bluuebunny/crossref_metadata_2025 huggingface dataset:
Nutritional and Hydration Status and Adherence to Dietary Recommendations in Dalmatian Dialysis Patients
Authors: Kolak Ela , Radić Josipa , Vučković Marijana , Bučan Nenadić Dora , Begović Mirna , Radić Mislav
Published: August 2022

Protein-energy wasting (PEW) is considered one of the major complications of chronic kidney disease (CKD), particularly in dialysis patients. Insufficient energy and protein intake, together with clinical complications, may contribute to the onset and severity of PEW. Therefore, the aim of the study was to analyze the differences in nutritional and hydration status and dietary intake among Dalmatian dialysis patients. Fifty-five hemodialysis (HD) and twenty peritoneal dialysis (PD) participants were included. For each study participant, data about body composition, anthropometric, laboratory, and clinical parameters were obtained. The Malnutrition Inflammation Score (MIS) and two separate 24-h dietary recalls were used to assess nutritional status and dietary intake. The Nutrient Adequacy Ratio (NAR) and Mean Adequacy Ratio (MAR) were calculated to compare actual dietary intake with recommended intake. Additionally, the estimated 10-year survival was calculated using the Charlson Comorbidity Index. The prevalence of malnutrition according to MIS was 47.3% in HD and 45% in PD participants. Significant differences in fat tissue parameters were found between HD and PD participants, whereas significant differences in hydration status and muscle mass parameters were not found. A significant difference in NAR between HD and PD participants was noticed for potassium and phosphorus intake, but not for MAR. MIS correlated negatively with anthropometric parameters, fat mass, visceral fat level and trunk fat mass, and iron and uric acid in HD participants, whereas no significant correlations were found in PD participants. The estimated 10-year survival correlated with several parameters of nutritional status in HD and PD participants, as well as nutrient intake in HD participants. These results indicate a high prevalence of malnutrition and inadequate dietary intake in the Dalmatian dialysis population which, furthermore, highlights the urgent need for individualized and structural nutritional support.
The Use of Probiotics Combined with Exercise Affects Thiol/Disulfide Homeostasis, an Oxidative Stress Parameter
Authors: Kayacan Yıldırım , Kola Aybike Zeynep , Guandalini Stefano , Yazar Hayrullah , Söğüt Mehtap Ünlü
Published: August 2022

Background: Intestinal microbiota play a role in the health and performance of athletes, and can be influenced by probiotics. Thus, in this study, we aimed to investigate the effect of the use of probiotics combined with chronic exercise on the thiol/disulfide homeostasis, a novel marker of oxidative stress. Methods: Male Wistar rats were randomly divided into four groups: control (Cn), exercise (Ex), probiotics (P), and probiotics + exercise (PEx). A capsule containing 6 × 108 CFU of L. rhamnosus, L. paracasei, L. acidophilus, and B. lactis was given daily for eight weeks to all the experimental animals. The total thiol (TT, μmol/L) and native thiol (NT, μmol/L) concentrations were measured to determine the oxidative stress parameters. The dynamic disulfide (DD, %), reduced thiol (RT, %), oxidized thiol (OT, %), and thiol oxidation reduction (TOR, %) ratios were analyzed. Results: The TT level was found to be significantly higher in the Ex group (p = 0.047, η2 = 0.259). The DD level, a marker of oxidation, was significantly lower in the PEx group (p = 0.042, η2 = 0.266); the highest value of this parameter was found in the Ex group. The use of probiotics alone had no effect on thiol/disulfide homeostasis. Conclusions: We showed, for the first time, that probiotics administered “with exercise” decreased dynamic disulfide and significantly reduced oxidative damage. Therefore, we speculate that the use of probiotics in sports involving intense exercise might be beneficial to reduce oxidative stress.
Suboptimal Plasma Vitamin C Is Associated with Lower Bone Mineral Density in Young and Early Middle-Aged Men: A Retrospective Cross-Sectional Study
Authors: Lan Kuo-Mao , Wang Li-Kai , Lin Yao-Tsung , Hung Kuo-Chuan , Wu Li-Ching , Ho Chung-Han , Chang Chia-Yu , Chen Jen-Yin
Published: August 2022

Background: This study was conducted to evaluate associations between bone mineral density (BMD) and four selected circulating nutrients, particularly vitamin C, among adults aged 20–49 years. Methods: In this retrospective cross-sectional study, the lumbar spine BMD of 866 men and 589 women were measured by dual-energy X-ray absorptiometry and divided into tertiles, respectively. Logistic regressions were used to identify the predictors of low BMD by comparing subjects with the highest BMD to those with the lowest. Results: Multivariate logistic regressions identified suboptimal plasma vitamin C (adjusted odds ratio (AOR) 1.64, 95% confidence interval (CI) 1.16, 2.31), suboptimal serum vitamin B12 (AOR 2.05, 95% CI 1.02, 4.12), and low BMI (BMI < 23) (AOR 1.68, 95% CI 1.12, 2.53) as independent predictors for low BMD in men. In women, low BMI was the only independent predictor for low BMD. Plasma vitamin C, categorized as suboptimal (≤8.8 mg/L) and sufficient (>8.8 mg/L), was positively significantly correlated with the lumbar spine BMD in men, but there was no association in women. Conclusions: Plasma vitamin C, categorized as suboptimal and sufficient, was positively associated with the lumbar spine BMD in young and early middle-aged men. A well-designed cohort study is needed to confirm the findings.
Effects of Different Routes and Forms of Vitamin D Administration on Mesenteric Lymph Node CD4+ T Cell Polarization and Intestinal Injury in Obese Mice Complicated with Polymicrobial Sepsis
Authors: Yeh Chiu-Li , Wu Jin-Ming , Chen Kuen-Yuan , Wu Ming-Hsun , Yang Po-Jen , Lee Po-Chu , Chen Po-Da , Yeh Sung-Ling , Lin Ming-Tsan
Published: August 2022

This study compared the efficacies of enteral cholecalciferol and/or intravenous (IV) calcitriol administration on mesenteric lymph node (MLN) cluster-of-differentiation-4-positive (CD4+) T cell distribution and intestinal barrier damage in obese mice complicated with sepsis. Mice were fed a high-fat diet for 16 weeks and then sepsis was induced by cecal ligation and puncture (CLP). Mice were divided into the following sepsis groups: without vitamin D (VD) (S); with oral cholecalciferol 1 day before CLP (G); with IV calcitriol 1 h after CLP (V); and with both cholecalciferol before and IV calcitriol after CLP (GV). All mice were sacrificed at 12 or 24 h after CLP. The findings show that the S group had a higher T helper (Th)17 percentage than the VD-treated groups at 12 h after CLP. The V group exhibited a higher Th1 percentage and Th1/Th2 ratio than the other groups at 24 h, whereas the V and GV groups had a lower Th17/regulatory T (Treg) ratio 12 h post-CLP in MLNs. In ileum tissues, the VD-treated groups had higher tight junction protein and cathelicidin levels, and higher mucin gene expression than the S group at 24 h post-CLP. Also, aryl hydrocarbon receptor (AhR) and its associated cytochrome P450 1A1 and interleukin 22 gene expressions were upregulated. In contrast, levels of lipid peroxides and inflammatory mediators in ileum tissues were lower in the groups with VD treatment after CLP. These results suggest that IV calcitriol seemed to have a more-pronounced effect on modulating the homeostasis of Th/Treg subsets in MLNs. Both oral cholecalciferol before and IV calcitriol after CLP promoted cathelicidin secretion, alleviated intestinal inflammation, and ameliorated the epithelial integrity in obese mice complicated with sepsis possibly via VD receptor and AhR signaling pathways.
Acute Effects of Inorganic Nitrate Intake on Brachial and Femoral Flow-Mediated Vasodilation, and on Carotid Artery Reactivity Responses: Results of a Randomized, Double-Blinded, Placebo-Controlled Cross-Over Study in Abdominally Obese Men
Authors: Smeets Ellen T. H. C. , Mensink Ronald P. , Kleinloog Jordi P. D. , Joris Peter J.
Published: August 2022

Most trials on the effects of inorganic nitrate intake have focused on only one specific aspect of the endothelial cell response to a stimulus, thereby possibly missing other important effects. The aim of the present randomized, double-blinded, placebo-controlled cross-over study was therefore to investigate in eighteen healthy abdominally obese men (18–60 years, waist circumference ≥ 102 cm) acute effects of potassium nitrate on brachial and femoral flow-mediated vasodilation (FMD), and on carotid artery reactivity (CAR) to a cold pressure test. Participants received in random order a drink providing 10 mmol potassium nitrate (i.e., 625 mg of nitrate) or an iso-molar placebo drink with potassium chloride. Fasted and 4 h post-drink FMD and blood pressure measurements were performed. CAR responses were assessed at 4 h. Circulating nitrate plus nitrite concentration increased following nitrate intake (p = 0.003). Compared with placebo, potassium nitrate did not affect brachial (mean [95% confidence interval]: −0.2% [−2.5, 2.1], p = 0.86) and femoral FMD responses (−0.6% [−3.0; 1.7], p = 0.54). CAR responses were also not different (−0.8% [−2.5, 0.9], p = 0.32). Finally, changes in blood pressure and heart rate did not differ. No adverse events were observed. In conclusion, this trial did not provide evidence for effects of a single dose of inorganic nitrate on 4 h vascular endothelial function in abdominally obese men.
Photosynthetic Production of Molecular Oxygen by Water Oxidation
Authors: Björn Lars Olof
Published: August 2022

This review deals with the production of oxygen by photo-oxidation of water, which is a topic fitting a journal devoted to oxygen. Most of the present biosphere, including mankind, depends on oxygen. Elucidating the mechanism is of importance for solving the present energy crisis. Photosynthesis evolved in bacteria, first in a form that did not produce oxygen. The oxygen-producing version arose with the advent of cyanobacteria about three billion years ago. The production of oxygen by photo-oxidation of water requires the co-operative action of four photons. These are harvested from daylight by chlorophyll and other pigments (e.g., phycobiliproteins) and are channeled to photosystem II and photosystem I. The oxygen-evolving complex resides in photosystem II, surrounded by protein subunits, and contains one ion of calcium, four ions of manganese, and a number of oxygen atoms. For each quantum of energy it receives from absorbed light, it proceeds one step through a cycle of states known as the Kok–Joliot cycle. For each turn of the cycle, one molecule of oxygen (O2) is produced.
Design, Rational Repurposing, Synthesis, In Vitro Evaluation, Homology Modeling and In Silico Study of Sulfuretin Analogs as Potential Antileishmanial Hit Compounds
Authors: Hassan Ahmed H.E. , Phan Trong-Nhat , Choi Yeonwoo , Moon Suyeon , No Joo Hwan , Lee Yong Sup
Published: August 2022

Direct growth inhibition of infectious organisms coupled with immunomodulation to counteract the immunosuppressive environment might be a beneficial therapeutic approach. Herein, a library of sulfuretin analogs were developed with potential capabilities to inhibit production of the immunosuppressive PGE2 and elicit direct growth inhibition against Leishmania donovani; the major causative agent of the fatal visceral leishmaniasis. Amongst explored library members bearing diverse methoxy and/or hydroxy substitution patterns at rings B and A, analog 1i retaining the C6-hydroxy moiety at ring-A, but possessing methoxy moieties in place of the polar dihydroxy moieties of sulfuretin ring-B, as well as analog 1q retaining the sulfuretin′s polar dihydroxy moieties at ring-B, but incorporating a C6-methoxy moiety instead of the C6-hydroxy moiety at ring-A, were the most promising hit compounds. Cytotoxicity evaluation suggested that analog 1i possesses a safety profile inducing the death of the parasite rather than host cells. In silico simulation provided insights into their possible binding with Leishmania donovani fumarate reductase. The current investigation presents sulfuretin analogs 1i and 1q as potential hit compounds for further development of multifunctional therapeutic agents against visceral leishmaniasis.
Hybrid Membrane-Derived Nanoparticles for Isoliquiritin Enhanced Glioma Therapy
Authors: Shi Wenwan , Cao Xia , Liu Qi , Zhu Qin , Liu Kai , Deng Tianwen , Yu Qingtong , Deng Wenwen , Yu Jiangnan , Wang Qilong , Xu Ximing
Published: August 2022

Due to the obstruction and heterogeneity of the blood-brain barrier, the clinical treatment of glioma has been extremely difficult. Isoliquiritigenin (ISL) exhibits antitumor effects, but its low solubility and bioavailability limit its application potential. Herein, we established a nanoscale hybrid membrane-derived system composed of erythrocytes and tumor cells. By encapsulating ISL in hybrid membrane nanoparticles, ISL is expected to be enhanced for the targeting and long-circulation in gliomas therapy. We fused erythrocytes with human glioma cells U251 and extracted the fusion membrane via hypotension, termed as hybrid membrane (HM). HM-camouflaged ISL nanoparticles (ISL@HM NPs) were prepared and featured with FT-IR, SEM, TEM, and DLS particle analysis. As the results concluded, the ISL active pharmaceutical ingredients (APIs) were successfully encapsulated with HM membranes, and the NPs loading efficiency was 38.9 ± 2.99% under maximum entrapment efficiency. By comparing the IC50 of free ISL and NPs, we verified that the solubility and antitumor effect of NPs was markedly enhanced. We also investigated the mechanism of the antitumor effect of ISL@HM NPs, which revealed a marked inhibition of tumor cell proliferation and promotion of senescence and apoptosis of tumor cells of the formulation. In addition, the FSC and WB results examined the effects of different concentrations of ISL@HM NPs on tumor cell disruption and apoptotic protein expression. Finally, it can be concluded that hybridized membrane-derived nanoparticles could prominently increase the solubility of insoluble materials (as ISL), and also enhance its targeting and antitumor effect.
Achillea fragrantissima (Forssk.) Sch.Bip Flower Dichloromethane Extract Exerts Anti-Proliferative and Pro-Apoptotic Properties in Human Triple-Negative Breast Cancer (MDA-MB-231) Cells: In Vitro and In Silico Studies
Authors: Alshuail Nora , Alehaideb Zeyad , Alghamdi Sahar , Suliman Rasha , Al-Eidi Hamad , Ali Rizwan , Barhoumi Tlili , Almutairi Mansour , Alwhibi Mona , Alghanem Bandar , Alamro Abir , Alghamdi Amani , Matou-Nasri Sabine
Published: August 2022

The aggressive triple-negative breast cancer (TNBC) is a challenging disease due to the absence of tailored therapy. The search for new therapies involves intensive research focusing on natural sources. Achillea fragrantissima (A. fragrantissima) is a traditional medicine from the Middle East region. Various solvent extracts from different A. fragrantissima plant parts, including flowers, leaves, and roots, were tested on TNBC MDA-MB-231 cells. Using liquid chromatography, the fingerprinting revealed rich and diverse compositions for A. fragrantissima plant parts using polar to non-polar solvent extracts indicating possible differences in bioactivities. Using the CellTiter-Glo™ viability assay, the half-maximal inhibitory concentration (IC50) values were determined for each extract and ranged from 32.4 to 161.7 µg/mL. The A. fragrantissima flower dichloromethane extract had the lowest mean IC50 value and was chosen for further investigation. Upon treatment with increasing A. fragrantissima flower dichloromethane extract concentrations, the MDA-MB-231 cells displayed, in a dose-dependent manner, enhanced morphological and biochemical hallmarks of apoptosis, including cell shrinkage, phosphatidylserine exposure, caspase activity, and mitochondrial outer membrane permeabilization, assessed using phase-contrast microscopy, fluorescence-activated single-cell sorting analysis, Image-iT™ live caspase, and mitochondrial transition pore opening activity, respectively. Anticancer target prediction and molecular docking studies revealed the inhibitory activity of a few A. fragrantissima flower dichloromethane extract-derived metabolites against carbonic anhydrase IX, an enzyme reported for its anti-apoptotic properties. In conclusion, these findings suggest promising therapeutic values of the A. fragrantissima flower dichloromethane extract against TNBC development.
Nitrostilbenes: Synthesis and Biological Evaluation as Potential Anti-Influenza Virus Agents
Authors: De Angelis Marta , De Filippis Barbara , Balaha Marwa , Giampietro Letizia , Miteva Mariya Timotey , De Chiara Giovanna , Palamara Anna Teresa , Nencioni Lucia , Mollica Adriano
Published: August 2022

Resveratrol (RSV) is a natural stilbene polyphenolic compound found in several plant species. It is characterized by antioxidant properties, and its role in controlling viral replication has been demonstrated for different viral infections. Despite its promising antiviral properties, RSV biological activity is limited by its low bioavailability and high metabolic rate. In this study, we optimized its structure by synthesizing new RSV derivatives that maintained the phenolic scaffold and contained different substitution patterns and evaluated their potential anti-influenza virus activity. The results showed that viral protein synthesis decreased 24 h post infection; particularly, the nitro-containing compounds strongly reduced viral replication. The molecules did not exert their antioxidant properties during infection; in fact, they were not able to rescue the virus-induced drop in GSH content or improve the antioxidant response mediated by the Nrf2 transcription factor and G6PD enzyme. Similar to what has already been reported for RSV, they interfered with the nuclear-cytoplasmic traffic of viral nucleoprotein, probably inhibiting cellular kinases involved in the regulation of specific steps of the virus life cycle. Overall, the data indicate that more lipophilic RSV derivatives have improved antiviral efficacy compared with RSV and open the way for new cell-targeted antiviral strategies.
Arabinoxylans-Based Oral Insulin Delivery System Targeting the Colon: Simulation in a Human Intestinal Microbial Ecosystem and Evaluation in Diabetic Rats
Authors: Martínez-López Ana L. , Carvajal-Millan Elizabeth , Canett-Romero Rafael , Prakash Satya , Rascón-Chu Agustín , López-Franco Yolanda L. , Lizardi-Mendoza Jaime , Micard Valerie
Published: August 2022

Arabinoxylans (AX) microcapsules loaded with insulin were prepared by enzymatic gelation of AX, using a triaxial electrospray method. The microcapsules presented a spherical shape, with an average size of 250 µm. The behavior of AX microcapsules was evaluated using a simulator of the human intestinal microbial ecosystem. AX microcapsules were mainly (70%) degraded in the ascending colon. The fermentation was completed in the descending colon, increasing the production of acetic, propionic, and butyric acids. In the three regions of the colon, the fermentation of AX microcapsules significantly increased populations of Bifidobacterium and Lactobacillus and decreased the population of Enterobacteriaceae. In addition, the results found in this in vitro model showed that the AX microcapsules could resist the simulated conditions of the upper gastrointestinal system and be a carrier for insulin delivery to the colon. The pharmacological activity of insulin-loaded AX microcapsules was evaluated after oral delivery in diabetic rats. AX microcapsules lowered the serum glucose levels in diabetic rats by 75%, with insulin doses of 25 and 50 IU/kg. The hypoglycemic effect and the insulin levels remained for more than 48 h. Oral relative bioavailability was 13 and 8.7% for the 25 and 50 IU/kg doses, respectively. These results indicate that AX microcapsules are a promising microbiota-activated system for oral insulin delivery in the colon.
Vemurafenib Inhibits Enterovirus A71 Genome Replication and Virus Assembly
Authors: Hu Bodan , Chik Kenn Ka-Heng , Chan Jasper Fuk-Woo , Cai Jian-Piao , Cao Hehe , Tsang Jessica Oi-Ling , Zou Zijiao , Hung Yin-Po , Tang Kaiming , Jia Lilong , Luo Cuiting , Yin Feifei , Ye Zi-Wei , Chu Hin , Yeung Man-Lung , Yuan Shuofeng
Published: August 2022

Enterovirus A71 (EV-A71) infection is a major cause of hand, foot, and mouth disease (HFMD), which may be occasionally associated with severe neurological complications. There is currently a lack of treatment options for EV-A71 infection. The Raf-MEK-ERK signaling pathway, in addition to its critical importance in the regulation of cell growth, differentiation, and survival, has been shown to be essential for virus replication. In this study, we investigated the anti-EV-A71 activity of vemurafenib, a clinically approved B-Raf inhibitor used in the treatment of late-stage melanoma. Vemurafenib exhibits potent anti-EV-A71 effect in cytopathic effect inhibition and viral load reduction assays, with half maximal effective concentration (EC50) at nanomolar concentrations. Mechanistically, vemurafenib interrupts both EV-A71 genome replication and assembly. These findings expand the list of potential antiviral candidates of anti-EV-A71 therapeutics.
Current Advancement of Immunomodulatory Drugs as Potential Pharmacotherapies for Autoimmunity Based Neurological Diseases
Authors: Ashraf Hajra , Solla Paolo , Sechi Leonardo Atonio
Published: August 2022

Dramatic advancement has been made in recent decades to understand the basis of autoimmunity-mediated neurological diseases. These diseases create a strong influence on the central nervous system (CNS) and the peripheral nervous system (PNS), leading to various clinical manifestations and numerous symptoms. Multiple sclerosis (MS) is the most prevalent autoimmune neurological disease while NMO spectrum disorder (NMOSD) is less common. Furthermore, evidence supports the presence of autoimmune mechanisms contributing to the pathogenesis of amyotrophic lateral sclerosis (ALS), which is a neurodegenerative disorder characterized by the progressive death of motor neurons. Additionally, autoimmunity is believed to be involved in the basis of Alzheimer’s and Parkinson’s diseases. In recent years, the prevalence of autoimmune-based neurological disorders has been elevated and current findings strongly suggest the role of pharmacotherapies in controlling the progression of autoimmune diseases. Therefore, this review focused on the current advancement of immunomodulatory drugs as novel approaches in the management of autoimmune neurological diseases and their future outlook.
In Vitro Release, Mucosal Permeation and Deposition of Cannabidiol from Liquisolid Systems: The Influence of Liquid Vehicles
Authors: Tabboon Peera , Pongjanyakul Thaned , Limpongsa Ekapol , Jaipakdee Napaphak
Published: August 2022

This work investigated the influence of liquid vehicles on the release, mucosal permeation and deposition of cannabidiol (CBD) from liquisolid systems. Various vehicles, including EtOH, nonvolatile low- and semi-polar solvents, and liquid surfactants, were investigated. The CBD solution was converted into free-flowing powder using carrier (microcrystalline cellulose) and coating materials (colloidal silica). A physical mixture of the CBD and carrier–coating materials was prepared as a control. The non-crystalline state of CBD in the liquisolid systems was confirmed using XRD, FTIR and SEM studies. The CBD liquisolid powder prepared with volatile and nonvolatile solvents had a better CBD release performance than the CBD formed as the surfactant-based and control powders. The liquisolid systems provided the CBD permeation flux through porcine esophageal mucosa ranging from 0.68 ± 0.11 to 13.68 ± 0.74 µg·cm−2·h−1, with the CBD deposition levels of 0.74 ± 0.04 to 2.62 ± 0.30 μg/mg for the dry mucosa. Diethylene glycol monoethyl ether showed significant CBD permeation enhancement (2.1 folds) without an increase in mucosal deposition, while the surfactants retarded the permeation (6.7–9.0 folds) and deposition (1.5–3.2 folds) significantly. In conclusion, besides the drug release, liquid vehicles significantly influence mucosal permeation and deposition, either enhanced or suppressed, in liquisolid systems. Special attention must be paid to the selection and screening of suitable liquid vehicles for liquisolid systems designed for transmucosal applications.
Development and Evaluation of a Peptide Heterodimeric Tracer Targeting CXCR4 and Integrin αvβ3 for Pancreatic Cancer Imaging
Authors: Jiang Yaqun , Long Yu , Ji Hao , Qiao Pengxin , Liu Qingyao , Xia Xiaotian , Qin Chunxia , Zhang Yongxue , Lan Xiaoli , Gai Yongkang
Published: August 2022

Nowadays, pancreatic cancer is still a formidable disease to diagnose. The CXC chemokine receptor 4 (CXCR4) and integrin αvβ3 play important roles in tumor development, progression, invasion, and metastasis, which are overexpressed in many types of human cancers. In this study, we developed a heterodimeric tracer 68Ga-yG5-RGD targeting both CXCR4 and integrin αvβ3, and evaluated its feasibility and utility in PET imaging of pancreatic cancer. The 68Ga-yG5-RGD could accumulate in CXCR4/integrin αvβ3 positive BxPC3 tumors in a high concentration and was much higher than that of 68Ga-yG5 (p < 0.001) and 68Ga-RGD (p < 0.001). No increased uptake of 68Ga-yG5-RGD was found in MX-1 tumors (CXCR4/integrin αvβ3, negative). In addition, the uptake of 68Ga-yG5-RGD in BxPC3 was significantly blocked by excess amounts of AMD3100 (an FDA-approved CXCR4 antagonist) and/or unlabeled RGD (p < 0.001), confirming its dual-receptor targeting properties. The ex vivo biodistribution and immunohistochemical results were consistent with the in vivo imaging results. The dual-receptor targeting strategy achieved improved tumor-targeting efficiency and prolonged tumor retention in BxPC3 tumors, suggesting 68Ga-yG5-RGD is a promising tracer for the noninvasive detection of tumors that express either CXCR4 or integrin αvβ3 or both, and therefore may have good prospects for clinical translation.
Antibacterial Activity from Momordica charantia L. Leaves and Flavones Enriched Phase
Authors: Muribeca Abraão de Jesus B. , Gomes Paulo Wender P. , Paes Steven Souza , da Costa Ana Paula Alves , Gomes Paulo Weslem Portal , Viana Jéssica de Souza , Reis José Diogo E. , Pamplona Sônia das Graças Santa R. , Silva Consuelo , Bauermeister Anelize , Santos Lourivaldo da Silva , da Silva Milton Nascimento
Published: August 2022

Momordica charantia L. (Cucurbitaceae) is a plant known in Brazil as “melão de São Caetano”, which has been related to many therapeutic applications in folk medicine. Herein, we describe antibacterial activities and related metabolites for an extract and fractions obtained from the leaves of that species. An ethanolic extract and its three fractions were used to perform in vitro antibacterial assays. In addition, liquid chromatography coupled to mass spectrometry and the molecular networking approach were used for the metabolite annotation process. Overall, 25 compounds were annotated in the ethanolic extract from M. charantia leaves, including flavones, terpenes, organic acids, and inositol pyrophosphate derivatives. The ethanolic extract exhibited low activity against Proteus mirabilis (MIC 312.5 µg·mL−1) and Klebsiella pneumoniae (MIC 625 µg·mL−1). The ethyl acetate phase showed interesting antibacterial activity (MIC 156.2 µg·mL−1) against Klebsiella pneumoniae, and it was well justified by the high content of glycosylated flavones. Therefore, based on the ethyl acetate phase antibacterial result, we suggest that M. charantia leaves could be considered as an alternative antibacterial source against K. pneumoniae and can serve as a pillar for future studies as well as pharmacological application against the bacteria.
Enhancement of the Bioavailability and Anti-Inflammatory Activity of Glycyrrhetinic Acid via Novel Soluplus®—A Glycyrrhetinic Acid Solid Dispersion
Authors: Wang Hao , Li Runwei , Rao Yuan , Liu Saixing , Hu Chunhui , Zhang Yong , Meng Linchao , Wu Qilin , Ouyang Qiuhong , Liang Hao , Qin Meng
Published: August 2022

Glycyrrhetinic acid (GA) is an anti-inflammatory drug with potential for development. However, the poor solubility of GA in water leads to extremely low bioavailability, which limits its clinical applications. Solid dispersions have become some of the most effective strategies for improving the solubility of poorly soluble drugs. Soluplus®, a non-cytotoxic amphiphilic solubilizer, significantly improves the solubility of BCS II drugs and improves the bioavailability of insoluble drugs. l-arginine (L-Arg) can be used as a small molecular weight excipient to assist in improving the solubility of insoluble drugs. In this study, we developed a new formulation for oral administration by reacting GA and L-Arg to form salts by co-solvent evaporation and then adding the polymer-solvent Soluplus® with an amphiphilic chemical structure to prepare a solid dispersion GA-SD. The chemical and physical properties of GA-SD were characterized by DLS, TEM, XRD, FT-IR and TG. The anti-inflammatory activity of GA-SD was verified by LPS stimulation of RAW 267.5 cells simulating a cellular inflammation model, TPA-induced ear edema model in mice, and ethanol-induced gastric ulcer model. The results showed that the amide bond and salt formation of GA-SD greatly improved GA solubility. GA-SD effectively improved the anti-inflammatory effect of free GA in vivo and in vitro, and GA-SD had no significant effect on liver and kidney function, no significant tissue toxicity, and good biosafety. In conclusion, GA-SD with L-Arg and Soluplus® is an effective method to improve the solubility and bioavailability of GA. As a safe and effective solid dispersion, it is a promising anti-inflammatory oral formulation and provides some references for other oral drug candidates with low bioavailability.
Essential Oil—Loaded Nanofibers for Pharmaceutical and Biomedical Applications: A Systematic Mini-Review
Authors: Partheniadis Ioannis , Stathakis Georgios , Tsalavouti Dimitra , Heinämäki Jyrki , Nikolakakis Ioannis
Published: August 2022

Essential oils (EOs) have been widely exploited for their biological properties (mainly as antimicrobials) in the food industry. Encapsulation of EOs has opened the way to the utilization of EOs in the pharmaceutical and biomedical fields. Electrospinning (ES) has proved a convenient and versatile method for the encapsulation of EOs into multifunctional nanofibers. Within the last five years (2017–2022), many research articles have been published reporting the use of ES for the fabrication of essential oil—loaded nanofibers (EONFs). The objective of the present mini-review article is to elucidate the potential of EONFs in the pharmaceutical and biomedical fields and to highlight their advantages over traditional polymeric films. An overview of the conventional ES and coaxial ES technologies for the preparation of EONFs is also included. Even though EONFs are promising systems for the delivery of EOs, gaps in the literature can be recognized (e.g., stability studies) emphasizing that more research work is needed in this field to fully unravel the potential of EONFs.
Bimodal Imaging of Tumors via Genetically Engineered Escherichia coli
Authors: Zhang Linlin , Wang Yuanyuan , Li Dengjin , Wang Liang , Li Zhenzhou , Yan Fei
Published: August 2022

Although there are emerging innovations of molecular imaging probes to detect and image tumors, most of these molecular dyes and nanoparticles have limitations of low targetability in tumors and fast clearance when administered systemically. In contrast, some bacteria, such as Escherichia coli MG1655, can selectively proliferate in a hypoxic environment inside of a tumor for several days, which highlights the potential for the development of a genetically encoded multimodal imaging probe to monitor the progress of the tumor. Here, we developed bimodal imaging tumor-homing bacteria (GVs-miRFP680 MG1655) that allow both optical and acoustic imaging in tumor-bearing mice. An in vivo optical image system and a Vevo 2100 imaging system were applied to detect different imaging properties of the engineered bacteria in vivo. Our results show that the GVs-miRFP680 MG1655 bacteria can effectively integrate the advantages of low tissue absorbance from near-infrared fluorescent proteins and non-invasiveness from gas vesicles. We successfully developed GVs-miRFP680 MG1655 bacteria, which have both acoustic and optical imaging abilities in vitro and in vivo. The acoustic signal can last for up to 25 min, while the near-infrared fluorescence signal can last for up to 96 h. The combination of different imaging modalities in the tumor-homing bacteria may contribute to the non-invasive monitoring of the therapeutic effect of bacterial therapy in the future.
Conjugation of a Cationic Cell-Penetrating Peptide with a Novel Kunitzin-like Trypsin Inhibitor: New Insights for Enhancement of Peptide Bioactivities
Authors: Yao Junting , Yin Weining , Chen Yuqing , Chen Xiaoling , Jiang Yangyang , Wang Tao , Ma Chengbang , Zhou Mei , Chen Tianbao , Shaw Chris , Wang Lei
Published: August 2022

Cationic cell-penetrating peptides (CPPs), such as transactivator of transcription (TAT) peptide, have been proposed as effective drug carriers to improve intracellular delivery of biological macromolecules. Amphibian skin-derived Kunitz-type trypsin inhibitors (KTIs), short counterparts of KTIs from plant sources, were found to possess potent serine protease inhibitory activity. However, poor transmembrane permeability of these molecules has largely hindered the study of the full spectrum of their biological actions. As a result, this study aimed to extend the biological activities of amphibian KTIs by their conjugation to cationic CPPs. Herein, a novel peptide (kunitzin-OV2) and its phenylalanine-substituted analogue F9-kunitzin-OV2 (F9-KOV2) were evaluated for inhibition of trypsin/chymotrypsin and showed weak antibacterial activity against Escherichia coli (E. coli). As expected, the conjugation to TAT peptide did not increase membrane lysis compared with the original kunitzin-OV2, but effectively assisted this complex to enter cells. TAT-kunitzin-OV2 (TAT-KOV2) exhibited a 32-fold increase in antibacterial activity and an enhanced bactericidal rate against E. coli. In addition, the conjugation enabled the parent peptides to exhibit antiproliferative activity against cancer cells. Interestingly, TAT-F9-kunitzin-OV2 (TAT-F9-KOV2) showed stronger antiproliferative activity against human breast cancer (MCF-7) and human glioblastoma (U251MG) cell lines, which TAT-KOV2 did not possess. Moreover, TAT-F9-KOV2 showed a 20–25-fold increase in antiproliferative capacity against human lung cancer (H157, H460) cell lines compared with TAT-KOV2. Therefore, the conjugation of CPPs effectively solves the problem of cell penetration that short KTIs lack and provides evidence for new potential applications for their subsequent development as new antibacterial and anticancer agents.
Fast-Fed Variability: Insights into Drug Delivery, Molecular Manifestations, and Regulatory Aspects
Authors: Rangaraj Nagarjun , Sampathi Sunitha , Junnuthula Vijayabhaskarreddy , Kolimi Praveen , Mandati Preethi , Narala Sagar , Nyavanandi Dinesh , Dyawanapelly Sathish
Published: August 2022

Among various drug administration routes, oral drug delivery is preferred and is considered patient-friendly; hence, most of the marketed drugs are available as conventional tablets or capsules. In such cases, the administration of drugs with or without food has tremendous importance on the bioavailability of the drugs. The presence of food may increase (positive effect) or decrease (negative effect) the bioavailability of the drug. Such a positive or negative effect is undesirable since it makes dosage estimation difficult in several diseases. This may lead to an increased propensity for adverse effects of drugs when a positive food effect is perceived. However, a negative food effect may lead to therapeutic insufficiency for patients suffering from life-threatening disorders. This review emphasizes the causes of food effects, formulation strategies to overcome the fast-fed variability, and the regulatory aspects of drugs with food effects, which may open new avenues for researchers to design products that may help to eliminate fast-fed variability.
pH Sensitive Erythrocyte-Derived Membrane for Acute Systemic Retention and Increased Infectivity of Coated Oncolytic Vaccinia Virus
Authors: Samoranos Kaelan T. , Krisiewicz Alexandra L. , Karpinecz Bianca C. , Glover Philip A. , Gale Trevor V. , Chehadeh Carla , Ashshan Sheikh , Koya Richard , Chung Eddie Y. , Lim Han L.
Published: August 2022

Oncolytic viruses have emerged as a promising modality in cancer treatment given their high synergy with highly efficient immune checkpoint inhibitors. However, their potency is limited by their rapid in vivo clearance. To overcome this, we coated oncolytic vaccinia viruses (oVV) with erythrocyte-derived membranes (EDMs), hypothesizing that they would not only remain in systemic circulation for longer as erythrocytes would when administered intravenously, but also respond to environmental pH cues due to their membrane surface sialic acid residues. For this, we developed a model based on DLVO theory to show that the acidic moieties on the surface of EDM confers it the ability to respond to pH-based stimuli. We corroborate our modeling results through in vitro cell culture models and show that EDM-coated oVV infects cancer cells faster under acidic conditions akin to the tumor microenvironment. When EDM-coated oVVs were intravenously injected into wild-type mice, they exhibited prolonged circulation at higher concentrations when compared to the unprocessed oVV. Furthermore, when EDM-coated oVV was directly injected into xenografted tumors, we observed that they were suppressed earlier than the tumors that received regular oVV, suggesting that the EDM coating does not hinder oVV infectivity. Overall, we found that EDM was able to serve as a multi-functional encapsulant that allowed the payload to remain in circulation at higher concentrations when administered intravenously while simultaneously exhibiting pH-responsive properties.
Design of Experiments as a Tool to Optimize the Process of Coating Minitablets with Commercial Gastro-Resistant Coating Mixtures
Authors: Frankiewicz Maja , Sznitowska Małgorzata
Published: August 2022

According to the Quality by Design (QbD) concept, Design of Experiment (DoE) was used to indicate critical process parameters and optimize the fluid bed coating of minitablets in a laboratory size batch. Full factorial design was employed to increase knowledge of the process for three kinds of minitablet (MT) cores using two commercial gastro-resistant coating mixtures. The statistical analysis showed that different critical process parameters were indicated for the tested minitablets: X3: the coating mixture flow rate for MTs with pantoprazole sodium and Eudragit L; X2: the product temperature; X3 and X4: the spraying pressure for MTs with pantoprazole sodium and Acryl Eze II; and X1 and X2: MTs with diclofenac sodium. Such differences were the result of features, such as the sub-coat, size, and mass of the cores and the core and coating mixture composition. No optimal parameters were found for any of the tested MT types. Therefore, DoE should be considered as a statistical tool to individually optimize the process for the product, equipment, and tested parameters. However, optimization of the fluid bed coating allowed us to predict the values of the process parameters necessary to obtain good-quality products. Therefore, fluid bed coating may be successfully used to obtain modified-release MTs of high quality after applying the statistical tool DoE.
How to Treat Melanoma? The Current Status of Innovative Nanotechnological Strategies and the Role of Minimally Invasive Approaches like PTT and PDT
Authors: Lopes Joana , Rodrigues Cecília M. P. , Gaspar Maria Manuela , Reis Catarina Pinto
Published: August 2022

Melanoma is the most aggressive type of skin cancer, the incidence and mortality of which are increasing worldwide. Its extensive degree of heterogeneity has limited its response to existing therapies. For many years the therapeutic strategies were limited to surgery, radiotherapy, and chemotherapy. Fortunately, advances in knowledge have allowed the development of new therapeutic strategies. Despite the undoubted progress, alternative therapies are still under research. In this context, nanotechnology is also positioned as a strong and promising tool to develop nanosystems that act as drug carriers and/or light absorbents to potentially improve photothermal and photodynamic therapies outcomes. This review describes the latest advances in nanotechnology field in the treatment of melanoma from 2011 to 2022. The challenges in the translation of nanotechnology-based therapies to clinical applications are also discussed. To sum up, great progress has been made in the field of nanotechnology-based therapies, and our understanding in this field has greatly improved. Although few therapies based on nanoparticulate systems have advanced to clinical trials, it is expected that a large number will come into clinical use in the near future. With its high sensitivity, specificity, and multiplexed measurement capacity, it provides great opportunities to improve melanoma treatment, which will ultimately lead to enhanced patient survival rates.
Cheminformatics Identification of Phenolics as Modulators of Penicillin-Binding Protein 2a of Staphylococcus aureus: A Structure–Activity-Relationship-Based Study
Authors: Aribisala Jamiu Olaseni , Sabiu Saheed
Published: August 2022

The acquisition of penicillin-binding protein (PBP) 2a in resistant strains of Staphylococcus aureus allows for the continuous production of cell walls even after the inactivation of intrinsic PBPs. Thus, the discovery of novel therapeutics with enhanced modulatory activity on PBP2a is crucial, and plant secondary metabolites, such as phenolics, have found relevance in this regard. In this study, using computational techniques, phenolics were screened against the active site of PBP2a, and the ability of the lead phenolics to modulate PBP2a’s active and allosteric sites was studied. The top-five phenolics (leads) identified through structure–activity-based screening, pharmacokinetics and synthetic feasibility evaluations were subjected to molecular dynamics simulations. Except for propan-2-one at the active site, the leads had a higher binding free energy at both the active and allosteric sites of PBP2a than amoxicillin. The leads, while promoting the thermodynamic stability of PBP2a, showed a more promising affinity at the allosteric site than the active site, with silicristin (−25.61 kcal/mol) and epicatechin gallate (−47.65 kcal/mol) having the best affinity at the active and allosteric sites, respectively. Interestingly, the modulation of Tyr446, the active site gatekeeper residue in PBP2a, was noted to correlate with the affinity of the leads at the allosteric site. Overall, these observations point to the leads’ ability to inhibit PBP2a, either directly or through allosteric modulation with conventional drugs. Further confirmatory in vitro studies on the leads are underway.
Solid Nanomedicines of Nifurtimox and Benznidazole for the Oral Treatment of Chagas Disease
Authors: Rolon Miriam , Hanna Eustine , Vega Celeste , Coronel Cathia , Dea-Ayuela Maria Auxiliadora , Serrano Dolores R. , Lalatsa Aikaterini
Published: August 2022

Chagas disease (CD) is a parasitic zoonosis endemic in Central and South America affecting nearly 10 million people, with 100 million people at high risk of contracting the disease. Treatment is only effective when received at the early stages of the disease and it involved two drugs (nifurtimox (NFX) and benznidazole (BNZ)). Both treatments require multiple daily administrations of high doses, suffer from variable efficacy and insufficient efficacy in chronic CD, many side effects, and a very long duration of treatment that results in poor compliance, while combined available therapies that lead to reduced duration of treatment are not available and polypharmacy reduces compliance and increases the cost further. Here we present self-nanoemulsified drug delivery systems (SNEDDS) able to produce easily scalable combined formulations of NFX and BNZ that can allow for tailoring of the dose and can be easily converted to oral solid dosage form by impregnation on mesoporous silica particles. SNEDDS demonstrated an enhanced solubilisation capacity for both drugs as demonstrated by flow-through studies and in vitro lipolysis studies. High loading of SNEDDS to Syloid 244 and 3050 silicas (2:1 w/w) allowed clinically translatable amounts of both NFX and BNZ to be loaded. Tablets prepared from NFX-BNZ combined SNEDDS loaded on Syloid 3050 silicas demonstration near complete dissolution in the flow through cell apparatus compared to NFX and BNZ commercial tablets respectively (Lampit® and Rochagan®). NFX-BNZ-SNEDDS demonstrated nanomolar efficacy in epimastigotes and amastigotes of T. cruzi with acceptable selectivity indexes and demonstrated enhanced survival and reduced parasitaemia in acute murine experimental models of CD. Thus, the results presented here illustrate the ability for an easily scalable and personalised combination oral therapy prepared from GRAS excipients, enabling treatment access worldwide for the treatment of CD.
Unidirectional Coherent Phonon Emission in an Optomechanic Nanobeam Containing Coupled Cavities
Authors: Korovin Alexander V. , Pennec Yan , Djafari-Rouhani Bahram
Published: August 2022

Nonreciprocal phonon emission is predicted theoretically from the coherent excitation of two coupled optomechanical cavities arranged along a phoxonic crystal nanobeam. The latter consists of a periodic array of holes and stubs and exhibits simultaneous photonic and phononic bandgaps. It is shown that nonreciprocal phonon emission arises from a combined effect of the spatial symmetry of the cavities and their underlying coupled phononic modes and the temporal phase shift between the excitation sources. This demonstration paves the way for the development of advanced integrated phonon networks and circuits, in which mechanical waves connect different elements in phononic and optomechanical structures.