bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical Exercise and Diet: Regulation of Gut Microbiota to Prevent and Treat Metabolic Disorders to Maintain Health
Authors: Zhang Li , Liu Yuan , Wang Xinzhou , Zhang Xin
Published: March 2023

Each person’s body is host to a large number and variety of gut microbiota, which has been described as the second genome and plays an important role in the body’s metabolic process and is closely related to health. It is common knowledge that proper physical activity and the right diet structure can keep us healthy, and in recent years, researchers have found that this boost to health may be related to the gut microbiota. Past studies have reported that physical activity and diet can modulate the compositional structure of the gut microbiota and further influence the production of key metabolites of the gut microbiota, which can be an effective way to improve body metabolism and prevent and treat related metabolic diseases. In this review, we outline the role of physical activity and diet in regulating gut microbiota and the key role that gut microbiota plays in improving metabolic disorders. In addition, we highlight the regulation of gut microbiota through appropriate physical exercise and diet to improve body metabolism and prevent metabolic diseases, aiming to promote public health and provide a new approach to treating such diseases.
Different Approaches to Ergogenic, Pre-, and Probiotic Supplementation in Sports with Different Metabolism Characteristics: A Mini Review
Authors: Wiącek Jakub , Karolkiewicz Joanna
Published: March 2023

Sport disciplines with different metabolic characteristics require different dietary approaches. Bodybuilders or sprinters (“anaerobic” athletes) need a high-protein diet (HPD) in order to activate muscle protein synthesis after exercise-induced muscle damage and use nitric oxide enhancers (such as citrulline and nitrates) to increase vasodilatation, whereas endurance athletes, such as runners or cyclists (“aerobic” athletes), prefer a high-carbohydrate diet (HCHD), which aims to restore the intramuscular glycogen, and supplements containing buffering agents (such as sodium bicarbonate and beta-alanine). In both cases, nutrient absorption, neurotransmitter and immune cell production and muscle recovery depend on gut bacteria and their metabolites. However, there is still insufficient data on the impact of an HPD or HCHD in addition to supplements on “anaerobic” and “aerobic” athletes’ gut microbiota and how this impact could be affected by nutritional interventions such as pre- and probiotic therapy. Additionally, little is known about the role of probiotics in the ergogenic effects of supplements. Based on the results of our previous research on an HPD in amateur bodybuilders and an HCHD in amateur cyclists, we reviewed human and animal studies on the effects of popular supplements on gut homeostasis and sport performance.
Oxygen Consumption Predicts Long-Term Outcome of Patients with Left Ventricular Assist Devices
Authors: Veraar Cecilia , Fischer Arabella , Bernardi Martin H. , Worf Isabella , Mouhieddine Mohamed , Schlöglhofer Thomas , Wiedemann Dominik , Dworschak Martin , Tschernko Edda , Lassnigg Andrea , Hiesmayr Michael
Published: March 2023

Reduced oxygen consumption (VO2), either due to insufficient oxygen delivery (DO2), microcirculatory hypoperfusion and/or mitochondrial dysfunction, has an impact on the adverse short- and long-term survival of patients after cardiac surgery. However, it is still unclear whether VO2 remains an efficient predictive marker in a population in which cardiac output (CO) and consequently DO2 is determined by a left ventricular assist device (LVAD). We enrolled 93 consecutive patients who received an LVAD with a pulmonary artery catheter in place to monitor CO and venous oxygen saturation. VO2 and DO2 of in-hospital survivors and non-survivors were calculated over the first 4 days. Furthermore, we plotted receiver-operating curves (ROC) and performed a cox-regression analysis. VO2 predicted in-hospital, 1- and 6-year survival with the highest area under the curve of 0.77 (95%CI: 0.6–0.9; p = 0.0004). A cut-off value of 210 mL/min VO2 stratified patients regarding mortality with a sensitivity of 70% and a specificity of 81%. Reduced VO2 was an independent predictor for in-hospital, 1- and 6-year mortality with a hazard ratio of 5.1 (p = 0.006), 3.2 (p = 0.003) and 1.9 (p = 0.0021). In non-survivors, VO2 was significantly lower within the first 3 days (p = 0.010, p < 0.001, p < 0.001 and p = 0.015); DO2 was reduced on days 2 and 3 (p = 0.007 and p = 0.003). In LVAD patients, impaired VO2 impacts short- and long-term outcomes. Perioperative and intensive care medicine must, therefore, shift their focus from solely guaranteeing sufficient oxygen supply to restoring microcirculatory perfusion and mitochondrial functioning.
Optimized High Throughput Ascochyta Blight Screening Protocols and Immunity to A. pisi in Pea
Authors: Annan Emmanuel N. , Nyamesorto Bernard , Yan Qing , McPhee Kevin , Huang Li
Published: March 2023

Ascochyta blight (AB) is a destructive disease of the field pea (Pisum sativum L.) caused by necrotrophic fungal pathogens known as the AB-disease complex. To identify resistant individuals to assist AB resistance breeding, low-cost, high throughput, and reliable protocols for AB screening are needed. We tested and optimized three protocols to determine the optimum type of pathogen inoculum, the optimal development stage for host inoculation, and the timing of inoculation for detached-leaf assays. We found that different plant development stages do not affect AB infection type on peas, but the timing of inoculation affects the infection type of detached leaves due to wound-induced host defense response. After screening nine pea cultivars, we discovered that cultivar Fallon was immune to A. pisi but not to A. pinodes or the mixture of the two species. Our findings suggest that AB screening can be done with any of the three protocols. A whole-plant inoculation assay is necessary for identifying resistance to stem/node infection. Pathogen inoculation must be completed within 1.5 h post-detachment to avoid false positives of resistance for detach-leaf assays. It is essential to use a purified single-species inoculum for resistant resource screenings to identify the host resistance to each single species.
Spherical Body Protein 4 from Babesia bigemina: A Novel Gene That Contains Conserved B-Cell Epitopes and Induces Cross-Reactive Neutralizing Antibodies in Babesia ovata
Authors: Mosqueda Juan , Hernandez-Silva Diego Josimar , Ueti Massaro W. , Cruz-Reséndiz Adolfo , Marquez-Cervantez Ricardo , Valdez-Espinoza Uriel Mauricio , Dang-Trinh Minh-Anh , Nguyen Thu-Thuy , Camacho-Nuez Minerva , Mercado-Uriostegui Miguel Angel , Aguilar-Tipacamú Gabriela , Ramos-Aragon Juan Alberto , Hernandez-Ortiz Ruben , Kawazu Shin-ichiro , Igarashi Ikuo
Published: March 2023

Bovine babesiosis is a tick-transmitted disease caused by intraerythrocytic protozoan parasites of the genus Babesia. Its main causative agents in the Americas are Babesia bigemina and Babesia bovis, while Babesia ovata affects cattle in Asia. All Babesia species secrete proteins stored in organelles of the apical complex, which are involved in all steps of the invasion process of vertebrate host cells. Unlike other apicomplexans, which have dense granules, babesia parasites instead have large, round intracellular organelles called spherical bodies. Evidence suggests that proteins from these organelles are released during the process of invading red blood cells, where spherical body proteins (SBPs) play an important role in cytoskeleton reorganization. In this study, we characterized the gene that encodes SBP4 in B. bigemina. This gene is transcribed and expressed in the erythrocytic stages of B. bigemina. The sbp4 gene consists of 834 nucleotides without introns that encode a protein of 277 amino acids. In silico analysis predicted a signal peptide that is cleaved at residue 20, producing a 28.88-kDa protein. The presence of a signal peptide and the absence of transmembrane domains suggest that this protein is secreted. Importantly, when cattle were immunized with recombinant B. bigemina SBP4, antibodies identified B. bigemina and B. ovata merozoites according to confocal microscopy observations and were able to neutralize parasite multiplication in vitro for both species. Four peptides with predicted B-cell epitopes were identified to be conserved in 17 different isolates from six countries. Compared with the pre-immunization sera, antibodies against these conserved peptides reduced parasite invasion in vitro by 57%, 44%, 42%, and 38% for peptides 1, 2, 3, and 4, respectively (p < 0.05). Moreover, sera from cattle infected with B. bigemina cattle contained antibodies that recognized the individual peptides. All these results support the concept of spb4 as a new gene in B. bigemina that should be considered a candidate for a vaccine to control bovine babesiosis.
Neutralization Sensitivity and Evolution of Virus in a Chronic HIV-1 Clade B Infected Patient with Neutralizing Activity against Membrane-Proximal External Region
Authors: Tang Wenqi , Yuan Zhenzhen , Wang Zheng , Ren Li , Li Dan , Wang Shuhui , Hao Yanling , Li Jing , Shen Xiuli , Ruan Yuhua , Shao Yiming , Liu Ying
Published: March 2023

The membrane-proximal external region (MPER) is a promising HIV-1 vaccine target owing to its linear neutralizing epitopes and highly conserved amino acids. Here, we explored the neutralization sensitivity and investigated the MPER sequences in a chronic HIV-1 infected patient with neutralizing activity against the MPER. Using single-genome amplification (SGA), 50 full-length HIV-1 envelope glycoprotein (env) genes were isolated from the patient’s plasma at two time points (2006 and 2009). The neutralization sensitivity of 14 Env-pseudoviruses to autologous plasma and monoclonal antibodies (mAbs) was evaluated. Env gene sequencing revealed that the diversity of Env increased over time and four mutation positions (659D, 662K, 671S, and 677N/R) were identified in the MPER. The K677R mutation increased the IC50 values of pseudoviruses approximately twofold for 4E10 and 2F5, and E659D increased the IC50 up to ninefold for 4E10 and fourfold for 2F5. These two mutations also decreased the contact between gp41 and mAbs. Almost all mutant pseudoviruses were resistant to autologous plasma at both the earlier and concurrent time points. Mutations 659D and 677R in the MPER decreased the neutralization sensitivity of Env-pseudoviruses, providing a detailed understanding of MPER evolution which might facilitate advances in the design of HIV-1 vaccines.
Synergistic Detrimental Effects of Cigarette Smoke, Alcohol, and SARS-CoV-2 in COPD Bronchial Epithelial Cells
Authors: Muralidharan Abenaya , Bauer Christopher D. , Katafiasz Dawn M. , Strah Heather M. , Siddique Aleem , Reid St Patrick , Bailey Kristina L. , Wyatt Todd A.
Published: March 2023

Lung conditions such as COPD, as well as risk factors such as alcohol misuse and cigarette smoking, can exacerbate COVID-19 disease severity. Synergistically, these risk factors can have a significant impact on immunity against pathogens. Here, we studied the effect of a short exposure to alcohol and/or cigarette smoke extract (CSE) in vitro on acute SARS-CoV-2 infection of ciliated human bronchial epithelial cells (HBECs) collected from healthy and COPD donors. We observed an increase in viral titer in CSE- or alcohol-treated COPD HBECs compared to untreated COPD HBECs. Furthermore, we treated healthy HBECs accompanied by enhanced lactate dehydrogenase activity, indicating exacerbated injury. Finally, IL-8 secretion was elevated due to the synergistic damage mediated by alcohol, CSE, and SARS-CoV-2 in COPD HBECs. Together, our data suggest that, with pre-existing COPD, short exposure to alcohol or CSE is sufficient to exacerbate SARS-CoV-2 infection and associated injury, impairing lung defences.
Drug-Utilization, Healthcare Facilities Accesses and Costs of the First Generation of JAK Inhibitors in Rheumatoid Arthritis
Authors: Convertino Irma , Lorenzoni Valentina , Gini Rosa , Turchetti Giuseppe , Fini Elisabetta , Giometto Sabrina , Bartolini Claudia , Paoletti Olga , Ferraro Sara , Cappello Emiliano , Valdiserra Giulia , Bonaso Marco , Blandizzi Corrado , Tuccori Marco , Lucenteforte Ersilia
Published: March 2023

This study is aimed at describing tofacitinib and baricitinib users by characterizing their prescription and healthcare histories, drug and healthcare utilization patterns, and direct costs from a healthcare system perspective. This retrospective cohort study was performed using Tuscan administrative healthcare databases, which selected two groups of Janus kinase inhibitors (JAKi) incident users (index date) from 1st January 2018 to 31 December 2019 and from 1 January 2018 to 30 June 2019. We included patients ≥18 years old, at least 10 years of data, and six months of follow-up. In the first analysis, we describe mean time, standard deviation (SD), from the first-ever disease-modifying antirheumatic drug (DMARD) to the JAKi, and costs of healthcare facilities and drugs in the 5 years preceding the index date. In the second analysis, we assessed Emergency Department (ED) accesses and hospitalizations for any causes, visits, and costs in the follow-up. In the first analysis, 363 incident JAKi users were included (mean age 61.5, SD 13.6; females 80.7%, baricitinib 78.5%, tofacitinib 21.5%). The time to the first JAKi was 7.2 years (SD 3.3). The mean costs from the fifth to the second year before JAKi increased from 4325 € (0; 24,265) to 5259 € (0; 41,630) per patient/year, driven by hospitalizations. We included 221 incident JAKi users in the second analysis. We observed 109 ED accesses, 39 hospitalizations, and 64 visits. Injury and poisoning (18.3%) and skin (13.8%) caused ED accesses, and cardiovascular (69.2%) and musculoskeletal (64.1%) caused hospitalizations. The mean costs were 4819 € (607.5; 50,493) per patient, mostly due to JAKi. In conclusion, the JAKi introduction in therapy occurred in compliance with RA guidelines and the increase in costs observed could be due to a possible selective prescription.
One-Pot Synthesis of 1-Thia-4-azaspiro[4.4/5]alkan-3-ones via Schiff Base: Design, Synthesis, and Apoptotic Antiproliferative Properties of Dual EGFR/BRAFV600E Inhibitors
Authors: Al-Wahaibi Lamya H. , El-Sheref Essmat M. , Hammouda Mohamed M. , Youssif Bahaa G. M.
Published: March 2023

In this investigation, novel 4-((quinolin-4-yl)amino)-thia-azaspiro[4.4/5]alkan-3-ones were synthesized via interactions between 4-(2-cyclodenehydrazinyl)quinolin-2(1H)-one and thioglycolic acid catalyzed by thioglycolic acid. We prepared a new family of spiro-thiazolidinone derivatives in a one-step reaction with excellent yields (67–79%). The various NMR, mass spectra, and elemental analyses verified the structures of all the newly obtained compounds. The antiproliferative effects of 6a–e, 7a, and 7b against four cancer cells were investigated. The most effective antiproliferative compounds were 6b, 6e, and 7b. Compounds 6b and 7b inhibited EGFR with IC50 values of 84 and 78 nM, respectively. Additionally, 6b and 7b were the most effective inhibitors of BRAFV600E (IC50 = 108 and 96 nM, respectively) and cancer cell proliferation (GI50 = 35 and 32 nM against four cancer cell lines, respectively). Finally, the apoptosis assay results revealed that compounds 6b and 7b had dual EGFR/BRAFV600E inhibitory properties and showed promising antiproliferative and apoptotic activity.
Development and Characterization of Hydroxyethyl Cellulose-Based Gels Containing Lactobacilli Strains: Evaluation of Antimicrobial Effects in In Vitro and Ex Vivo Models
Authors: Sousa Marcela Almeida dos Santos de , Ferreira Alexia Figueiredo , da Silva Camila Caetano , Silva Marcos Andrade , Bazan Tamyris Alicely Xavier Nogueira , Monteiro Cristina de Andrade , Monteiro Andrea de Souza , Sousa Joicy Cortez de Sá , da Silva Luís Cláudio Nascimento , Zagmignan Adrielle
Published: March 2023

This study aimed to develop a hydroxyethyl cellulose-based topical formulation containing probiotics and to evaluate its antimicrobial action using in vivo and ex vivo models. Initially, the antagonistic effects of Lacticaseibacillus rhamnosus ATCC 10863, Limosilactobacillus fermentum ATCC 23271, Lactiplantibacillus plantarum ATCC 8014 and Lactiplantibacillus plantarum LP-G18-A11 were analyzed against Enterococcus faecalis ATCC 29212, Klebsiella pneumoniae ATCC 700603, Staphylococcus aureus ATCC 27853 and Pseudomonas aeruginosa ATCC 2785. The best action was seen for L. plantarum LP-G18-A11, which presented high inhibition against S. aureus and P. aeruginosa. Then, lactobacilli strains were incorporated into hydroxyethyl cellulose-based gels (natrosol); however, only the LP-G18-A11-incorporated gels (5% and 3%) showed antimicrobial effects. The LP-G18-A11 gel (5%) maintained its antimicrobial effects and viability up to 14 and 90 days at 25 °C and 4 °C, respectively. In the ex vivo assay using porcine skin, the LP-G18-A11 gel (5%) significantly reduced the skin loads of S. aureus and P. aeruginosa after 24 h, while only P. aeruginosa was reduced after 72 h. Moreover, the LP-G18-A11 gel (5%) showed stability in the preliminary and accelerated assays. Taken together, the results show the antimicrobial potential of L. plantarum LP-G18-A11, which may be applied in the development of new dressings for the treatment of infected wounds.
Suramin Affects the Renal VEGF-A/VEGFR Axis in Short-Term Streptozotocin-Induced Diabetes
Authors: Chyła-Danił Gabriela , Sałaga-Zaleska Kornelia , Kreft Ewelina , Krzesińska Aleksandra , Herman Sylwia , Kuchta Agnieszka , Sakowicz-Burkiewicz Monika , Lenartowicz Małgorzata , Jankowski Maciej
Published: March 2023

Diabetic nephropathy (DN) accounts for approximately 50% of end-stage renal diseases. Vascular endothelial growth factor A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in DN, but its role is unclear. The lack of pharmacological tools to modify renal concentrations further hinders the understanding of its role in DN. In this study, rats were evaluated after 3 weeks of streptozotocin-induced diabetes and two suramin treatments (10 mg/kg, ip). Vascular endothelial growth factor A expression was evaluated by western blot of glomeruli and immunofluorescence of the renal cortex. RT-PCR for receptors Vegfr1 mRNA and Vegfr2 mRNA quantitation was performed. The soluble adhesive molecules (sICAM-1, sVCAM-1) in blood were measured by ELISA and the vasoreactivity of interlobar arteries to acetylcholine was evaluated using wire myography. Suramin administration reduced the expression and intraglomerular localisation of VEGF-A. Increased VEGFR-2 expression in diabetes was reduced by suramin to non-diabetic levels. Diabetes reduced the sVCAM-1 concentrations. Suramin in diabetes restored acetylcholine relaxation properties to non-diabetic levels. In conclusion, suramin affects the renal VEGF-A/VEGF receptors axis and has a beneficial impact on endothelium-dependent relaxation of renal arteries. Thus, suramin may be used as a pharmacological agent to investigate the potential role of VEGF-A in the pathogenesis of renal vascular complications in short-term diabetes.
Pharmacological Profile of the Purinergic P2Y Receptors That Modulate, in Response to ADPβS, the Vasodepressor Sensory CGRPergic Outflow in Pithed Rats
Authors: Miguel-Martínez Alejandro D. , Linares-Bedolla Juan , Villanueva-Castillo Belinda , Haanes Kristian A. , MaassenVanDenBrink Antoinette , Villalón Carlos M.
Published: March 2023

Calcitonin gene-related peptide (CGRP), an endogenous neuropeptide released from perivascular sensory nerves, exerts a powerful vasodilatation. Interestingly, adenosine triphosphate (ATP) stimulates the release of CGRP by activation of prejunctional P2X2/3 receptors, and adenosine 5′-O-2-thiodiphosphate (ADPβS), a stable adenosine diphosphate (ADP) analogue, produces vasodilator/vasodepressor responses by endothelial P2Y1 receptors. Since the role of ADP in the prejunctional modulation of the vasodepressor sensory CGRPergic drive and the receptors involved remain unknown, this study investigated whether ADPβS inhibits this CGRPergic drive. Accordingly, 132 male Wistar rats were pithed and subsequently divided into two sets. In set 1, ADPβS (5.6 and 10 µg/kg·min) inhibited the vasodepressor CGRPergic responses by electrical stimulation of the spinal T9–T12 segment. This inhibition by ADPβS (5.6 µg/kg·min) was reverted after i.v. administration of the purinergic antagonists MRS2500 (300 µg/kg; P2Y1) or MRS2211 (3000 µg/kg; P2Y13), but not by PSB0739 (300 µg/kg; P2Y12), MRS2211 (1000 µg/kg; P2Y13) or the KATP blocker glibenclamide (20 mg/kg). In set 2, ADPβS (5.6 µg/kg·min) failed to modify the vasodepressor responses to exogenous α-CGRP. These results suggest that ADPβS inhibits CGRP release in perivascular sensory nerves. This inhibition, apparently unrelated to activation of ATP-sensitive K+ channels, involves P2Y1 and probably P2Y13, but not P2Y12 receptors.
pH-Dependent Behavior of Novel 5-FU Delivery System in Environmental Conditions Comparable to the Gastro-Intestinal Tract
Authors: Lazar Geza , Nekvapil Fran , Glamuzina Branko , Tamaș Tudor , Barbu-Tudoran Lucian , Suciu Maria , Cinta Pinzaru Simona
Published: March 2023

A biogenic carrier for 5-fluorouracil (5-FU) loading and subsequent tableting as a new drug formulation for slow release has been proposed using the biomineral from blue crab carapace. Due to its highly ordered 3D porous nanoarchitecture, the biogenic carbonate carrier could achieve increased effectiveness in colorectal cancer cure provided that the formulation would successfully pass through the gastric acid conditions. Following the recently proven viability of the concept by demonstrating the slow release of the drug from the carrier using the highly sensitive SERS technique, here we investigated the 5-FU release from the composite tablet drug in pH conditions replicating the gastric environment. The released drug from the tablet was studied in solutions with three relevant pH values, pH 2, pH 3, and pH 4. The 5-FU SERS spectral signature for each pH value was used to build calibration curves for quantitative SERS analysis. The results suggested a similarly slow-releasing pattern in acid pH environments to that in neutral conditions. Although biogenic calcite dissolution was expected in acid conditions, the X-ray diffraction and Raman spectroscopy showed preservation of calcite mineral along with the monohydrocalcite during acid solution exposure for two hours. The total released amount in a time course of seven hours, however, was lower in acidic pH solutions, with a maximum fraction of ~40% of the total amount of loaded drug, for pH 2, as opposed to ~80% for neutral values. Nonetheless, these results clearly prove that the novel composite drug retains its slow-releasing character in environmental conditions compatible with the gastrointestinal pH and that it is a viable and biocompatible alternative for oral delivery of anticancer drug to reach the lower gastro-intestinal tract.
Intragastric Carbon Dioxide Release Prolongs the Gastric Residence Time of Postprandially Administered Caffeine
Authors: Senekowitsch Stefan , Foja Constantin , Wildgrube Toni , Schick Philipp , Rosenbaum Christoph , Krause Julius , Brokmann Friederike , Kromrey Marie-Luise , Engeli Stefan , Weitschies Werner , Grimm Michael
Published: March 2023

Sparkling water is said to increase gastric motility by the release of carbon dioxide, thereby potentially affecting the pharmacokinetics of orally administered drugs. The hypothesis of the present work was that the induction of gastric motility by intragastric release of carbon dioxide from effervescent granules could promote the mixing of drugs into the chyme under postprandial conditions, resulting in a prolonged drug absorption. For this purpose, an effervescent and a non-effervescent granule formulation of caffeine as a marker for gastric emptying were developed. In a three-way crossover study with twelve healthy volunteers, the salivary caffeine pharmacokinetics, after administration of the effervescent granules with still water and the administration of the non-effervescent granules with still and sparkling water, were investigated after intake of a standard meal. While the administration of the effervescent granules with 240 mL of still water led to a significantly prolonged gastric residence of the substance compared to the administration of the non-effervescent granules with 240 mL still water, the application of the non-effervescent granules with 240 mL sparkling water did not prolong gastric residence via mixing into caloric chyme. Overall, the mixing of caffeine into the chyme following the administration of the effervescent granules did not seem to be a motility mediated process.
Design and Characterization of a Novel Venetoclax-Zanubrutinib Nano-Combination for Enhancing Leukemic Cell Uptake and Long-Acting Plasma Exposure
Authors: Griffin James , Wu Yan , Mu Qingxin , Li Xinyan , Ho Rodney J. Y.
Published: March 2023

Leukemia remains incurable partly due to difficulties in reaching and maintaining therapeutic drug concentrations in the target tissues and cells. Next-generation drugs targeted to multiple cell checkpoints, including the orally active venetoclax (Bcl-2 target) and zanubrutinib (BTK target), are effective and have improved safety and tolerability compared to conventional, nontargeted chemotherapies. However, dosing with a single agent frequently leads to drug resistance; asynchronous coverage due to the peak-and-trough time-course of two or more oral drugs has prevented drug combinations from simultaneously knocking out the respective drugs’ targets for sustained leukemia suppression. Higher doses of the drugs may potentially overcome asynchronous drug exposure in leukemic cells by saturating target occupancy, but higher doses often cause dose-limiting toxicities. To synchronize multiple drug target knockout, we have developed and characterized a drug combination nanoparticle (DcNP), which enables the transformation of two short-acting, orally active leukemic drugs, venetoclax and zanubrutinib, into long-acting nanoformulations (VZ-DCNPs). VZ-DCNPs exhibit synchronized and enhanced cell uptake and plasma exposure of both venetoclax and zanubrutinib. Both drugs are stabilized by lipid excipients to produce the VZ-DcNP nanoparticulate (d ~ 40 nm) product in suspension. The VZ-DcNP formulation has enhanced uptake of the two drugs (VZ) in immortalized leukemic cells (HL-60), threefold over that of its free drug counterpart. Additionally, drug-target selectivity of VZ was noted with MOLT-4 and K562 cells that overexpress each target. When given subcutaneously to mice, the half-lives of venetoclax and zanubrutinib were extended by approximately 43- and 5-fold, respectively, compared to an equivalent free VZ. Collectively, these data suggest that VZ in VZ-DcNP warrant consideration for preclinical and clinical development as a synchronized and long-acting drug-combination for the treatment of leukemia.
Bacterial Lectin FimH and Its Aggregation Hot-Spots: An Alternative Strategy against Uropathogenic Escherichia coli
Authors: Nasi Georgia I. , Georgakopoulou Konstantina I. , Theodoropoulou Marilena K. , Papandreou Nikos C. , Chrysina Evangelia D. , Tsiolaki Paraskevi L. , Iconomidou Vassiliki A.
Published: March 2023

Type I fimbriae are the main adhesive organelles of uropathogenic Escherichia coli (UPEC), consisting of four different subunits. Their component with the most important role in establishing bacterial infections is the FimH adhesin located at the fimbrial tip. This two-domain protein mediates adhesion to host epithelial cells through interaction with terminal mannoses on epithelial glycoproteins. Here, we propose that the amyloidogenic potential of FimH can be exploited for the development of therapeutic agents against Urinary Tract Infections (UTIs). Aggregation-prone regions (APRs) were identified via computational methods, and peptide-analogues corresponding to FimH lectin domain APRs were chemically synthesized and studied with the aid of both biophysical experimental techniques and molecular dynamic simulations. Our findings indicate that these peptide-analogues offer a promising set of antimicrobial candidate molecules since they can either interfere with the folding process of FimH or compete for the mannose-binding pocket.
Carbon Dots: Opportunities and Challenges in Cancer Therapy
Authors: Bhattacharya Tanima , Shin Gye Hwa , Kim Jun Tae
Published: March 2023

Recently, carbon dots (CDs) have been actively studied and reported for their various properties. In particular, the specific characteristics of carbon dots have been considered as a possible technique for cancer diagnosis and therapy. This is also a cutting-edge technology that offers fresh ideas for treating various disorders. Though carbon dots are still in their infancy and have not yet shown their value to society, their discovery has already resulted in some noteworthy advancements. The application of CDs indicates conversion in natural imaging. Photography using CDs has demonstrated extraordinary appropriateness in bio-imaging, the discovery of novel drugs, the delivery of targeted genes, bio-sensing, photodynamic therapy, and diagnosis. This review seeks to provide a comprehensive understanding of CDs, including their benefits, characteristics, applications, and mode of action. In this overview, many CD design strategies will be highlighted. In addition, we will discuss numerous studies on cytotoxic testing to demonstrate the safety of CDs. The current study will address the production method, mechanism, ongoing research, and application of CDs in cancer diagnosis and therapy.
An Enhanced Dissolving Cyclosporin-A Inhalable Powder Efficiently Reduces SARS-CoV-2 Infection In Vitro
Authors: D’Angelo Davide , Quarta Eride , Glieca Stefania , Varacca Giada , Flammini Lisa , Bertoni Simona , Brandolini Martina , Sambri Vittorio , Grumiro Laura , Gatti Giulia , Dirani Giorgio , Taddei Francesca , Bianchera Annalisa , Sonvico Fabio , Bettini Ruggero , Buttini Francesca
Published: March 2023

This work illustrates the development of a dry inhalation powder of cyclosporine-A for the prevention of rejection after lung transplantation and for the treatment of COVID-19. The influence of excipients on the spray-dried powder’s critical quality attributes was explored. The best-performing powder in terms of dissolution time and respirability was obtained starting from a concentration of ethanol of 45% (v/v) in the feedstock solution and 20% (w/w) of mannitol. This powder showed a faster dissolution profile (Weibull dissolution time of 59.5 min) than the poorly soluble raw material (169.0 min). The powder exhibited a fine particle fraction of 66.5% and an MMAD of 2.97 µm. The inhalable powder, when tested on A549 and THP-1, did not show cytotoxic effects up to a concentration of 10 µg/mL. Furthermore, the CsA inhalation powder showed efficiency in reducing IL-6 when tested on A549/THP-1 co-culture. A reduction in the replication of SARS-CoV-2 on Vero E6 cells was observed when the CsA powder was tested adopting the post-infection or simultaneous treatment. This formulation could represent a therapeutic strategy for the prevention of lung rejection, but is also a viable approach for the inhibition of SARS-CoV-2 replication and the COVID-19 pulmonary inflammatory process.
Nanotechnology in Cancer Diagnosis and Treatment
Authors: Alrushaid Noor , Khan Firdos Alam , Al-Suhaimi Ebtesam Abdullah , Elaissari Abdelhamid
Published: March 2023

Traditional cancer diagnosis has been aided by the application of nanoparticles (NPs), which have made the process easier and faster. NPs possess exceptional properties such as a larger surface area, higher volume proportion, and better targeting capabilities. Additionally, their low toxic effect on healthy cells enhances their bioavailability and t-half by allowing them to functionally penetrate the fenestration of epithelium and tissues. These particles have attracted attention in multidisciplinary areas, making them the most promising materials in many biomedical applications, especially in the treatment and diagnosis of various diseases. Today, many drugs are presented or coated with nanoparticles for the direct targeting of tumors or diseased organs without harming normal tissues/cells. Many types of nanoparticles, such as metallic, magnetic, polymeric, metal oxide, quantum dots, graphene, fullerene, liposomes, carbon nanotubes, and dendrimers, have potential applications in cancer treatment and diagnosis. In many studies, nanoparticles have been reported to show intrinsic anticancer activity due to their antioxidant action and cause an inhibitory effect on the growth of tumors. Moreover, nanoparticles can facilitate the controlled release of drugs and increase drug release efficiency with fewer side effects. Nanomaterials such as microbubbles are used as molecular imaging agents for ultrasound imaging. This review discusses the various types of nanoparticles that are commonly used in cancer diagnosis and treatment.
Development and Characterization of Pullulan-Based Orodispersible Films of Iron
Authors: Gupta Maram Suresh , Kumar Tegginamath Pramod , Reddy Dinesh , Pathak Kamla , Gowda Devegowda Vishakante , Babu A. V. Naresh , Aodah Alhussain H. , Khafagy El-Sayed , Alotaibi Hadil Faris , Abu Lila Amr Selim , Moin Afrasim , Hussin Talib
Published: March 2023

Iron deficiency is the principal cause of nutritional anemia and it constitutes a major health problem, especially during pregnancy. Despite the availability of various non-invasive traditional oral dosage forms such as tablets, capsules, and liquid preparations of iron, they are hard to consume for special populations such as pregnant women, pediatric, and geriatric patients with dysphagia and vomiting tendency. The objective of the present study was to develop and characterize pullulan-based iron-loaded orodispersible films (i-ODFs). Microparticles of iron were formulated by a microencapsulation technique, to mask the bitter taste of iron, and ODFs were fabricated by a modified solvent casting method. Morphological characteristics of the microparticles were identified by optical microscopy and the percentage of iron loading was evaluated by inductively coupled plasma optical emission spectroscopy (ICP-OES). The fabricated i-ODFs were evaluated for their morphology by scanning electron microscopy. Other parameters including thickness, folding endurance, tensile strength, weight variation, disintegration time, percentage moisture loss, surface pH, and in vivo animal safety were evaluated. Lastly, stability studies were carried out at a temperature of 25 °C/60% RH. The results of the study confirmed that pullulan-based i-ODFs had good physicochemical properties, excellent disintegration time, and optimal stability at specified storage conditions. Most importantly, the i-ODFs were free from irritation when administered to the tongue as confirmed by the hamster cheek pouch model and surface pH determination. Collectively, the present study suggests that the film-forming agent, pullulan, could be successfully employed on a lab scale to formulate orodispersible films of iron. In addition, i-ODFs can be processed easily on a large scale for commercial use.
SMART Pharmacists Serving the New Needs of the Post-COVID Patients, Leaving No-One Behind
Authors: Šipetić Tatjana , Rajković Dragana , Bogavac Stanojević Nataša , Marinković Valentina , Meštrović Arijana , Rouse Michael J.
Published: March 2023

This study aims to demonstrate the improvements in clinical symptoms in patients with post-COVID syndrome after a community pharmacy-based intervention in Serbia. The Pharmaceutical Chamber of Serbia (“Chamber”) invited pharmacists to deliver post-COVID patient care counselling, supported by the SMART Pharmacist Program, offering education and guidance. Present symptoms, duration and patient self-reported severity of symptoms on a scale of 1–5 on the first visit were recorded. After the counselling and proposed self-medication treatment, the time of the follow-up visit and the severity of the recorded symptoms were also recorded. The prospective data collection lasted from December 2021 to September 2022. In total, 871 patients with post-COVID symptoms were included in the study, served by 53 pharmacists. The most frequently reported post-COVID symptoms coincided with the literature, mostly related to the respiratory system (51.2%), immunity status (32.2%), fatigue and exhaustion (30.7%), skin, hair and nails (27.4%) and cognitive functions (27.9%). A total of 26.5% of patients were referred to their family physician (general practitioner), and 69.5% returned to the pharmacist for a follow-up visit. On the first visit, the median severity of patients’ symptoms was three, while on the second visit it dropped to one. The pharmacists’ intervention led to a significant improvement in the post-COVID patients’ condition.
The Pharmacist Prescriber: A Psychological Perspective on Complex Conversations about Medicines: Introducing Relational Prescribing and Open Dialogue in Physical Health
Authors: Rogalski David , Barnett Nina , Bueno de Mesquita Amanda , Jubraj Barry
Published: March 2023

Pharmacists have traditionally supported the prescribing process, arguably in reactive or corrective roles. The advent of pharmacist prescribing in 2004 represented a major shift in practice, leading to greater responsibility for making clinical decisions with and for patients. Prescribing rights require pharmacists to take a more prescriptive role that will allow them to contribute to long-standing prescribing challenges such as poor medication adherence, overprescribing, and the need for shared decision-making and person-centered care. Central to these endeavors are the development and possession of effective consultation skills. University schools of pharmacists in the UK now routinely include consultation skills training, which is also provided by national education bodies. These challenges remain difficult to overcome, even though it is understood, for example, that increasing the effectiveness of adherence interventions may have a far greater impact on the health of the population than any improvement in specific medical treatments. More recently, a concerted effort has been made to tackle overprescribing and the harm that may occur through the inappropriate use of medication. In routine pharmacy work, these priorities may linger at the bottom of the list due to the busy and complex nature of the work. Solutions to these problems of adherence, optimizing benefits of medication, and overprescribing have typically been pragmatic and structured. However, an arguably reductionist approach to implementation fails to address the complex patient interactions around prescribing and taking medication, and the heterogeneity of the patient’s experience, leaving the answers elusive. We suggest that it is essential to explore how person-centered care is perceived and to emphasize the relational aspects of clinical consultations. The development of routine pharmacist prescribing demands building on the core values of person-centered care and shared decision making by introducing the concepts of “relational prescribing” and “open dialogue” to cultivate an essential pharmacotherapeutic alliance to deliver concrete positive patient outcomes. We provide a vignette of how a clinical case can be approached using principles of relational prescribing and open dialogue. We believe these are solutions that are not additional tasks but must be embedded into pharmacy practice. This will improve professional satisfaction and resilience, and encourage curiosity and creativity, particularly with the advent of all pharmacists in Great Britain becoming prescribers at graduation from 2026.
An Autofocus Method Based on Improved Differential Confocal Microscopy in Two-Photon Lithography
Authors: Yang Zhenyu , He Minfei , Zhou Guozun , Kuang Cuifang , Liu Xu
Published: March 2023

Two-photon lithography (TPL) plays a vital role in microstructure fabrication due to its high processing accuracy and maskless characteristics. To optimize the manufacturing quality deteriorated by the defocus of the substrate, an autofocus approach based on improved differential confocal microscopy (IDCM) is proposed in this paper. Through analyzing the intensity response signals from two detectors with symmetrical axial offset, the defocus amount is measured and compensated for with high precision and noise immunity to stabilize the substrate. The verification experiments on the coverslip reported a detection sensitivity of 5 nm, a repetitive measurement accuracy of less than 15 nm, and a focusing accuracy reaching around 5 nm. The consistency between simulation and characterization demonstrated the effectiveness and superior performance of the autofocus system for the high production quality of the metalens array. The proposed autofocus method shows promise for further application to the fabrication of complex structures on various substrates.
Seed Transmission of Begomoviruses: A Potential Threat for Bitter Gourd Cultivation
Authors: Gomathi Devi Ravisankar , Jothika Chinnaraj , Sankari Arjunan , Lakshmi Sethuraman , Malathi Varagur Ganesan , Renukadevi Perumal
Published: March 2023

Bitter gourd (Momordica charantia L.), one of the valued vegetable crops in India, is severely affected by yellow mosaic disease caused by two begomoviruses, tomato leaf curl New Delhi virus (ToLCNDV) and bitter gourd yellow mosaic virus (BgYMV). The symptoms are yellowing, distortion of leaf, puckering, and malformed fruits. Increased incidence of the disease and appearance of symptoms even in young emerging seedling stage were suggestive of seed transmission of the viruses, which was examined in detail. To study the seed transmission, two sources—seeds of elite hybrids H1, H2, H3, H4, and Co1 procured from a seed market; and seeds from infected plants in the farmer’s field were tested. Detection of the virus by DAS-ELISA using polyclonal antibody indicated embryo infection up to 63%, 26%, 20%, and 10% in hybrids H1, H2, H3, and H4, respectively, for market-procured seeds. In PCR analysis with primers specific for ToLCNDV and BgYMV, infection by ToLCNDV was as high as 76% and mixed infection was 24%. In contrast, in seeds derived from field-infected plants, the percentage detection was less. Grow-out tests with market-procured seeds revealed no transmission for BgYMV compared with 5% transmission for ToLCNDV. Whether seed-borne inocula could serve as an inoculum for new infection in a field and further progress of the disease was investigated in a microplot study. The study clearly revealed variation in seed transmission between different sources, lots, cultivars, and viruses. The virus present in symptomatic and asymptomatic plants was easily transmitted by whitefly. In another microplot experiment, the potential of seed-borne virus as inoculum was proved. There was 43.3% initial seed transmission in the microplot, increasing to 70% after release of 60 whiteflies.
Identification of Candidate Genes for Salt Tolerance at the Seedling Stage Using Integrated Genome-Wide Association Study and Transcriptome Analysis in Rice
Authors: Kim Tae-Heon , Kim Suk-Man
Published: March 2023

Salt stress is a major constraint in rice production worldwide. Salt stress is estimated to cause annual losses of 30–50% in rice production. Discovering and deploying salt-resistance genes are the most effective ways to control salt stress. We performed a genome-wide association study (GWAS) to detect QTLs related to salt tolerance at the seedling stage using the japonica-multiparent advanced generation intercross (MAGIC) population. Four QTLs (qDTS1-1, qDTS1-2, qDTS2, and qDTS9) associated with salt tolerance were identified on chromosomes 1, 2, and 9. Among these QTLs, a novel QTL, qDTS1-2, was located between flanking SNPs (1354576 and id1028360) on chromosome 1, with the largest −log10(P) value of 5.81 and a total phenotypic variance of 15.2%. RNA-seq analysis revealed that among the seven differentially expressed genes (DEGs) commonly identified in both P6 and JM298 showing salt tolerance, two upregulated genes, Os01g0963600 (ASR transcription factor) and Os01g0975300 (OsMYB48), related to salt and drought tolerance, were also involved in the target region of qDTS1-2. The results of this study can provide insights into further understanding of salt tolerance mechanisms and developing DNA markers for marker-assisted selection (MAS) breeding to improve the salt tolerance of cultivars in rice breeding programs.
Time Effects of Global Change on Forest Productivity in China from 2001 to 2017
Authors: Wang Jiangfeng , Li Yanhong , Gao Jie
Published: March 2023

With global warming, the concentrations of fine particulate matter (PM2.5) and greenhouse gases, such as CO2, are increasing. However, it is still unknown whether these increases will affect vegetation productivity. Exploring the impacts of global warming on net primary productivity (NPP) will help us understand how ecosystem function responds to climate change in China. Using the Carnegie-Ames-Stanford Approach (CASA) ecosystem model based on remote sensing, we investigated the spatiotemporal changes in NPP across 1137 sites in China from 2001 to 2017. Our results revealed that: (1) Mean Annual Temperature (MAT) and Mean Annual Precipitation (MAP) were significantly positively correlated with NPP (p < 0.01), while PM2.5 concentration and CO2 emissions were significantly negatively correlated with NPP (p < 0.01). (2) The positive correlation between temperature, rainfall and NPP gradually weakened over time, while the negative correlation between PM2.5 concentration, CO2 emissions and NPP gradually strengthened over time. (3) High levels of PM2.5 concentration and CO2 emissions had negative effects on NPP, while high levels of MAT and MAP had positive effects on NPP.
Discovering the Repeatome of Five Species Belonging to the Asteraceae Family: A Computational Study
Authors: Ventimiglia Maria , Castellacci Marco , Usai Gabriele , Vangelisti Alberto , Simoni Samuel , Natali Lucia , Cavallini Andrea , Mascagni Flavia , Giordani Tommaso
Published: March 2023

Genome divergence by repeat proliferation and/or loss is a process that plays a crucial role in species evolution. Nevertheless, knowledge of the variability related to repeat proliferation among species of the same family is still limited. Considering the importance of the Asteraceae family, here we present a first contribution towards the metarepeatome of five Asteraceae species. A comprehensive picture of the repetitive components of all genomes was obtained by genome skimming with Illumina sequence reads and by analyzing a pool of full-length long terminal repeat retrotransposons (LTR-REs). Genome skimming allowed us to estimate the abundance and variability of repetitive components. The structure of the metagenome of the selected species was composed of 67% repetitive sequences, of which LTR-REs represented the bulk of annotated clusters. The species essentially shared ribosomal DNA sequences, whereas the other classes of repetitive DNA were highly variable among species. The pool of full-length LTR-REs was retrieved from all the species and their age of insertion was established, showing several lineage-specific proliferation peaks over the last 15-million years. Overall, a large variability of repeat abundance at superfamily, lineage, and sublineage levels was observed, indicating that repeats within individual genomes followed different evolutionary and temporal dynamics, and that different events of amplification or loss of these sequences may have occurred after species differentiation.