and cost-effective manner with excellent control over the nanoparticle size. In this work, we designed and fabricated T- and Y-shaped Si-made microfluidic devices and used them to produce PDNPs of three kinase inhibitors of different lipophilicity and water-solubility, namely imatinib, dasatinib and tofacitinib, without the use of colloidal stabilizers. PDNPs display hydrodynamic diameter in the 90–350 nm range as measured by dynamic light scattering and a rounded shape as visualized by high-resolution scanning electron microscopy. Powder X-ray diffraction and differential scanning calorimetry confirmed that this method results in highly amorphous nanoparticles. In addition, we show that the flow rate of solvent, the anti-solvent, and the channel geometry of the device play a key role governing the nanoparticle size.
Development of a Nanostructured Lipid Carrier (NLC) by a Low-Energy Method, Comparison of Release Kinetics and Molecular Dynamics Simulation
Authors: Ortiz Andrea C. , Yañez Osvaldo , Salas-Huenuleo Edison , Morales Javier O.
Published: April 2021

Lipid nanocarriers have a great potential for improving the physicochemical characteristics and behavior of poorly water-soluble drugs, such as aqueous dispersibility and oral bioavailability. This investigation presents a novel nanostructured lipid carrier (NLC) based on a mixture of solid lipid glycerides, fatty acid esters of PEG 1500 (Gelucire® 44/14), and an oil mix composed of capric and caprylic triglycerides (Miglyol® 812). These NLCs were developed by a simple low-energy method based on melt emulsification to yield highly encapsulating and narrowly distributed nanoparticles (~100 nm, PdI = 0.1, and zeta potential = ~−10 mV). Rhodamine 123 was selected as a poorly water-soluble drug model and owing to its spectroscopic properties. The novel NLCs were characterized by dynamic light scattering (DLS), zeta potential, nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and colloidal stability. The drug release was determined through a dialysis bag and vertical Franzs’ cells to provide insights about the methods’ suitability, revealing similar performance regardless of their different fluid dynamics. Rhodamine 123 followed a characteristic biphasic release profile owing to the swelling of the hydrophilic polymer coating and diffusion process from the lipid core as revealed by the Korsmeyers–Peppas kinetic modeling. Moreover, to elucidate the formation and incorporation of Rhodamine 123 into the NLC core, several molecular dynamics simulations were conducted. The temperature was shown to be an important condition to improve the formation of the nanoparticles. In addition, the liquid lipid incorporation to the formulation forms nanoparticles with imperfect centers, in contrast to nanoparticles without it. Moreover, Miglyol® 812 improves hydrophobic molecule solubility. These results suggest the potential of novel NLC as a drug delivery system for poorly water-soluble drugs.
Dexamethasone-Loaded Lipomers: Development, Characterization, and Skin Biodistribution Studies
Authors: Pena-Rodríguez Eloy , Lajarin-Reinares Maria , Mata-Ventosa Aida , Pérez-Torras Sandra , Fernández-Campos Francisco
Published: April 2021

Follicular targeting has gained more attention in recent decades, due to the possibility of obtaining a depot effect in topical administration and its potential as a tool to treat hair follicle-related diseases. Lipid core ethyl cellulose lipomers were developed and optimized, following which characterization of their physicochemical properties was carried out. Dexamethasone was encapsulated in the lipomers (size, 115 nm; polydispersity, 0.24; zeta-potential (Z-potential), +30 mV) and their in vitro release profiles against dexamethasone in solution were investigated by vertical diffusion Franz cells. The skin biodistribution of the fluorescent-loaded lipomers was observed using confocal microscopy, demonstrating the accumulation of both lipomers and fluorochromes in the hair follicles of pig skin. To confirm this fact, immunofluorescence of the dexamethasone-loaded lipomers was carried out in pig hair follicles. The anti-inflammatory (via TNFα) efficacy of the dexamethasone-loaded lipomers was demonstrated in vitro in an HEK001 human keratinocytes cell culture and the in vitro cytotoxicity of the nanoformulation was investigated.
Frequency Dependence of a Piezo-Resistive Method for Pressure Measurements of Laser-Induced Shock Waves in Solids
Authors: Gonzalez-Romero Ricardo , Strojnik Marija , Garcia-Torales Guillermo , Gomez-Rosas Gilberto
Published: April 2021

A shock wave is a mechanical high-pressure pulse that travels inside a medium with a full width at half-maximum of a few nanoseconds that may be induced with a high-power laser pulse. A piezo-resistive measurement method to determine the shock wave pressure has been widely employed even though there is inner inaccuracy in the calibration process. We are interested in developing a precise theoretical model of laser material processing for applications in material sciences that includes the frequency dependence of the electronic post processing. We show an approach to determine the correction factor to frequency response at a high frequency of a piezo-resistive experimental setup and the results of the pressure measurements obtained in this experimental setup. The theoretical and experimental work demonstrates the feasibility of piezo-resistive methods to measure a laser-induced shock wave pressure in the nanosecond range. The correction factor of the frequency dependence calibration allows the technique to be applied in different shock wave experiments.
Growth Stage of Alopecurus myosuroides Huds. Determines the Efficacy of Pinoxaden
Authors: Pintar Ana , Svečnjak Zlatko , Šoštarčić Valentina , Lakić Josip , Barić Klara , Brzoja Dragojka , Šćepanović Maja
Published: April 2021

Alopecurus myosuroides Huds. is an important pinoxaden-resistant grass weed in many countries of Europe. Recently, the low efficacy of pinoxaden was reported in winter cereals in Croatia, but a preliminary dose–response trial showed no herbicide resistance for the investigated weed population. Therefore, a two-year experiment was conducted under greenhouse conditions to determine the efficacy of various pinoxaden doses (20, 40 and 80 g a.i. ha−1) on weed visual injuries and biomass reduction after herbicide application at different growth stages. As expected, the maximum weed biomass reduction (97.3%) was achieved by applying the highest dose (80 g a.i. ha−1) at the earliest growth stage (ZCK 12–14). A pinoxaden dose of 20 g a.i. ha−1 resulted in satisfactory weed biomass reduction (88.9%) only when applied at ZCK 12–14. The recommended dose (40 g a.i. ha−1) also provided sufficient weed control up to the growth stage ZCK 21–25. Slightly delayed (ZCK 31–32) application of the recommended dose brought about a low weed biomass reduction (60.1%). Double than the recommended dose also failed to provide satisfactory weed control at the advanced weed growth stages (ZCK 31–32 and ZCK 37–39). Thus, reported low efficacy of pinoxaden is most likely because of delayed herbicide application when A. myosuroides is overgrown.
Date Palm Extract (Phoenix dactylifera) PEGylated Nanoemulsion: Development, Optimization and Cytotoxicity Evaluation
Authors: Khalil Hany Ezzat , Alqahtani Nashi K. , Darrag Hossam M. , Ibrahim Hairul-Islam Mohamed , Emeka Promise M. , Badger-Emeka Lorina I. , Matsunami Katsuyoshi , Shehata Tamer M. , Elsewedy Heba S.
Published: April 2021

Date palm fruit (Phoenix dactylifera) is reputed to have numerous biological activities, including anticancer properties. To utilize the great fortune of this fruit, the current study aimed to maximize its pharmacological activity. Date palm extract (DPE) of Khalas cultivar was obtained in powder form and then was formulated into nanoemulsion (NE). The optimized DPE-NE was formulated along with its naked counterpart followed by studying their physical and chemical properties. A qualitative assessment of total serum protein associated with the surface of formulations was implemented. Studies for the in vitro release of DPE from developed NE before and after incubation with serum were investigated. Eventually, an MTT assay was conducted. Total phenolic and flavonoid contents were 22.89 ± 0.013 mg GAE/g of dry DPE and 9.90 ± 0.03 mg QE/g of dry DPE, respectively. Homogenous NE formulations were attained with appropriate particle size and viscosity that could be administered intravenously. The optimized PEGylated NE exhibited a proper particle size, PDI, and zeta potential. Total serum protein adsorbed on PEG-NE surface was significantly low. The release of the drug through in vitro study was effectively extended for 24 h. Ultimately; PEGylated NE of DPE attained significant inhibition for cancer cell viability with IC50 values of 18.6 ± 2.4 and 13.5 ± 1.8 µg/mL for MCF-7 and HepG2 cell lines, respectively. PEGylated NE of DPE of Khalas cultivar will open the gate for future adjuvants for cancer therapy.
Search for Resistant Genotypes to Cuscuta campestris Infection in Two Legume Species, Vicia sativa and Vicia ervilia
Authors: Córdoba Eva María , Fernández-Aparicio Mónica , González-Verdejo Clara Isabel , López-Grau Carmela , del Valle Muñoz-Muñoz María , Nadal Salvador
Published: April 2021

The dodders (Cuscuta spp.) are parasitic plants that feed on the stems of their host plants. Cuscuta campestris is one of the most damaging parasitic plants for the worldwide agricultural production of broad-leaved crops. Its control is limited or non-existent, therefore resistance breeding is the best alternative both economically and environmentally. Common vetch (Vicia sativa) and bitter vetch (Vicia ervilia) are highly susceptible to C. campestris, but no resistant genotypes have been identified. Thus, the aim of this study was to identify in V. sativa and V.ervilia germplasm collections genotypes resistant to C. campestris infection for use in combating this parasitic plant. Three greenhouse screening were conducted to: (1) identify resistant responses in a collection of 154 accessions of bitter vetch and a collection of 135 accessions of common vetch genotypes against infection of C. campestris; (2) confirm the resistant response identified in common vetch accessions; and (3) characterize the effect of C. campestris infection on biomass of V. sativa resistant and susceptible accessions. Most common vetch and bitter vetch genotypes tested were susceptible to C. campestris. However, the V. sativa genotype Vs.1 exhibited high resistance. The resistant phenotype was characterized by a delay in the development of C. campestris posthaustorial growth and a darkening resembling a hypersensitive-like response at the penetration site. The resistant mechanism was effective in limiting the growth of C. campestris as the ratio of parasite/host shoot dry biomass was more significantly reduced than the rest of the accessions. To the best or our knowledge, this is the first identification of Cuscuta resistance in V. sativa genotypes.
Changes in Diversity Due to Long-Term Management in a High Natural Value Grassland
Authors: Vaida Ioana , Păcurar Florin , Rotar Ioan , Tomoș Liviu , Stoian Vlad
Published: April 2021

High nature value (HNV) grassland systems are increasingly important for the ecosystem services they provide and for their socio-economic impact in the current constant-changing context. The aim of our paper is to evaluate the long-term effect of organic fertilizers on HNV systems in the Apuseni Mountains, Romania. As an objective we want to identify the optimal intensity of conservation management and its recognition based on indicator value plant species. The experiments were established in 2001 on the boreal floor and analyze the effect of a gradient of four organic treatments with manure. Fertilization with 10 t ha−1 manure ensures an increase in yield and has a small influence on diversity, and could be a real possibility for the maintenance and sustainable use of HNV. Each fertilization treatment determined species with indicator value that are very useful in the identification and management of HNV. The indicator species are useful in forecasting the fluctuations and successions in grasslands, determined by the modification of the dominance-codominance ratio and the real coverage of each species.
Taxonomic Revisiting and Phylogenetic Placement of Two Endangered Plant Species: Silene leucophylla Boiss. and Silene schimperiana Boiss. (Caryophyllaceae)
Authors: EL-Banhawy Ahmed , Nour Iman H. , Acedo Carmen , ElKordy Ahmed , Faried Ahmed , AL-Juhani Widad , Gawhari Ahmed M. H. , Olwey Asmaa O. , Ellmouni Faten Y.
Published: April 2021

The genus Silene L. is one of the largest genera in Caryophyllaceae, and is distributed in the Northern Hemisphere and South America. The endemic species Silene leucophylla and the near-endemic S. schimperiana are native to the Sinai Peninsula, Egypt. They have reduced population size and are endangered on national and international scales. These two species have typically been disregarded in most studies of the genus Silene. This research integrates the Scanning Electron Microscope (SEM), species micromorphology, and the phylogenetic analysis of four DNA markers: ITS, matK, rbcL and psb-A/trn-H. Trichomes were observed on the stem of Silene leucophylla, while the S. schimperiana has a glabrous stem. Irregular epicuticle platelets with sinuate margin were found in S. schimperiana. Oblong, bone-shaped, and irregularly arranged epidermal cells were present on the leaf of S. leucophylla, while Silene schimperiana leaf has “tetra-, penta-, hexa-, and polygonal” epidermal cells. Silene leucophylla and S. schimperiana have amphistomatic stomata. The Bayesian phylogenetic analysis of each marker individually or in combination represented the first phylogenetic study to reveal the generic and sectional classification of S. leucophylla and S. schimperiana. Two Silene complexes are proposed based on morphological and phylogenetic data. The Leucophylla complex was allied to section Siphonomorpha and the Schimperiana complex was related to section Sclerocalycinae. However, these two complexes need further investigation and more exhaustive sampling to infer their complex phylogenetic relationships.
Terrestrial Morphotypes of Aquatic Plants Display Improved Seed Germination to Deal with Dry or Low-Rainfall Periods
Authors: Fernández-Zamudio Rocío , García-Murillo Pablo , Díaz-Paniagua Carmen
Published: April 2021

In temporary ponds, seed germination largely determines how well aquatic plant assemblages recover after dry periods. Some aquatic plants have terrestrial morphotypes that can produce seeds even in dry years. Here, we performed an experiment to compare germination patterns for seeds produced by aquatic and terrestrial morphotypes of Ranunculus peltatus subsp. saniculifolius over the course of five inundation events. During the first inundation event, percent germination was higher for terrestrial morphotype seeds (36.1%) than for aquatic morphotype seeds (6.1%). Seed germination peaked for both groups during the second inundation event (terrestrial morphotype: 47%; aquatic morphotype: 34%). Even after all five events, some viable seeds had not yet germinated (terrestrial morphotype: 0.6%; aquatic morphotype: 5%). We also compared germination patterns for the two morphotypes in Callitriche brutia: the percent germination was higher for terrestrial morphotype seeds (79.5%) than for aquatic morphotype seeds (41.9%). Both aquatic plant species use two complementary strategies to ensure population persistence despite the unpredictable conditions of temporary ponds. First, plants can produce seeds with different dormancy periods that germinate during different inundation periods. Second, plants can produce terrestrial morphotypes, which generate more seeds during dry periods, allowing for re-establishment when conditions are once again favorable.
Design a Database of Italian Vascular Alimurgic Flora (AlimurgITA): Preliminary Results
Authors: Paura Bruno , Di Marzio Piera , Salerno Giovanni , Brugiapaglia Elisabetta , Bufano Annarita
Published: April 2021

Despite the large number of data published in Italy on WEPs, there is no database providing a complete knowledge framework. Hence the need to design a database of the Italian alimurgic flora: AlimurgITA. Only strictly alimurgic taxa were chosen, excluding casual alien and cultivated ones. The collected data come from an archive of 358 texts (books and scientific articles) from 1918 to date, chosen with appropriate criteria. For each taxon, the part of the plant used, the method of use, the chorotype, the biological form and the regional distribution in Italy were considered. The 1103 taxa of edible flora already entered in the database equal 13.09% of Italian flora. The most widespread family is that of the Asteraceae (20.22%); the most widely used taxa are Cichorium intybus and Borago officinalis. The not homogeneous regional distribution of WEPs (maximum in the south and minimum in the north) has been interpreted. Texts published reached its peak during the 2001–2010 decade. A database for Italian WEPs is important to have a synthesis and to represent the richness and complexity of this knowledge, also in light of its potential for cultural enhancement, as well as its applications for the agri-food system.