bluuebunny/crossref_metadata_2025 huggingface dataset:
Orphan Nuclear Receptor RORγ Modulates the Genome-Wide Binding of the Cholesterol Metabolic Genes during Mycotoxin-Induced Liver Injury
Authors: Li Kaiqi , Li Hao , Zhang Kexin , Zhang Jinying , Hu Ping , Li Yanwei , Gu Haotian , Liu Hao-Yu , Yang Zhangping , Cai Demin
Published: July 2021

Maintaining lipid homeostasis is crucial to liver function, the key organ that governs the whole-body energy metabolism. In contrast, lipid dysregulation has been implicated in mycotoxin-induced liver injury, by which the pathophysiological regulation and the molecular components involved remain elusive. Here we focused on the potential roles of orphan nuclear receptor (NR) RORγ in lipid programming, and aimed to explore its action on cholesterol regulation in the liver of mycotoxin-exposed piglets. We found that liver tissues were damaged in the mycotoxin-exposed piglets compared to the healthy controls, revealed by histological analysis, elevated seral ALT, AST and ALP levels, and increased caspase 3/7 activities. Consistent with the transcriptomic finding of down-regulated cholesterol metabolism, we demonstrated that both cholesterol contents and cholesterol biosynthesis/transformation gene expressions in the mycotoxin-exposed livers were reduced, including HMGCS1, FDPS, SQLE, EBP, FDFT1 and VLDLR. Furthermore, we reported that RORγ binds to the cholesterol metabolic genes in porcine hepatocytes using a genome-wide ChIP-seq analysis, whereas mycotoxin decreased the RORγ binding occupancies genome-wide, especially at the cholesterol metabolic pathway. In addition, we revealed the enrichment of co-factors p300 and SRC, the histone marks H3K27ac and H3K4me2, together with RNA Polymerase II (Pol-II) at the locus of HMGCS1 in hepatocytes, which were reduced by mycotoxin-exposure. Our results provide a deep insight into the cholesterol metabolism regulation during mycotoxin-induced liver injury, and propose NRs as therapeutic targets for anti-mycotoxin treatments.
Exosome-Mediated Activation of Neuronal Cells Triggered by γ-Aminobutyric Acid (GABA)
Authors: Inotsuka Ryo , Udono Miyako , Yamatsu Atsushi , Kim Mujo , Katakura Yoshinori
Published: July 2021

γ-Aminobutyric acid (GABA) is a potent bioactive amino acid, and several studies have shown that oral administration of GABA induces relaxation, improves sleep, and reduces psychological stress and fatigue. In a recent study, we reported that exosomes derived from GABA-treated intestinal cells serve as signal transducers that mediate brain–gut interactions. Therefore, the purpose of this study was to verify the functionality of GABA-derived exosomes and to examine the possibility of improving memory function following GABA administration. The results showed that exosomes derived from GABA-treated intestinal cells (Caco-2) activated neuronal cells (SH-SY5Y) by regulating genes related to neuronal cell functions. Furthermore, we found that exosomes derived from the serum of GABA-treated mice also activated SH-SY5Y cells, indicating that exosomes, which are capable of activating neuronal cells, circulate in the blood of mice orally administered GABA. Finally, we performed a microarray analysis of mRNA isolated from the hippocampus of mice that were orally administered GABA. The results revealed changes in the expression of genes related to brain function. Gene Set Enrichment Analysis (GSEA) showed that oral administration of GABA affected the expression of genes related to memory function in the hippocampus.
Macular Pigment Reflectometry: Developing Clinical Protocols, Comparison with Heterochromatic Flicker Photometry and Individual Carotenoid Levels
Authors: Davey Pinakin Gunvant , Rosen Richard B. , Gierhart Dennis L.
Published: July 2021

The study was designed to: (1) Analyze and create protocols of obtaining measurements using the Macular Pigment Reflectometry (MPR). (2) To assess the agreement of MPOD measurements obtained using the heterochromatic flicker photometry (MPS II) and MPR. (3) To obtain the lutein and zeaxanthin optical density obtained using the MPR in the central one-degree of the macula. The measurements were performed using the MPR and heterochromatic flicker photometry. The MPR measurements were performed twice without pupillary dilation and twice following pupillary dilation. The MPR measurements were performed for a 40-s period and the spectrometer signal was parsed at different time points: 10–20, 10–30, 10–40, 20–30, 20–40, and 30–40 s. The MPR analyzes the high-resolution spectrometer signal and calculates MPOD, lutein optical density and zeaxanthin optical density automatically. The MPR-MPOD data was compared with MPPS II-MPOD results. The MPR-MPOD values are highly correlated and in good agreement with the MPS II-MPOD. Of the various parsing of the data, the data 10–30 interval was the best at obtaining the MPOD, lutein, and zeaxanthin values (8–12% coefficient of repeatability). The lutein to zeaxanthin ratio in the central one-degree of the macula was 1:2.40. Dilation was not needed to obtain the MPOD values but provided better repeatability of lutein and zeaxanthin optical density. MPR generates MPOD measurements that is in good agreement with MPS II. The device can produce lutein and zeaxanthin optical density which is not available from other clinical devices.
Oat and Barley in the Food Supply and Use of Beta Glucan Health Claims
Authors: Hughes Jaimee , Grafenauer Sara
Published: July 2021

Beta glucan is a type of soluble dietary fibre found in oats and barley with known cholesterol-lowering benefits. Many countries globally have an approved beta glucan health claim related to lowering blood cholesterol, an important biomarker for cardiovascular disease. However, the use of these claims has not been examined. The aim of this study was to explore the range and variety of oat and barley products in the Australian and global market within a defined range of grain food and beverage categories and examine the frequency of beta glucan health claims. Australian data were collected via a recognised nutrition audit process from the four major Australian supermarkets in metropolitan Sydney (January 2018 and September 2020) and Mintel Global New Product Database was used for global markets where a claim is permitted. Categories included breakfast cereals, bread, savoury biscuits, grain-based muesli bars, flour, noodles/pasta and plant-based milk alternatives and information collected included ingredients lists and nutrition and health claims. Products from Australia (n = 2462) and globally (n = 44,894) were examined. In Australia, 37 products (1.5%) made use of the beta glucan claim (84% related to oat beta glucan and 16% related to barley beta glucan, specifically BARLEYmax®). Of products launched globally, 0.9% (n = 403) displayed beta glucan cholesterol-lowering claims. Despite the number of products potentially eligible to make beta glucan claims, their use in Australia and globally is limited. The value of dietary modification in cardiovascular disease treatment and disease progression deserves greater focus, and health claims are an opportunity to assist in communicating the role of food in the management of health and disease. Further assessment of consumer understanding of the available claims would be of value.
Genetically Higher Level of Mannose Has No Impact on Cardiometabolic Risk Factors: Insight from Mendelian Randomization
Authors: Mazidi Mohsen , Dehghan Abbas , Banach Maciej ,   on behalf of the Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group and the International Lipid Expert Panel (ILEP)
Published: July 2021

Background: There is a handful of controversial data from observational studies on the serum levels of mannose and risks of coronary artery disease (CAD) and other cardiometabolic risk factors. We applied Mendelian Randomization (MR) analysis to obtain estimates of the causal effect of serum mannose on the risk of CAD and on cardiometabolic risk factors. Methods: Two-sample MR was implemented by using summary-level data from the largest genome-wide association studies (GWAS) conducted on serum mannose and CAD and cardiometabolic risk factors. The inverse variance weighted method (IVW) was used to estimate the effects, and a sensitivity analysis including the weighted median (WM)-based method, MR-Egger, MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied. Radial MR Methods was applied to remove outliers subject to pleiotropic bias. We further conducted a leave-one-out analysis. Results: Mannose had no significant effect on CAD (IVW: odds ratio: 0.96 (95% Confidence Interval (95%CI): 0.71−1.30)), total cholesterol (TC) (IVW: 95%CI: 0.60−1.08), low density lipoprotein (LDL) (IVW: 95%CI = 0.68−1.15), high density lipoprotein (HDL) (IVW: 95%CI = 0.85−1.20), triglycerides (TG) (IVW: 95%CI = 0.38−1.08), waist circumference (WC) (IVW: 95%CI = 0.94−1.37), body mass index (BMI) (IVW: 95%CI = 0.93−1.29) and fasting blood glucose (FBG) (IVW: 95%CI = 0.92−1.33), with no heterogeneity for CAD, HDL, WC and BMI (all p > 0.092), while a significant heterogeneity was observed for TC (IVW: Q = 44.503), LDL (IVW: Q = 33.450), TG (IVW: Q = 159.645) and FBG (IVW: Q = 0. 32.132). An analysis of MR-PRESSO and radial plots did not highlight any outliers. The results of the leave-one-out method demonstrated that the links were not driven by a single instrument. Conclusions: We did not find any effect of mannose on adiposity, glucose, TC, LDL, TG and CAD.
Ketogenic Diet, Physical Activity, and Hypertension—A Narrative Review
Authors: Di Raimondo Domenico , Buscemi Silvio , Musiari Gaia , Rizzo Giuliana , Pirera Edoardo , Corleo Davide , Pinto Antonio , Tuttolomondo Antonino
Published: July 2021

Several studies link cardiovascular diseases (CVD) with unhealthy lifestyles (unhealthy dietary habits, alcohol consumption, smoking, and low levels of physical activity). Therefore, the strong need for CVD prevention may be pursued through an improved control of CVD risk factors (impaired lipid and glycemic profiles, high blood pressure, and obesity), which is achievable through an overall intervention aimed to favor a healthy lifestyle. Focusing on diet, different recommendations emphasize the need to increase or avoid consumption of entire classes of food, with only partly known and only partly foreseeable consequences on the overall level of health. In recent years, the ketogenic diet (KD) has been proposed to be an effective lifestyle intervention for metabolic syndrome, and although the beneficial effects on weight loss and glucose metabolism seems to be well established, the effects of a prolonged KD on the ability to perform different types of exercise and the influence of KD on blood pressure (BP) levels, both in normotensives and in hypertensives, are not so well understood. The objective of this review is to analyze, on the basis of current evidence, the relationship between KD, regular physical activity, and BP.
Menaquinone 4 Reduces Bone Loss in Ovariectomized Mice through Dual Regulation of Bone Remodeling
Authors: Wang Huakai , Zhang Nan , Li Longxian , Yang Pan , Ma Yongxi
Published: July 2021

Epidemiologic studies showed that higher vitamin K (VK) consumption correlates with a reduced risk of osteoporosis, yet the dispute remains about whether VK is effective in improving bone mineral density (BMD). We sought to discover the anti-osteoporotic effect of menaquinone-4 (MK-4) and evaluate the expression of critical genes related to bone formation and bone resorption pathways in the body. Fifty female C57BL/6 mice (aged 13 weeks) were randomly arranged to a sham-operated group (SHAM, treated with corn oil) and four ovariectomized groups that were administered corn oil (OVX group), estradiol valerate (EV, 2 mg/kg body weight as the positive control), low or high doses of VK (LVK and HVK; 20 and 40 mg MK-4/kg body weight, respectively) by gavage every other day for 12 weeks. Body and uterine weight, serum biochemical indicators, bone microarchitecture, hematoxylin-eosin (HE) staining, and the mRNA expression of critical genes related to bone formation and bone resorption pathways were assessed. Either dose of MK-4 supplementation increased the alkaline phosphatase (ALP), decreased the undercarboxylated osteocalcin (ucOC) and tartrate-resistant acid phosphatase (TRACP, p < 0.05) levels, and presented higher BMD, percent bone volume (BV/TV), trabecular thickness (Tb.Th), and lower trabecular separation (Tb.Sp) and structure model index (SMI, p < 0.05) compared with the OVX group. Additionally, both doses of MK4 increased the mRNA expression of Runx2 and Bmp2 (p < 0.05), whereas the doses down-regulated Pu.1 and Nfatc1 (p < 0.05) mRNA expression, the high dose decreased Osx and Tgfb (p < 0.05) mRNA expression, and the low dose decreased Mitd and Akt1 (p < 0.05) mRNA expression. These data show the dual regulatory effects of MK-4 on bone remodeling in ovariectomized mice: the promotion of bone anabolic activity and inhibition of osteoclast differentiation, which provides a novel idea for treating osteoporosis.
The Relationship between Music and Food Intake: A Systematic Review and Meta-Analysis
Authors: Cui Tianxiang , Xi Jiaxuan , Tang Chanyuan , Song Jianwen , He Jinbo , Brytek-Matera Anna
Published: July 2021

Food intake has been shown to be related to several environmental factors including the presence of music. However, previous findings of the relationship between music and food intake are inconsistent. In the present study, a systematic review and meta-analysis was conducted to quantitatively review the extent to which music is associated with food intake as well as to investigate potential moderators that might have contributed to the heterogeneity of the existing findings. Literature was searched on four databases (i.e., PsycINFO, Web of Science, PubMed, and ProQuest Dissertations and Theses) and Google Scholar. Nine articles published from 1989 to 2020 met our inclusion criteria. A meta-analysis was carried out via a three-level random-effects model. The overall effect size (i.e., Hedges’ g) was 0.19 (95% Confidence Interval: −0.003, 0.386; SE = 0.10, t = 1.99, p = 0.054), indicating a marginally significant but small effect size. Body Mass Index (F(1, 21) = 5.11, p = 0.035) was found to significantly contribute to the heterogeneity of effect sizes, with larger positive effects of music on food intake for individuals with higher BMI. However, music-related features did not significantly moderate the relationship between music and food intake. More experimental studies are needed to update the current meta-analysis and get a better understanding of this topic.
Diet, Sleep, and Mental Health: Insights from the UK Biobank Study
Authors: Hepsomali Piril , Groeger John A.
Published: July 2021

Diet has long been the focus of attention as a leading risk factor for non-communicable diseases. As such, a better understanding of it is crucial to establish priorities for dietary guidelines and to inform, design, and implement strategies for preventing, helping manage, and stopping the progression of sleep and mental health-related symptoms/disorders. The aim of the current study is to conduct the largest investigation of diet, sleep, and mental health to date by utilizing the UK Biobank (UKB) dataset to identify the associations between diet and (i) sleep quality/health, and (ii) mental health symptomatology. This cross-sectional population-based study involved 502,494 middle-aged adults. UKB food frequency, sleep, and psychological factors and mental health questionnaires at baseline were used. Scores were also calculated for healthy diet, healthy sleep, mental health symptomatology, partial fibre intake, and milk intake. We observed positive associations with healthy diet and sleep and mental health, especially benefits of high intakes of vegetable, fruit, fish, water, and fibre. However, processed meat and milk intake were adversely associated with sleep and mental health. These findings make clear that there are health and wellbeing benefits and drawbacks of different diets, but do not, at this stage, demonstrate the clear causal relationships, which would support dietary interventions that might play a role in the treatment and also self-management of sleep and mental health disorders/symptoms. Further research is required to understand mechanisms of actions of which diet acts on to modulate sleep and mental health, while taking comorbidity of sleep and mental health disorders/symptoms into consideration.
The Effect of Hemp (Cannabis sativa L.) Seeds and Hemp Seed Oil on Vascular Dysfunction in Obese Male Zucker Rats
Authors: Majewski Michał , Jurgoński Adam
Published: July 2021

Seeds of industrial hemp (Cannabis sativa L.) contain a large amount of protein (26.3%), dietary fiber (27.5%), and fatty acids (33.2%), including linoleic, α-linolenic, and some amount of γ-linolenic acid. In our study, obese male Zucker rats (n = 6) at 8 weeks of age were supplemented for a further 4 weeks with either ground hemp seeds (12% diet) or lipid fractions in the form of hemp seed oil (4% diet). Hemp oil decreased blood plasma HDL-cholesterol (x0.76, p ≤ 0.0001), triglycerides (x0.55, p = 0.01), and calculated atherogenic parameters. Meanwhile, hemp seeds decreased HDL-cholesterol (x0.71, p ≤ 0.0001) and total cholesterol (x0.81, p = 0.006) but not the atherogenic index. The plasma antioxidant capacity of water-soluble compounds was decreased by the seeds (x0.30, p = 0.0015), which in turn was associated with a decrease in plasma uric acid (x0.18, p = 0.03). Dietary hemp seeds also decreased plasma urea (x0.80, p = 0.02), while the oil decreased the plasma total protein (x0.90, p = 0.05). Hemp seeds and the oil decreased lipid peroxidation in the blood plasma and in the heart (reflected as malondialdehyde content), improved contraction to noradrenaline, and up-regulated the sensitivity of potassium channels dependent on ATP and Ca2+. Meanwhile, acetylcholine-induced vasodilation was improved by hemp seeds exclusively. Dietary supplementation with ground hemp seeds was much more beneficial than the oil, which suggests that the lipid fractions are only partially responsible for this effect.
Inflammation Markers in Adipose Tissue and Cardiovascular Risk Reduction by Pomegranate Juice in Obesity Induced by a Hypercaloric Diet in Wistar Rats
Authors: Michicotl-Meneses Maria Monica , Thompson-Bonilla María del Rocío , Reyes-López César A. , García-Pérez Blanca Estela , López-Tenorio Itzel I. , Ordaz-Pichardo Cynthia , Jaramillo-Flores María Eugenia
Published: July 2021

Pomegranate juice (Punica granatum) has been used since ancient times in traditional medicine (Unani Medicine, Ayurveda); its main compounds are anthocyanins and ellagic acid, which have anti-inflammatory, antioxidant, hepatoprotective, and cardiovascular health effects. The objective was to evaluate the effect of pomegranate juice on inflammation, blood pressure, and vascular and physiological markers associated with obesity induced by a high-fat diet in a murine model. The results show that pomegranate juice reduces the concentration of low-density lipoprotein cholesterol (cLDL) 39% and increases the concentration of high-density lipoprotein cholesterol (cHDL) by 27%, leading to a 12%–18% decrease in the risk of cardiovascular diseases (CVD). In addition to reducing blood pressure by 24%, it also had an antiatherogenic effect by decreasing sE-selectin levels by 42%. On the other hand, the juice significantly increased adiponectin levels in adipose tissue, decreased levels of inflammation markers (tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor-1 (PAI-1), interleukin-17A (IL-17A), interleukin-6 (IL-6), interleukin-1β (IL-1β)), and inhibited the monocyte chemoattractant protein-1 (MCP-1). Pomegranate juice requires clinical studies to prove its immunoregulatory and therapeutic effects on cardiovascular and atherogenic risks.
Intravenous Vitamin K1 for the Correction of Prolonged Prothrombin Times in Non-Bleeding Critically Ill Patients: A Prospective Observational Study
Authors: Dahlberg Sofia , Schött Ulf , Eriksson Emilia Ängeby , Tahirsylaj Yllnor , Schurgers Leon , Kander Thomas
Published: July 2021

The aim of this study was to evaluate the effects of vitamin K1 on various vitamin K-dependent proteins in critically ill patients with prolonged Owren PT. We included critically ill non-bleeding adult patients without liver failure or anticoagulation treatment, with Owren PT > 1.2, who were prescribed intravenous vitamin K1. Blood was drawn at baseline and at 20–28 h after vitamin K1 administration. At both time points, we measured various vitamin K-dependent proteins and coagulation assays. ClinicalTrials.gov; Identifier: NTC3782025. In total, 52 patients were included. Intravenous vitamin K1 reduced Owren PT, Quick PT, protein induced by vitamin K absence/antagonist-II and desphospho-uncarboxylated matrix Gla protein (dp-ucMGP), but not to normal levels. Concomitantly, there were increases in thrombin generation and the activity of coagulation factors II, VII, IX and X that was only counteracted with a small increase in Protein C activity. In conclusion, the results suggest that vitamin K1 strengthens coagulation as measured by PT decrease and increases in the activity of vitamin K-dependent clotting factors and thrombin generation. The decreased dp-ucMGP, and its potential positive short- and long-term non-coagulative effects, merits further research.
Do Gut Microbes Taste?
Authors: Leung Ryan , Covasa Mihai
Published: July 2021

Gut microbiota has emerged as a major metabolically active organ with critical functions in both health and disease. The trillions of microorganisms hosted by the gastrointestinal tract are involved in numerous physiological and metabolic processes including modulation of appetite and regulation of energy in the host spanning from periphery to the brain. Indeed, bacteria and their metabolic byproducts are working in concert with the host chemosensory signaling pathways to affect both short- and long-term ingestive behavior. Sensing of nutrients and taste by specialized G protein-coupled receptor cells is important in transmitting food-related signals, optimizing nutrition as well as in prevention and treatment of several diseases, notably obesity, diabetes and associated metabolic disorders. Further, bacteria metabolites interact with specialized receptors cells expressed by gut epithelium leading to taste and appetite response changes to nutrients. This review describes recent advances on the role of gut bacteria in taste perception and functions. It further discusses how intestinal dysbiosis characteristic of several pathological conditions may alter and modulate taste preference and food consumption via changes in taste receptor expression.
Implementation of Adenovirus-Mediated Pulmonary Expression of Human ACE2 in HLA Transgenic Mice Enables Establishment of a COVID-19 Murine Model for Assessment of Immune Responses to SARS-CoV-2 Infection
Authors: Chitlaru Theodor , Bar-Haim Erez , Bar-On Liat , Rotem Shahar , Cohen Hila , Elia Uri , Gur David , Aftalion Moshe , Alkalay Ron , Makdasi Efi , Evgy Yentl , Falach Reut , Israeli Ma’ayan , Bercovich-Kinori Adi , Achdout Hagit , Yahalom-Ronen Yfat , Rosenfeld Ronit , Cohen Ofer
Published: July 2021

HLA transgenic mice are instrumental for evaluation of human-specific immune responses to viral infection. Mice do not develop COVID-19 upon infection with SARS-CoV-2 due to the strict tropism of the virus to the human ACE2 receptor. The aim of the current study was the implementation of an adenovirus-mediated infection protocol for human ACE2 expression in HLA transgenic mice. Transient pulmonary expression of the human ACE2 receptor in these mice results in their sensitisation to SARS-CoV-2 infection, consequently providing a valuable animal model for COVID-19. Infection results in a transient loss in body weight starting 3 days post-infection, reaching 20–30% loss of weight at day 7 and full recovery at days 11–13 post-infection. The evolution of the disease revealed high reproducibility and very low variability among individual mice. The method was implemented in two different strains of HLA immunized mice. Infected animals developed strong protective humoral and cellular immune responses specific to the viral spike-protein, strictly depending on the adenovirus-mediated human ACE2 expression. Convalescent animals were protected against a subsequent re-infection with SARS-CoV-2, demonstrating that the model may be applied for assessment of efficacy of anti-viral immune responses.
A Pilot Study on the Microbiome of Amblyomma hebraeum Tick Stages Infected and Non-Infected with Rickettsia africae
Authors: Kisten Dalicia , Brinkerhoff Jory , Tshilwane Selaelo Ivy , Mukaratirwa Samson
Published: July 2021

Variation in tick microbiota may affect pathogen acquisition and transmission but for many vector species, including Amblyomma hebraeum, components and determinants of the microbiome are unidentified. This pilot study aimed to determine baseline microbial community within A. hebraeum nymphs infected- and non-infected with Rickettsia africae from the environment, and within adult ticks infected- and non-infected with R. africae collected from cattle sampled from two locations in the Eastern Cape province of South Africa. Adult A. hebraeum ticks (N = 13) and A. hebraeum nymph (N = 15) preliminary screened for R. africae were randomly selected and subjected to Illumina sequencing targeting the v3–v4 hypervariable regions of the 16S rRNA gene. No significant difference in microbial community composition, as well as rarefied OTU richness and diversity were detected between adults and nymphs. Nymphs showed a higher richness of bacterial taxa indicating blood-feeding could have resulted in loss of microbial diversity during the moulting stage from nymph to adult. Core OTUs that were in at least 50% of nymphs and adults negative and positive for Rickettsia at 1% minimum relative abundance were Rickettsia, Coxiella and Ruminococcaceae UCG-005 with a single genus Arsenophonus occurring only in nymphs negative for Rickettsia. Ehrlichia spp. was present in only four nymphal ticks positive for Rickettsia. Interestingly, Rickettsia aeschlimannii was found in one nymph and one adult, indicating the first ever detection of the species in A. hebraeum. Furthermore, A. hebraeum harboured a Coxiella-like endosymbiont, which should be investigated further as Coxiella may affect the viability and transmission of other organisms.
Characterisation of Antiviral Activity of Cathelicidins from Naked Mole Rat and Python bivittatus on Human Herpes Simplex Virus 1
Authors: Damour Alexia , Garcia Magali , Cho Hye-Sun , Larivière Andy , Lévêque Nicolas , Park Chankyu , Bodet Charles
Published: July 2021

Hg-CATH and Pb-CATH4 are cathelicidins from Heterocephalus glaber and Python bivittatus that have been previously identified as potent antibacterial peptides. However, their antiviral properties were not previously investigated. In this study, their activity against the herpes simplex virus (HSV)-1 was evaluated during primary human keratinocyte infection. Both of them significantly reduced HSV-1 DNA replication and production of infectious viral particles in keratinocytes at noncytotoxic concentrations, with the stronger activity of Pb-CATH4. These peptides did not show direct virucidal activity and did not exhibit significant immunomodulatory properties, except for Pb-CATH4, which exerted a moderate proinflammatory action. All in all, our results suggest that Hg-CATH and Pb-CATH4 could be potent candidates for the development of new therapies against HSV-1.
Carica papaya Leaf Extract Silver Synthesized Nanoparticles Inhibit Dengue Type 2 Viral Replication In Vitro
Authors: Bere Antonia Windkouni , Mulati Omuyundo , Kimotho James , Ng’ong’a Florence
Published: July 2021

The current global occurrence of dengue infection annually is approximately 400 million, with a case fatality rate of 2.5%. However, there are no antiviral agents. Carica papaya leaf extract is known for its medicinal value, due to the presence of organic compounds that possess antimicrobial, anti-inflammatory, and antioxidant activities. This study determined the anti-dengue effect of C. papaya leaf extract silver synthesized nanoparticles. In this study, aqueous and non-aqueous extractions were carried out, followed by the synthesis of silver nanoparticles as well as characterization through Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy. The in vitro anti-dengue effect was evaluated using a focus reduction neutralization test on kidney Vero E2 cell lines. In silico studies involved molecular docking to determine the potential interactions between the bioactive compounds in C. papaya leaf extract and the viral NS5 protein. C. papaya leaf methanol extract silver synthesized nanoparticle was the most promising with an IC50 of 9.20 µg/mL. Molecular docking showed 5,7 dimethoxycoumarin as the best ligand, with binding energy of −7.75 kcal/mol, indicating high affinity for the NS5 protein. These results highlight that C. papaya leaf methanol extract silver synthesized nanoparticles could be used to inhibit dengue virus type 2 viral replication. However, we recommend further studies to determine their toxicity and the safety profiles.
Pulmonary Delivery of Anticancer Drugs via Lipid-Based Nanocarriers for the Treatment of Lung Cancer: An Update
Authors: Abdulbaqi Ibrahim M. , Assi Reem Abou , Yaghmur Anan , Darwis Yusrida , Mohtar Noratiqah , Parumasivam Thaigarajan , Saqallah Fadi G. , Wahab Habibah A.
Published: July 2021

Lung cancer (LC) is the leading cause of cancer-related deaths, responsible for approximately 18.4% of all cancer mortalities in both sexes combined. The use of systemic therapeutics remains one of the primary treatments for LC. However, the therapeutic efficacy of these agents is limited due to their associated severe adverse effects, systemic toxicity and poor selectivity. In contrast, pulmonary delivery of anticancer drugs can provide many advantages over conventional routes. The inhalation route allows the direct delivery of chemotherapeutic agents to the target LC cells with high local concertation that may enhance the antitumor activity and lead to lower dosing and fewer systemic toxicities. Nevertheless, this route faces by many physiological barriers and technological challenges that may significantly affect the lung deposition, retention, and efficacy of anticancer drugs. The use of lipid-based nanocarriers could potentially overcome these problems owing to their unique characteristics, such as the ability to entrap drugs with various physicochemical properties, and their enhanced permeability and retention (EPR) effect for passive targeting. Besides, they can be functionalized with different targeting moieties for active targeting. This article highlights the physiological, physicochemical, and technological considerations for efficient inhalable anticancer delivery using lipid-based nanocarriers and their cutting-edge role in LC treatment.
Just a Reflection: Does Drug Repurposing Perpetuate Sex-Gender Bias in the Safety Profile?
Authors: Campesi Ilaria , Racagni Giorgio , Franconi Flavia
Published: July 2021

Vaccines constitute a strategy to reduce the burden of COVID-19, but the treatment of COVID-19 is still a challenge. The lack of approved drugs for severe COVID-19 makes repurposing or repositioning of approved drugs a relevant approach because it occurs at lower costs and in a shorter time. Most preclinical and clinical tests, including safety and pharmacokinetic profiles, were already performed. However, infective and inflammatory diseases such as COVID-19 are linked with hypoalbuminemia and downregulation of both phase I and phase II drug-metabolizing enzymes and transporters, which can occur in modifications of pharmacokinetics and consequentially of safety profiles. This appears to occur in a sex- and gender-specific way because of the sex and gender differences present in the immune system and inflammation, which, in turn, reflect on pharmacokinetic parameters. Therefore, to make better decisions about drug dosage regimens and to increases the safety profile in patients suffering from infective and inflammatory diseases such as COVID-19, it is urgently needed to study repurposing or repositioning drugs in men and in women paying attention to pharmacokinetics, especially for those drugs that are previously scarcely evaluated in women.
The Cysteine-Containing Cell-Penetrating Peptide AP Enables Efficient Macromolecule Delivery to T Cells and Controls Autoimmune Encephalomyelitis
Authors: Kim Won-Ju , Kim Gil-Ran , Cho Hyun-Jung , Choi Je-Min
Published: July 2021

T cells are key immune cells involved in the pathogenesis of several diseases, rendering them important therapeutic targets. Although drug delivery to T cells is the subject of continuous research, it remains challenging to deliver drugs to primary T cells. Here, we used a peptide-based drug delivery system, AP, which was previously developed as a transdermal delivery peptide, to modulate T cell function. We first identified that AP-conjugated enhanced green fluorescent protein (EGFP) was efficiently delivered to non-phagocytic human T cells. We also confirmed that a nine-amino acid sequence with one cysteine residue was the optimal sequence for protein delivery to T cells. Next, we identified the biodistribution of AP-dTomato protein in vivo after systemic administration, and transduced it to various tissues, such as the spleen, liver, intestines, and even to the brain across the blood–brain barrier. Next, to confirm AP-based T cell regulation, we synthesized the AP-conjugated cytoplasmic domain of CTLA-4, AP-ctCTLA-4 peptide. AP-ctCTLA-4 reduced IL-17A expression under Th17 differentiation conditions in vitro and ameliorated experimental autoimmune encephalomyelitis, with decreased numbers of pathogenic IL-17A+GM-CSF+ CD4 T cells. These results collectively suggest the AP peptide can be used for the successful intracellular regulation of T cell function, especially in the CNS.
Chronic Kidney Disease-Induced Arterial Media Calcification in Rats Prevented by Tissue Non-Specific Alkaline Phosphatase Substrate Supplementation Rather Than Inhibition of the Enzyme
Authors: Opdebeeck Britt , Neven Ellen , Millán José Luis , Pinkerton Anthony B. , D’Haese Patrick C. , Verhulst Anja
Published: July 2021

Patients with chronic kidney disease (CKD) suffer from arterial media calcification and a disturbed bone metabolism. Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes the calcification inhibitor pyrophosphate (PPi) into inorganic phosphate (Pi) and thereby stimulates arterial media calcification as well as physiological bone mineralization. This study investigates whether the TNAP inhibitor SBI-425, PPi or the combination of both inhibit arterial media calcification in an 0.75% adenine rat model of CKD. Treatments started with the induction of CKD, including (i) rats with normal renal function (control diet) treated with vehicle and CKD rats treated with either (ii) vehicle, (iii) 10 mg/kg/day SBI-425, (iv) 120 µmol/kg/day PPi and (v) 120 µmol/kg/day PPi and 10 mg/kg/day SBI-425. All CKD groups developed a stable chronic renal failure reflected by hyperphosphatemia, hypocalcemia and high serum creatinine levels. CKD induced arterial media calcification and bone metabolic defects. All treatments, except for SBI-425 alone, blocked CKD-related arterial media calcification. More important, SBI-425 alone and in combination with PPi increased osteoid area pointing to a less efficient bone mineralization. Clearly, potential side effects on bone mineralization will need to be assessed in any clinical trial aimed at modifying the Pi/PPi ratio in CKD patients who already suffer from a compromised bone status.
Functional Duality of Chondrocyte Hypertrophy and Biomedical Application Trends in Osteoarthritis
Authors: Park Sunghyun , Bello Alvin , Arai Yoshie , Ahn Jinsung , Kim Dohyun , Cha Kyung-Yup , Baek Inho , Park Hansoo , Lee Soo-Hong
Published: July 2021

Chondrocyte hypertrophy is one of the key indicators in the progression of osteoarthritis (OA). However, compared with other OA indications, such as cartilage collapse, sclerosis, inflammation, and protease activation, the mechanisms by which chondrocyte hypertrophy contributes to OA remain elusive. As the pathological processes in the OA cartilage microenvironment, such as the alterations in the extracellular matrix, are initiated and dictated by the physiological state of the chondrocytes, in-depth knowledge of chondrocyte hypertrophy is necessary to enhance our understanding of the disease pathology and develop therapeutic agents. Chondrocyte hypertrophy is a factor that induces OA progression; it is also a crucial factor in the endochondral ossification. This review elaborates on this dual functionality of chondrocyte hypertrophy in OA progression and endochondral ossification through a description of the characteristics of various genes and signaling, their mechanism, and their distinguishable physiological effects. Chondrocyte hypertrophy in OA progression leads to a decrease in chondrogenic genes and destruction of cartilage tissue. However, in endochondral ossification, it represents an intermediate stage at the process of differentiation of chondrocytes into osteogenic cells. In addition, this review describes the current therapeutic strategies and their mechanisms, involving genes, proteins, cytokines, small molecules, three-dimensional environments, or exosomes, against the OA induced by chondrocyte hypertrophy. Finally, this review proposes that the contrasting roles of chondrocyte hypertrophy are essential for both OA progression and endochondral ossification, and that this cellular process may be targeted to develop OA therapeutics.
Photodynamic Therapy and Hyperthermia in Combination Treatment—Neglected Forces in the Fight against Cancer
Authors: Bienia Aleksandra , Wiecheć-Cudak Olga , Murzyn Aleksandra Anna , Krzykawska-Serda Martyna
Published: July 2021

Cancer is one of the leading causes of death in humans. Despite the progress in cancer treatment, and an increase in the effectiveness of diagnostic methods, cancer is still highly lethal and very difficult to treat in many cases. Combination therapy, in the context of cancer treatment, seems to be a promising option that may allow minimizing treatment side effects and may have a significant impact on the cure. It may also increase the effectiveness of anti-cancer therapies. Moreover, combination treatment can significantly increase delivery of drugs to cancerous tissues. Photodynamic therapy and hyperthermia seem to be ideal examples that prove the effectiveness of combination therapy. These two kinds of therapy can kill cancer cells through different mechanisms and activate various signaling pathways. Both PDT and hyperthermia play significant roles in the perfusion of a tumor and the network of blood vessels wrapped around it. The main goal of combination therapy is to combine separate mechanisms of action that will make cancer cells more sensitive to a given therapeutic agent. Such an approach in treatment may contribute toward increasing its effectiveness, optimizing the cancer treatment process in the future.
Purification and Identification of Novel Antioxidant Peptides Isolated from Geoffroea decorticans Seeds with Anticoagulant Activity
Authors: Cotabarren Juliana , Ozón Brenda , Claver Santiago , Garcia-Pardo Javier , Obregón Walter David
Published: July 2021

Geoffroea decorticans is a xerophilous deciduous tree present in most arid forests of southern South America, which is commonly used in traditional medicine. The seeds of this tree have been previously investigated for their singular chemical composition, but their protein content has been poorly investigated. Herein, we report the isolation, purification, and characterization of a set of thermostable peptides derived from Geoffroea decorticans seeds (GdAPs) with strong antioxidant and anticoagulant activities. The most potent antioxidant peptides showed a half maximal inhibitory concentration (IC50) of 35.5 ± 0.3 µg/mL determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH). They also caused a dose-dependent prolongation of the aPTT clotting time with an IC50 value of ~82 µg/mL. Interestingly, MALDI-TOF/MS analysis showed the presence of three major peptides with low molecular weights of 2257.199 Da, 2717.165 Da, and 5422.002 Da. The derived amino-acid sequence of GdAPs revealed their unique structural features, exhibiting homology with various proteins present in the genome of Arachis hypogaea. All in all, our data suggest a direct applicability of GdAPs for pharmaceutical purposes.
Multivariate Analysis Approaches for Dimension and Shape Discrimination of Vitis vinifera Varieties
Authors: Kupe Muhammed , Sayinci Bahadır , Demir Bünyamin , Ercisli Sezai , Aslan Kürşat Alp , Gundesli Muhammet Ali , Baron Mojmir , Sochor Jiri
Published: July 2021

In this study, berry dimensions and shape traits, which are important for the design of the grape processing system and the classification of 10 different grape varieties grown in same ecological conditions (‘Ata Sarısı’, ‘Barış’, ‘Dımışkı’, ‘Hatun Parmağı’, ‘Helvani’, ‘Horoz Karası’, ‘Hönüsü’, ‘İtalia’, ‘Mevlana Sarısı’, and ‘Red Globe’) were determined; differences between the varieties were identified with the use of discriminant analysis. The largest grape varieties were identified as ‘Ata Sarısı’ and ‘Red Globe’. The ‘Red Globe’ and ‘Helvani’ varieties had geometrically sphere-like shape. The ‘Barış’ variety had the lowest size averages. According to elliptic Fourier analysis, the primary source of shape variation was ellipse and sphere-looking varieties. However, shape variation was seen due to the existence of a small number of drop-like varieties. According to discriminant analysis, shape differences of the varieties were defined by two discriminant functions. Based on these discriminant functions, the greatest classification performance was achieved for ‘Mevlana Sarısı’ and ‘Dımışkı’. In scatter plots, three shape definitions (sphere, ellipse, and drop) were made for grape varieties. Cluster analysis revealed 4 sub-groups. The first sub-group included the ‘Mevlana Sarısı’ variety; the second sub-group included the ‘Hönüsü’, ‘Hatun Parmağı’, ‘Dımışkı’, and ‘Horoz Karası’ varieties; the third sub-group included the ‘Ata Sarısı’ variety; the fourth sub-group included the ‘Barış’, ‘Helvani’, ‘İtalia’, and ‘Red Globe’ varieties. The variety in the first group had a geometrically ellipse-like shape, the largest length, and the smallest width. The size data were the smallest for the second sub-group. The third sub-group, with the ellipse-like shape, had the large size data. The grape varieties the closest to the sphere were classified in the fourth group, and these varieties had the large sizes.
Discrimination of the Essential Oils Obtained from Four Apiaceae Species Using Multivariate Analysis Based on the Chemical Compositions and Their Biological Activity
Authors: Jamalova Dilafruz N. , Gad Haidy A. , Akramov Davlat K. , Tojibaev Komiljon S. , Musayeib Nawal M. Al , Ashour Mohamed L. , Mamadalieva Nilufar Z.
Published: July 2021

The chemical composition of the essential oils obtained from the aerial parts of four Apiaceae species, namely Elaeosticta allioides (EA), E. polycarpa (EP), Ferula clematidifolia (FC), and Hyalolaena intermedia (HI), were determined using gas chromatography. Altogether, 100 volatile metabolites representing 78.97, 81.03, 85.78, and 84.49% of the total components present in EA, EP, FC, and HI oils, respectively, were reported. allo-Ocimene (14.55%) was the major component in FC, followed by D-limonene (9.42%). However, in EA, germacrene D (16.09%) was present in a high amount, while heptanal (36.89%) was the predominant compound in HI. The gas chromatographic data were subjected to principal component analysis (PCA) to explore the correlations between these species. Fortunately, the PCA score plot could differentiate between the species and correlate Ferula to Elaeosticta species. Additionally, the antioxidant activity was evaluated in vitro using the 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), 2,2-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), and the ferric reducing power (FRAP) assays. In addition, the antimicrobial activity using the agar diffusion method was assessed, and the minimum inhibitory concentrations (MICs) were determined. Furthermore, the cell viability MTT assay was performed to evaluate the cytotoxicity of the essential oils against hepatic (HepG-2) and cervical (HeLa) cancer cell lines. In the DPPH assay, FC exhibited the maximum activity against all the antioxidant assays with IC50 values of 19.8 and 23.0 μg/mL for the DPPH and ABTS assays, respectively. Ferula showed superior antimicrobial and cytotoxic activities as well. Finally, a partial least square regression model was constructed to predict the antioxidant capacity by utilizing the metabolite profiling data. The model showed excellent predictive ability by applying the ABTS assay.
Crosslinking Behavior of UV-Cured Polyorganosilazane as Polymer-Derived Ceramic Precursor in Ambient and Nitrogen Atmosphere
Authors: Qazzazie-Hauser Afnan , Honnef Kirsten , Hanemann Thomas
Published: July 2021

Polymer-derived ceramics (PDCs) based on silicon precursor represent an outstanding material for ceramic coatings thanks to their extraordinary versatile processibility. A promising example of a silicone precursor, polyorganosilazane (Durazane 1800), was studied concerning its crosslinking behavior by mixing it with three different photoinitiators, and curing it by two different UV-LED sources under both nitrogen and ambient atmosphere. The chemical conversion during polymerization and pyrolysis was monitored by FTIR spectroscopy. Pyrolysis was performed in a nitrogen atmosphere at 950 °C. The results demonstrate that polyorganosilazane can be cured by the energy-efficient UV-LED source at room temperature in nitrogen and ambient atmosphere. In nitrogen atmosphere, already common reactions for polysilazanes, including polyaddition of the vinyl group, dehydrogenation reactions, hydrosilylation, and transamination reaction, are responsible for crosslinking. Meanwhile, in ambient atmosphere, hydrolysis and polycondensation reactions occur next to the aforementioned reactions. In addition, the type of photoinitiator has an influence on the conversion of the reactive bonds and the chemical composition of the resulting ceramic. Furthermore, thermogravimetric analysis (TGA) was conducted in order to measure the ceramic yield of the cured samples as well as to study their decomposition. The ceramic yield was observed in the range of 72 to 78% depending on the composition and the curing atmosphere. The curing atmosphere significantly impacts the chemical composition of the resulting ceramics. Depending on the chosen atmosphere, either silicon carbonitride (SiCN) or a partially oxidized SiCN(O) can be produced.
Reaction Mechanism and Mechanical Property Improvement of Poly(Lactic Acid) Reactive Blending with Epoxy Resin
Authors: Kiattipornpithak Krittameth , Thajai Nanthicha , Kanthiya Thidarat , Rachtanapun Pornchai , Leksawasdi Noppol , Phimolsiripol Yuthana , Rohindra David , Ruksiriwanich Warintorn , Sommano Sarana , Jantanasakulwong Kittisak
Published: July 2021

Polylactic acid (PLA) was melt-blended with epoxy resin to study the effects of the reaction on the mechanical and thermal properties of the PLA. The addition of 0.5% (wt/wt) epoxy to PLA increased the maximum tensile strength of PLA (57.5 MPa) to 67 MPa, whereas the 20% epoxy improved the elongation at break to 12%, due to crosslinking caused by the epoxy reaction. The morphology of the PLA/epoxy blends showed epoxy nanoparticle dispersion in the PLA matrix that presented a smooth fracture surface with a high epoxy content. The glass transition temperature of PLA decreased with an increasing epoxy content owing to the partial miscibility between PLA and the epoxy resin. The Vicat softening temperature of the PLA was 59 °C and increased to 64.6 °C for 0.5% epoxy. NMR confirmed the reaction between the -COOH groups of PLA and the epoxy groups of the epoxy resin. This reaction, and partial miscibility of the PLA/epoxy blend, improved the interfacial crosslinking, morphology, thermal properties, and mechanical properties of the blends.