bluuebunny/crossref_metadata_2025 huggingface dataset:
Oral Cholecalciferol Supplementation in Sahara Black People with Chronic Kidney Disease Modulates Cytokine Storm, Oxidative Stress Damage and Athero-Thromboembolic Risk
Authors: Zoubiri Houda , Tahar Amina , AitAbderrhmane Samir , Saidani Messaoud , Koceir Elhadj-Ahmed
Published: May 2022

The 25-hydroxyvitamin D3 (25OHD3) deficiency in chronic kidney disease (CKD) is associated with immune system dysfunction (pro-inflammatory cytokines storm) through macrophages renal infiltration, oxidative stress (OxS) damage and athero-thromboembolic risk. Conversely, cholecalciferol supplementation (25OHD-S) prevents kidney fibrosis by inhibition of vascular calcification and nephrotic apoptosis (nephrons reduction). The objective of this study was to investigate the pleiotropic effects of 25OHD-S on immunomodulation, antioxidant status and in protecting against thromboembolic events in deficiency CKD Black and White individuals living in the Southern Sahara (SS). The oral 25OHD-S was evaluated in 60,000 IU/month/36 weeks versus in 2000 IU/day/24 weeks in Black (n = 156) and White (n = 150). Total serum vitamin D was determined by liquid chromatography-tandem mass spectrometry. All biomarkers of pro-inflammatory cytokines (PIC) were assessed by ELISA tests. OxS markers were assessed by Randox kits. Homocysteine and lipoproteine (a) were evaluated by biochemical methods as biomarkers of atherothromboembolic risk. All statistical analyses were performed with Student’s t-test and one-way ANOVA. The Pearson test was used to calculate the correlation coefficient. The means will be significantly different at a level of p value < 0.05. Multiple logistic regressions were performed using Epi-info and Statview software. Vitamin D deficiency alters the PIC profile, OxS damage and atherothrombogenic biomarkers in both SS groups in the same manner; however, these disorders are more acute in Black compared to White SS individuals. The results showed that the serum 25OHD3 concentrations became normal (>75 nmol/L or >30 ng/mL) in the two groups. We have shown that the dose and duration of 25OHD-S treatment are not similar in Black SS residents compared to White SS subjects, whilst the same inhabit the south Sahara environment. It appears that a high dose intermittent over a long period (D60: 36 weeks) was more efficient in Black people; while a lower dose for a short time is sufficient (D2: 24 weeks) in their White counterparts. The oral 25OHD-S attenuates PIC overproduction and OxS damage, but does not reduce athero-thromboembolic risk, particularly in Black SS residents.
Biological Relevance of Free Radicals in the Process of Physiological Capacitation and Cryocapacitation
Authors: Benko Filip , Ďuračka Michal , Baňas Štefan , Lukáč Norbert , Tvrdá Eva
Published: May 2022

Before fertilization, spermatozoa must undergo a process called capacitation in order to fulfill their fertilization potential. This includes a series of structural, biochemical, and functional changes before a subsequent acrosome reaction and fusion with the oocyte. However, low temperatures during cryopreservation may induce a premature activation of capacitation-like changes, also known as cryocapacitation, immediately after thawing, which may lead to a decreased viability, motility, and fertilization ability of cryopreserved spermatozoa. Furthermore, cryopreservation is responsible for the overgeneration of reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and hydroxyl radicals, which may result in the development of oxidative stress, cell membrane damage, and lipid peroxidation. Despite that, both capacitation and cryocapacitation are considered to be oxidative events; however, potential beneficial or detrimental effects of ROS depend on a wide array of circumstances. This review summarizes the available information on the role of free radicals in the process of capacitation and cryocapacitation of spermatozoa.
Oxidative Stress and Its Role in Cd-Induced Epigenetic Modifications: Use of Antioxidants as a Possible Preventive Strategy
Authors: Hernández-Cruz Estefani Yaquelin , Arancibia-Hernández Yalith Lyzet , Loyola-Mondragón Deyanira Yael , Pedraza-Chaverri José
Published: May 2022

Oxidative stress (OS) represents one of the main mechanisms of toxicity induced by environmental pollutants such as cadmium (Cd). OS is a natural physiological process where the presence of oxidants, such as reactive oxygen-derived species (ROS), outweighs the strategy of antioxidant defenses, culminating in the interruption of signaling and redox control. It has been suggested that Cd increases ROS mainly by inducing damage to the electron transport chain and by increasing the activity of nicotinamide adenine dinucleotide hydrogen phosphate (NADPH) oxidase (NOX) and the concentration of free iron (Fe), as well as causing a decrease in antioxidant defense. On the other hand, OS has been related to changes in the biology of the epigenome, causing adverse health effects. Recent studies show that Cd generates alterations in deoxyribonucleic acid (DNA) methylation, histone modifications, and noncoding RNA (ncRNA) expression. However, the role of OS in Cd-induced epigenetic modifications is still poorly explored. Therefore, this review provides an update on the basic concepts of OS and its relationship with Cd-induced epigenetic changes. Furthermore, the use of antioxidant compounds is proposed to mitigate Cd-induced epigenetic alterations.
Anisakid Nematodes and Potential Risk of Human Anisakiasis through the Consumption of Hake, Merluccius spp., Sold Fresh in Spanish Supermarkets
Authors: Fuentes Màrius V. , Madrid Elena , Cuesta Clara , Gimeno Carla , Baquedano-Rodríguez Marta , Soriano-Sánchez Isaac , Bolívar Ana María , Sáez-Durán Sandra , Trelis María , Debenedetti Ángela L.
Published: May 2022

Nematode parasite species belonging to the Anisakis simplex complex are the most important cause of human anisakiasis through the consumption of (mainly) undercooked, previously not frozen, or conveniently treated fish. In Spain, the consumption of hake has been recognized as an important source of this parasitosis. With the aim of shedding light on the risk factors that can influence the potential risk of human anisakiasis in Spain through the consumption of fresh hake sold by nationwide supermarket chains, a total of 536 small hake specimens belonging to the species Merluccius bilinearis caught off the Northeast American coasts and Merluccius merluccius caught in the Northeast Atlantic and Mediterranean waters was analysed. Anisakids morphologically identified as Anisakis type I were found as the most prevalent and the most abundant species and were considered the main potential cause of human anisakiasis. Intrinsic and extrinsic factors concerning the hake, such as its origin and season of capture, its size, as well as the days passed between its capture and consumption, should be taken into account to avoid this human parasitosis. It is essential that consumers have access to fish label information which should include, as regulated by the European Commission, traceability data.
The Differences in the Susceptibility Patterns to Triclabendazole Sulfoxide in Field Isolates of Fasciola hepatica Are Associated with Geographic, Seasonal, and Morphometric Variations
Authors: Fernandez-Baca Martha V. , Hoban Cristian , Ore Rodrigo A. , Ortiz Pedro , Choi Young-Jun , Murga-Moreno César , Mitreva Makedonka , Cabada Miguel M.
Published: May 2022

Triclabendazole (TCBZ) resistance is an emerging problem in fascioliasis that is not well understood. Studies including small numbers of parasites fail to capture the complexity of susceptibility variations between and within Fasciolahepatica populations. As the first step to studying the complex resistant phenotype–genotype associations, we characterized a large sample of adult F. hepatica with diverging TCBZ susceptibility. We collected parasites from naturally infected livestock slaughtered in the Cusco and Cajamarca regions of Peru. These parasites were exposed to TCBZ sulfoxide (TCBZ.SO) in vitro to determine their susceptibility. We used a motility score to determine the parasite’s viability. We titrated drug concentrations and times to detect 20% non-viable (susceptible conditions) or 80% non-viable (resistant conditions) parasites. We exposed 3348 fully motile parasites to susceptible (n = 1565) or resistant (n = 1783) conditions. Three hundred and forty-one (21.8%) were classified as susceptible and 462 (25.9%) were classified as resistant. More resistant parasites were found in Cusco than in Cajamarca (p < 0.001). Resistant parasites varied by slaughterhouse (p < 0.001), month of the year (p = 0.008), fluke length (p = 0.016), and year of collection (p < 0.001). The in vitro susceptibility to TCBZ.SO in wildtype F. hepatica was associated with geography, season, and morphometry.
Establishment and Application of a Multiplex PCR Assay for the Rapid Detection of Rhizoctonia solani Anastomosis Group (AG)-3PT, the Pathogen Causing Potato Black Scurf and Stem Canker
Authors: Iradukunda Linda , Wang Yan-Ping , Nkurikiyimfura Oswald , Wang Tian , Yang Li-Na , Zhan Jiasui
Published: May 2022

Rhizoctonia solani anastomosis group 3 (AG-3) is the main causative agent of the soil-borne disease known as potato black scurf, which poses a huge threat to potato production. Rapid and accurate identification of R. solani AG-3 isolates in soil and potato seed tubers prior to planting is essential for good production. In this study, a multiplex PCR assay was established for the detection of R. solani AG-3. Two pairs of target-specific primers were designed from sequences for endopolygalacturonase and pyridoxine biosynthesis genes downloaded from GenBank. The main factors influencing PCR amplification, such as annealing temperature and primer concentration, were optimized. Results show that the proposed multiplex PCR assay is highly sensitive and specific for the target genes in the pathogen even when the DNA concentration is reduced to 20 fg/μL. The resulting calibration plot shows a linear relationship between electrophoretic band peaks and genomic DNA concentration (R2 = 0.98). The primer specificity was confirmed by applying them to other R. solani AG groups and plant pathogen species on which no amplicons were produced. Using the primers, we successfully detected small amounts of R. solani AG-3 present in soil and potato tuber samples. Taken together, the detection assay developed in this study has high sensitivity, strong specificity, and accuracy and can be used to detect and identify soil and potato seed tubers infected with Rhizoctonia solani AG-3.
Chronic Fatigue Exhibits Heterogeneous Autoimmunity Characteristics Which Reflect Etiology
Authors: Danilenko Olga , Gavrilova Natalia , Churilov Leonid
Published: May 2022

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is considered to be associated with post-viral complications and mental stress, but the role of autoimmunity also remains promising. A comparison of autoimmune profiles in chronic fatigue of different origin may bring insights on the pathogenesis of this disease. Thirty-three patients with CFS/ME were divided into three subgroups. The first group included Herpesviridae carriers (group V), the second group included stress-related causes of chronic fatigue (distress, group D), and the third group included idiopathic CFS/ME (group I). Were evaluated thirty-six neural and visceral autoantigens with the ELISA ELI-test (Biomarker, Russia) and compared to 20 healthy donors, either without any fatigue (group H), or “healthy but tired” (group HTd) with episodes of fatigue related to job burnout not fitting the CFS/ME criteria. β2-glycoprotein-I autoantibodies were increased in CFS/ME patients, but not in healthy participants, that alludes the link between CFS/ME and antiphospholipid syndrome (APS) earlier suspected by Berg et al. (1999). In CFS/ME patients, an increase in levels of autoantibodies towards the non-specific components of tissue debris (double-stranded DNA, collagen) was shown. Both CFS and HTd subgroups had elevated level of autoantibodies against serotonin receptors, glial fibrillary acidic protein and protein S100. Only group V showed an elevation in the autoantibodies towards voltage-gated calcium channels, and only group D had elevated levels of dopamine-, glutamate- and GABA-receptor autoantibodies, as well as NF200-protein autoantibodies. Therefore, increased autoimmune reactions to the multiple neural antigens and to adrenal medullar antigen, but not to other tissue-specific somatic ones were revealed. An increase in autoantibody levels towards some neural and non-tissue-specific antigens strongly correlated with a CFS/ME diagnosis. Autoimmune reactions were described in all subtypes of the clinically significant chronic fatigue. Visceral complaints in CFS/ME patients may be secondary to the neuroendocrine involvement and autoimmune dysautonomia. CFS may be closely interrelated with antiphospholipid syndrome, that requires further study.
Dihydroconiferyl Ferulate Isolated from Dendropanax morbiferus H.Lév. Suppresses Stemness of Breast Cancer Cells via Nuclear EGFR/c-Myc Signaling
Authors: Ko Yu-Chan , Liu Ren , Sun Hu-Nan , Yun Bong-Sik , Choi Hack Sun , Lee Dong-Sun
Published: May 2022

Breast cancer is the leading cause of global cancer incidence and breast cancer stem cells (BCSCs) have been identified as the target to overcome breast cancer in patients. In this study, we purified a BCSC inhibitor from Dendropanax morbiferus H.Lév. leaves through several open column and high-performance liquid chromatography via activity-based purification. The purified cancer stem cell (CSC) inhibitor was identified as dihydroconiferyl ferulate using nuclear magnetic resonance and mass spectrometry. Dihydroconiferyl ferulate inhibited the proliferation and mammosphere formation of breast cancer cells and reduced the population of CD44high/CD24low cells. Dihydroconiferyl ferulate also induced apoptosis, inhibited the growth of mammospheres and reduced the level of total and nuclear EGFR protein. It suppressed the EGFR levels, the interaction of Stat3 with EGFR, and c-Myc protein levels. Our findings show that dihydroconiferyl ferulate reduced the level of nuclear epidermal growth factor receptor (EGFR) and induced apoptosis of BCSCs through nEGFR/Stat3-dependent c-Myc deregulation. Dihydroconiferyl ferulate exhibits potential as an anti-CSC agent through nEGFR/Stat3/c-Myc signaling.
Bromodomain and Extra-Terminal Protein Inhibitors: Biologic Insights and Therapeutic Potential in Pediatric Brain Tumors
Authors: Groves Andrew , Clymer Jessica , Filbin Mariella G.
Published: May 2022

Pediatric brain tumors have surpassed leukemia as the leading cause of cancer-related death in children. Several landmark studies from the last two decades have shown that many pediatric brain tumors are driven by epigenetic dysregulation within specific developmental contexts. One of the major determinants of epigenetic control is the histone code, which is orchestrated by a number of enzymes categorized as writers, erasers, and readers. Bromodomain and extra-terminal (BET) proteins are reader proteins that bind to acetylated lysines in histone tails and play a crucial role in regulating gene transcription. BET inhibitors have shown efficacy in a wide range of cancers, and a number have progressed to clinical phase testing. Here, we review the evidence for BET inhibitors in pediatric brain tumor experimental models, as well as their translational potential.
Synthesis, Physicochemical, Labeling and In Vivo Characterization of 44Sc-Labeled DO3AM-NI as a Hypoxia-Sensitive PET Probe
Authors: Szücs Dániel , Csupász Tibor , Szabó Judit P. , Kis Adrienn , Gyuricza Barbara , Arató Viktória , Forgács Viktória , Vágner Adrienn , Nagy Gábor , Garai Ildikó , Szikra Dezső , Tóth Imre , Trencsényi György , Tircsó Gyula , Fekete Anikó
Published: May 2022

Hypoxia promotes angiogenesis, which is crucial for tumor growth, and induces malignant progression and increases the therapeutic resistance. Positron emission tomography (PET) enables the detection of the hypoxic regions in tumors using 2-nitroimidazole-based radiopharmaceuticals. We describe here a physicochemical study of the Sc(DO3AM-NI) complex, which indicates: (a) relatively slow formation of the Sc(DO3AM-NI) chelate in acidic solution; (b) lower thermodynamic stability than the reference Sc(DOTA); (c) however, it is substantially more inert and consequently can be regarded as an excellent Sc-binder system. In addition, we report a comparison of 44Sc-labeled DO3AM-NI with its known 68Ga-labeled analog as a hypoxia PET probe. The in vivo and ex vivo biodistributions of 44Sc- and 68Ga-labeled DO3AM-NI in healthy and KB tumor-bearing SCID mice were examined 90 and 240 min after intravenous injection. No significant difference was found between the accumulation of 44Sc- and 68Ga-labeled DO3AM-NI in KB tumors. However, a significantly higher accumulation of [68Ga]Ga(DO3AM-NI) was found in liver, spleen, kidney, intestine, lung, heart and brain than for [44Sc]Sc(DO3AM-NI), leading to a lower tumor/background ratio. The tumor-to-muscle (T/M) ratio of [44Sc]Sc(DO3AM-NI) was approximately 10–15-fold higher than that of [68Ga]Ga(DO3AM-NI) at all time points. Thus, [44Sc]Sc(DO3AM-NI) allows the visualization of KB tumors with higher resolution, making it a promising hypoxia-specific PET radiotracer.
HDAC Inhibitors for the Therapy of Triple Negative Breast Cancer
Authors: Maccallini Cristina , Ammazzalorso Alessandra , De Filippis Barbara , Fantacuzzi Marialuigia , Giampietro Letizia , Amoroso Rosa
Published: May 2022

Triple negative breast cancer (TNBC) is an urgent as well as huge medical challenge, which is associated with poor prognosis and responsiveness to chemotherapies. Since epigenetic changes are highly implicated in TNBC tumorigenesis and development, inhibitors of histone deacetylases (HDACIs) could represent a promising therapeutic strategy. Although clinical trials involving single HDACIs showed disappointing results against TNBC, recent studies emphasize the high potential impact of HDACIs in controlling TNBC. In addition, encouraging results stem from new compounds designed to obtain isoform selectivity and/or polypharmacological HDAC approach. The present review provides a discussion of the HDACIs pharmacophoric models and of the structural modifications, leading to compounds with a potent activity against TNBC progression.
Investigation of the Role of the TRPA1 Ion Channel in Conveying the Effect of Dimethyl Trisulfide on Vascular and Histological Changes in Serum-Transfer Arthritis
Authors: Bátai István Z. , Dombi Ágnes , Borbély Éva , Fehér Ádám , Papp Ferenc , Varga Zoltan , Mócsai Attila , Helyes Zsuzsanna , Pintér Erika , Pozsgai Gábor
Published: May 2022

Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases. Its therapy is often challenging, even in the era of biologicals. Previously, we observed the anti-inflammatory effects of garlic-derived organic polysulfide dimethyl trisulfide (DMTS). Some of these effects were mediated by activation of the TRPA1 ion channel. TRPA1 was mostly expressed in a subset of nociceptor neurons. We decided to investigate the action of DMTS in K/BxN serum-transfer arthritis, which is a relevant model of RA. TRPA1 gene knockout (KO) and wild-type (WT) mice were used. The interaction of DMTS and TRPA1 was examined using a patch clamp in CHO cells. Arthritis was characterized by mechanical hyperalgesia, paw swelling, movement range of the ankle joint, hanging performance, plasma extravasation rate, myeloperoxidase activity, and histological changes in the tibiotarsal joint. DMTS activated TRPA1 channels dose-dependently. DMTS treatment reduced paw swelling and plasma extravasation in both TRPA1 WT and KO animals. DMTS-treated TRPA1 KO animals developed milder collagen deposition in the inflamed joints than WT ones. TRPA1 WT mice did not exhibit significant cartilage damage compared to ones administered a vehicle. We concluded that DMTS and related substances might evolve into novel complementary therapeutic aids for RA patients.
Pharmacovigilance Signals of the Opioid Epidemic over 10 Years: Data Mining Methods in the Analysis of Pharmacovigilance Datasets Collecting Adverse Drug Reactions (ADRs) Reported to EudraVigilance (EV) and the FDA Adverse Event Reporting System (FAERS)
Authors: Chiappini Stefania , Vickers-Smith Rachel , Guirguis Amira , Corkery John M. , Martinotti Giovanni , Harris Daniel R. , Schifano Fabrizio
Published: May 2022

In the past twenty years, the consumption of opioid medications has reached significant proportions, leading to a rise in drug misuse and abuse and increased opioid dependence and related fatalities. Thus, the purpose of this study was to determine whether there are pharmacovigilance signals of abuse, misuse, and dependence and their nature for the following prescription opioids: codeine, dihydrocodeine, fentanyl, oxycodone, pentazocine, and tramadol. Both the pharmacovigilance datasets EudraVigilance (EV) and the FDA Adverse Events Reporting System (FAERS) were analyzed to identify and describe possible misuse-/abuse-/dependence-related issues. A descriptive analysis of the selected Adverse Drug Reactions (ADRs) was performed, and pharmacovigilance signal measures (i.e., reporting odds ratio, proportional reporting ratio, information component, and empirical Bayesian geometric mean) were computed for preferred terms (PTs) of abuse, misuse, dependence, and withdrawal, as well as PTs eventually related to them (e.g., aggression). From 2003 to 2018, there was an increase in ADR reports for the selected opioids in both datasets. Overall, 16,506 and 130,293 individual ADRs for the selected opioids were submitted to EV and FAERS, respectively. Compared with other opioids, abuse concerns were mostly recorded in relation to fentanyl and oxycodone, while tramadol and oxycodone were more strongly associated with drug dependence and withdrawal. Benzodiazepines, antidepressants, other opioids, antihistamines, recreational drugs (e.g., cocaine and alcohol), and several new psychoactive substances, including mitragynine and cathinones, were the most commonly reported concomitant drugs. ADRs reports in pharmacovigilance databases confirmed the availability of data on the abuse and dependence of prescription opioids and should be considered a resource for monitoring and preventing such issues. Psychiatrists and clinicians prescribing opioids should be aware of their misuse and dependence liability and effects that may accompany their use, especially together with concomitant drugs.
European Safety Analysis of mRNA and Viral Vector COVID-19 Vaccines on Glucose Metabolism Events
Authors: di Mauro Gabriella , Mascolo Annamaria , Longo Miriam , Maiorino Maria Ida , Scappaticcio Lorenzo , Bellastella Giuseppe , Esposito Katherine , Capuano Annalisa
Published: May 2022

Few data have been published on the effects of impaired glucose metabolism induced by COVID-19 vaccines. We decided to perform a study to describe Individual Case Safety Reports (ICSRs) of impaired glucose metabolism events reported in the European database (Eudravigilance, EV). ICSRs were retrieved from the online website of Eudravigilance. The reporting odds ratios (ROR) were computed to assess the reporting frequency for COVID-19 mRNA vaccines compared to COVID-19 viral vector-based vaccines. A total of 3917 ICSRs with a COVID-19 vaccine suspected were retrieved, with a total of 4275 impaired glucose metabolism events. Overall, the most reported events were related to “high glucose levels” (2012; 47.06%). The mRNA vaccines were associated with an increased reporting frequency of “type 1 diabetes mellitus” (ROR 1.86; 95% CI 1.33–2.60), “type 2 diabetes mellitus” (ROR 1.58; 95% CI 1.03–2.42), “high glucose levels” (ROR 1.16; 95% CI 1.06–1.27), “diabetes mellitus inadequate control” (ROR 1.63; 95% CI 1.25–2.11), and “hypoglycemia” (ROR 1.62; 95% CI 1.41–1.86) compared to viral vector-based vaccines. mRNA COVID-19 vaccines were associated with an increased reporting frequency of alterations of glucose homeostasis compared to viral-vector COVID-19 vaccines. Clinicians should be aware of these events to better manage glycemic perturbations. Larger nationwide studies are warranted to verify these findings.
Three-Dimensional (3D) Printing in Cancer Therapy and Diagnostics: Current Status and Future Perspectives
Authors: Safhi Awaji Y.
Published: May 2022

Three-dimensional (3D) printing is a technique where the products are printed layer-by-layer via a series of cross-sectional slices with the exact deposition of different cell types and biomaterials based on computer-aided design software. Three-dimensional printing can be divided into several approaches, such as extrusion-based printing, laser-induced forward transfer-based printing systems, and so on. Bio-ink is a crucial tool necessary for the fabrication of the 3D construct of living tissue in order to mimic the native tissue/cells using 3D printing technology. The formation of 3D software helps in the development of novel drug delivery systems with drug screening potential, as well as 3D constructs of tumor models. Additionally, several complex structures of inner tissues like stroma and channels of different sizes are printed through 3D printing techniques. Three-dimensional printing technology could also be used to develop therapy training simulators for educational purposes so that learners can practice complex surgical procedures. The fabrication of implantable medical devices using 3D printing technology with less risk of infections is receiving increased attention recently. A Cancer-on-a-chip is a microfluidic device that recreates tumor physiology and allows for a continuous supply of nutrients or therapeutic compounds. In this review, based on the recent literature, we have discussed various printing methods for 3D printing and types of bio-inks, and provided information on how 3D printing plays a crucial role in cancer management.
In Vitro, In Vivo and In Silico Characterization of a Novel Kappa-Opioid Receptor Antagonist
Authors: Puls Kristina , Olivé-Marti Aina-Leonor , Pach Szymon , Pinter Birgit , Erli Filippo , Wolber Gerhard , Spetea Mariana
Published: May 2022

Kappa-opioid receptor (KOR) antagonists are promising innovative therapeutics for the treatment of the central nervous system (CNS) disorders. The new scaffold opioid ligand, Compound A, was originally found as a mu-opioid receptor (MOR) antagonist but its binding/selectivity and activation profile at the KOR and delta-opioid receptor (DOR) remain elusive. In this study, we present an in vitro, in vivo and in silico characterization of Compound A by revealing this ligand as a KOR antagonist in vitro and in vivo. In the radioligand competitive binding assay, Compound A bound at the human KOR, albeit with moderate affinity, but with increased affinity than to the human MOR and without specific binding at the human DOR, thus displaying a preferential KOR selectivity profile. Following subcutaneous administration in mice, Compound A effectively reverse the antinociceptive effects of the prototypical KOR agonist, U50,488. In silico investigations were carried out to assess the structural determinants responsible for opioid receptor subtype selectivity of Compound A. Molecular docking, molecular dynamics simulations and dynamic pharmacophore (dynophore) generation revealed differences in the stabilization of the chlorophenyl moiety of Compound A within the opioid receptor binding pockets, rationalizing the experimentally determined binding affinity values. This new chemotype bears the potential for favorable ADMET properties and holds promise for chemical optimization toward the development of potential therapeutics.
Clinical Utility of Medication-Based Risk Scores to Reduce Polypharmacy and Potentially Avoidable Healthcare Utilization
Authors: Silva-Almodóvar Armando , Nahata Milap C.
Published: May 2022

The management of multiple chronic health conditions often requires patients to be exposed to polypharmacy to improve their health and enhance their quality of life. However, exposure to polypharmacy has been associated with an increased risk for adverse effects, drug-drug interactions, inappropriate prescribing, medication nonadherence, increased healthcare utilization such as emergency department visits and hospitalizations, and costs. Medication-based risk scores have been utilized to identify patients who may benefit from deprescribing interventions and reduce rates of inappropriate prescribing. These risk scores may also be utilized to prompt targeted discussions between patients and providers regarding medications or medication classes contributing to an individual’s risk for harm, eventually leading to the deprescribing of the offending medication(s). This opinion will describe existing medication-based risk scores in the literature, their utility in identifying patients at risk for specific adverse events, and how they may be incorporated in healthcare settings to reduce rates of potentially inappropriate polypharmacy and avoidable healthcare utilization and costs.
The pH-Responsive Liposomes—The Effect of PEGylation on Release Kinetics and Cellular Uptake in Glioblastoma Cells
Authors: Rustad Eirik A. L. , von Hofsten Susannah , Kumar Robin , Lænsman Eirik A. , Berge Gerd , Škalko-Basnet Nataša
Published: May 2022

Nanomedicine has been, to a certain degree, a success story in the development of superior anticancer therapies. However, there are tumors that remain a huge challenge for nanoformulations, for instance, brain tumors such as glioblastoma, the most common and aggressive brain tumor. To utilize the fact that such tumors are characterized by an acidic extracellular environment, we selected pH-responsive liposomes as a potential drug delivery system for superior delivery to GBM. Liposomes comprising PEGylated lipid of two chain lengths with encapsulated fluorescent marker calcein were characterized and challenged against non-PEGylated vesicles. The in vitro calcein release from three liposomal formulations (<200 nm), namely non-PEGylated (pH-Lip) and PEGylated, pH-Lip–PEG750, and pH-Lip–PEG2000, was followed at three pH conditions to prove the pH-responsiveness. The intracellular delivery of a liposomally encapsulated marker was determined in GL261 glioblastoma cell lines in vitro using both flow cytometry and confocal microscopy. The inclusion of PEG2000 within liposomal formulation resulted in reduced in vitro pH-responsiveness compared to pH-Lip and pH-Lip750. All three pH-responsive liposomal formulations improved intracellular uptake in GL261 cells compared to non-pH-responsive liposomes, with negligible differences regarding PEG length. The proposed formulations should be further evaluated in glioblastoma models.
Inorganic Nanomaterials in Tissue Engineering
Authors: Bianchi Eleonora , Vigani Barbara , Viseras César , Ferrari Franca , Rossi Silvia , Sandri Giuseppina
Published: May 2022

In recent decades, the demand for replacement of damaged or broken tissues has increased; this poses the attention on problems related to low donor availability. For this reason, researchers focused their attention on the field of tissue engineering, which allows the development of scaffolds able to mimic the tissues’ extracellular matrix. However, tissue replacement and regeneration are complex since scaffolds need to guarantee an adequate hierarchical structured morphology as well as adequate mechanical, chemical, and physical properties to stand the stresses and enhance the new tissue formation. For this purpose, the use of inorganic materials as fillers for the scaffolds has gained great interest in tissue engineering applications, due to their wide range of physicochemical properties as well as their capability to induce biological responses. However, some issues still need to be faced to improve their efficacy. This review focuses on the description of the most effective inorganic nanomaterials (clays, nano-based nanomaterials, metal oxides, metallic nanoparticles) used in tissue engineering and their properties. Particular attention has been devoted to their combination with scaffolds in a wide range of applications. In particular, skin, orthopaedic, and neural tissue engineering have been considered.
Simultaneous Spray Drying for Combination Dry Powder Inhaler Formulations
Authors: Shepard Kimberly B. , Pluntze Amanda M. , Vodak David T.
Published: May 2022

Spray drying is a particle engineering technique used to manufacture respirable pharmaceutical powders that are suitable for delivery to the deep lung. It is amenable to processing both small molecules and biologic actives, including proteins. In this work, a simultaneous spray-drying process, termed simul-spray, is described; the process involves two different active pharmaceutical ingredient (API) solutions that are simultaneously atomized through separate nozzles into a single-spray dryer. Collected by a single cyclone, simul-spray produces a uniform mixture of two different active particles in a single-unit operation. While combination therapies for dry powder inhalers containing milled small molecule API are commercially approved, limited options exist for preparing combination treatments that contain both small molecule APIs and biotherapeutic molecules. Simul-spray drying is also ideal for actives which cannot withstand a milling-based particle engineering process, or which require a high dose that is incompatible with a carrier-based formulation. Three combination case studies are demonstrated here, in which bevacizumab is paired with erlotinib, cisplatin, or paclitaxel in a dry powder inhaler formulation. These model systems were chosen for their potential relevance to the local treatment of lung cancer. The resulting formulations preserved the biologic activity of the antibody, achieved target drug concentration, and had aerosol properties suitable for pulmonary delivery.
Micro/Nanosystems for Magnetic Targeted Delivery of Bioagents
Authors: Garello Francesca , Svenskaya Yulia , Parakhonskiy Bogdan , Filippi Miriam
Published: May 2022

Targeted delivery of pharmaceuticals is promising for efficient disease treatment and reduction in adverse effects. Nano or microstructured magnetic materials with strong magnetic momentum can be noninvasively controlled via magnetic forces within living beings. These magnetic carriers open perspectives in controlling the delivery of different types of bioagents in humans, including small molecules, nucleic acids, and cells. In the present review, we describe different types of magnetic carriers that can serve as drug delivery platforms, and we show different ways to apply them to magnetic targeted delivery of bioagents. We discuss the magnetic guidance of nano/microsystems or labeled cells upon injection into the systemic circulation or in the tissue; we then highlight emergent applications in tissue engineering, and finally, we show how magnetic targeting can integrate with imaging technologies that serve to assist drug delivery.
Development of Abiraterone Acetate Nanocrystal Tablets to Enhance Oral Bioavailability: Formulation Optimization, Characterization, In Vitro Dissolution and Pharmacokinetic Evaluation
Authors: Liu Yuanfen , Li Yuqi , Xu Pengcheng , Shen Yan , Tang Baoqiang , Wang Qiyue
Published: May 2022

Abiraterone acetate is a prodrug of abiraterone used in combination with prednisone as a standard therapeutic strategy for hormone-resistant prostate cancer (mCRPC). Due to the poor solubility and permeability, the release and absorption of abiraterone acetate are low and reduce its bioavailability. In this project, abiraterone acetate tablets prepared using nanocrystal technology were developed to overcome the drawbacks of normal tablets by enhancing in vitro dissolution rate and oral bioavailability. The abiraterone acetate nanocrystal suspensions were prepared by top-down wet milling method using a planetary ball mill with the mixture of Poloxamer 407 and Poloxamer 188 as the optimized stabilizer at a ratio of 7:1. The optimized nanocrystals were freeze-dried and characterized using DLS, TEM, DSC, and XRD. The abiraterone acetate nanocrystal tablets significantly improve the in vitro dissolution rate of abiraterone acetate compared to raw materials. Although exhibiting a similar dissolution rate compared to the Zytiga® tablets, the nanocrystal tablets significantly improve the oral bioavailability with Cmax and AUC0–t being 3.51-fold and 2.80-fold higher, respectively, in the pharmacokinetic study. The present data indicate that nanocrystal is a promising strategy for improving the dissolution and bioavailability of abiraterone acetate.
Post-COVID Syndrome: The Research Progress in the Treatment of Pulmonary sequelae after COVID-19 Infection
Authors: Ruggiero Valentina , Aquino Rita P. , Del Gaudio Pasquale , Campiglia Pietro , Russo Paola
Published: May 2022

Post-COVID syndrome or long COVID is defined as the persistence of symptoms after confirmed SARS-CoV-2 infection, the pathogen responsible for coronavirus disease. The content herein presented reviews the reported long-term consequences and aftereffects of COVID-19 infection and the potential strategies to adopt for their management. Recent studies have shown that severe forms of COVID-19 can progress into acute respiratory distress syndrome (ARDS), a predisposing factor of pulmonary fibrosis that can irreversibly compromise respiratory function. Considering that the most serious complications are observed in the airways, the inhalation delivery of drugs directly to the lungs should be preferred, since it allows to lower the dose and systemic side effects. Although further studies are needed to optimize these techniques, recent studies have also shown the importance of in vitro models to recreate the SARS-CoV-2 infection and study its sequelae. The information reported suggests the necessity to develop new inhalation therapies in order to improve the quality of life of patients who suffer from this condition.
Characterization of Physical and Biological Properties of a Caries-Arresting Liquid Containing Copper Doped Bioglass Nanoparticles
Authors: Bang Se-Jung , Jun Soo-Kyung , Kim Yu-Jin , Ahn Jun-Yong , Vu Huong Thu , Mandakhbayar Nandin , Han Mi-Ran , Lee Jun-Haeng , Kim Jong-Bin , Kim Jong-Soo , Knowles Jonathan C. , Kim Hye-Sung , Lee Hae-Hyoung , Shin Ji-Sun , Lee Jung-Hwan
Published: May 2022

Silver diamine fluoride (SDF) is an outstanding dental material for arresting and preventing caries, but some drawbacks, such as high flowability due to low viscosity and cytotoxicity to the pulp, have been reported. To overcome these problems, copper-doped bioactive glass nanoparticles (CuBGns) were combined with SDF. After synthesis, CuBGns were examined by physical analysis and added in SDF at different weight/volume% (SDF@CuBGn). After assessing physical properties (viscosity and flowability) of SDF@CuBGn, physicochemical properties (morphology before and after simulated body fluid (SBF) immersion and ion release) of SDF@CuBGn-applied hydroxyapatite (HA) discs were evaluated. Biological properties were further evaluated by cytotoxicity test to pulp stem cells and antibacterial effect on cariogenic organisms (Streptococcus mutans and Staphylococcus aureus). Combining CuBGns in SDF increased the viscosity up to 3 times while lowering the flowability. More CuBGns and functional elements in SDF (Ag and F) were deposited on the HA substrate, even after SBF immersion test for 14 days, and they showed higher Cu, Ca, and Si release without changing F and Ag release. Cell viability test suggested lower cytotoxicity in SDF@CuBGn-applied HA, while CuBGns in SDF boosted antibacterial effect against S. aureus, ~27% in diameter of agar diffusion test. In conclusion, the addition of CuBGn to SDF enhances viscosity, Ag and F deposition, and antibacterial effects while reducing cell toxicity, highlighting the role of bioactive CuBGns for regulating physical and biological effects of dental materials.
Dissolution from Ethylene Vinyl Acetate Copolymer Long-Acting Implants: Effect of Model Active Ingredient Size and Shape
Authors: Gohn Anne M. , Nolte Amy , Ravotti Ethan , Forster Seth P. , Giles Morgan , Rudd Nathan , Mendis Gamini
Published: May 2022

In recent pharmaceutical applications, an active pharmaceutical ingredient (API) can be mixed with a polymer material to yield a composite long-acting drug-delivery device. These devices boast higher patient compliance, localized drug delivery, and lower dosage concentrations, which can increase patient safety. As a laboratory-safe option, calcium carbonate (CaCO3) was used as a drug surrogate to mimic the release kinetics of a low-solubility API. The release of CaCO3 from a poly(ethylene vinyl acetate) (EVA) polymer matrix was studied in ultra-high-purity water. The geometry of CaCO3, along with the manufacturing technique, was manipulated to study the implications on surrogate drug release. It was found that injection molding proved to yield higher burst release, due to higher pressures achievable during manufacturing. The extrusion process can affect the surface concentration of the pharmaceutical ingredient when extruded through a water bath, resulting in a lower initial burst concentration. Regarding CaCO3 geometry, the particle size was more critical than the surface area in terms of CaCO3 release. Larger particles showed a higher release rate, though they also displayed higher variability in release. These data can be used to engineer specific release profiles when designing composite formulations and manufacturing methods for pharmaceutical-drug-delivery applications.
Simultaneous Characterization and Determination of Warfarin and Its Hydroxylation Metabolites in Rat Plasma by Chiral Liquid Chromatography-Tandem Mass Spectrometry
Authors: Jin Shasha , Li Zhihong , Yang Qing , Fang Boyu , Xiang Xiaoqiang , Peng Chao , Cai Weimin
Published: May 2022

Warfarin is extensively used for venous thromboembolism and other coagulopathies. In clinical settings, warfarin is administered as a mixture of S- and R-warfarin, and both enantiomers are metabolized by multiple cytochrome P450 enzymes into many hydroxylation metabolites. Due to the high degree of structural similarity of hydroxylation metabolites, their profile possesses significant challenges. The previous methods generally suffer from lacking baseline resolution and/or involving complex analysis processes. To overcome this limitation, a sensitive and specific chiral liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to simultaneously identify warfarin and hydroxywarfarins enantiomers. Chromatographic separation was achieved on a HYPERSIL CHIRAL-OT column. The mass spectrometric detection was carried out in negative ion MRM mode with electrospray ionization source. The optimized method exhibited satisfactory within-run and between-run accuracy and precision with lower limit of quantification (LLOQ) of 10.0 ng/mL and 1.0 ng/mL for warfarin and 7-, 10(R)-OH-warfarin enantiomers, respectively. Linear responses of warfarin enantiomers and 7-, and 10(R)-OH-warfarin enantiomers in rat plasma were observed over the range of 10.0–8000 ng/mL, and 1.00–800 ng/mL, respectively. The analytes were shown to be stable in various experimental conditions in rat plasma. Protein precipitation was used in sample preparation without a matrix effect. This method was successfully applied to pharmacokinetic study for quantitating the concentrations of S/R-warfarin, S/R-7-OH-warfarin, and S/R-10(R)-OH-warfarin and relatively quantitating 3′-, 4-, 6-, and 8-OH warfarin enantiomers in rat plasma.
Royal Jelly as a Nutraceutical Natural Product with a Focus on Its Antibacterial Activity
Authors: Bagameri Lilla , Baci Gabriela-Maria , Dezmirean Daniel Severus
Published: May 2022

Royal jelly (RJ) is one of the most valued natural products and is known for its health-promoting properties. Due to its therapeutic effects, it has been used in medicine since antiquity. Nowadays, several studies indicate that RJ acts as a powerful antimicrobial agent. Indeed, researchers shed light on its antioxidant and anticancer activity. RJ’s biological properties are related to its bioactive compounds, such as proteins, peptides, phenolic, and fatty acids. The aim of this review is to highlight recent findings on RJ’s main bioactive compounds correlated with its health-promoting properties. The available literature suggests that these bioactive compounds can be used as an alternative approach in order to enhance human health. Moreover, throughout this paper, we underline the prominent antibacterial effect of RJ against several target bacterial strains. In addition, we briefly discuss other therapeutic activities, such as antioxidative and anticancer effects, of this outstanding natural product.
Choline Kinase α Inhibitors MN58b and RSM932A Enhances the Antitumor Response to Cisplatin in Lung Tumor Cells
Authors: Lacal Juan Carlos , Perona Rosario , de Castro Javier , Cebrián Arancha
Published: May 2022

Lung cancer is one of the main causes of death in developed countries, and non-small cell lung cancer (NSCLC) is the most frequent type (80% of patients). In advanced NSCLC, platinum-based chemotherapy is the frontline palliative treatment, but less than 5% of patients achieve prolonged survival. Immunotherapy has recently been proposed as the standard of care (SoC) as either monotherapy or in combination with chemotherapy for advanced NSCLC. The levels of expression of PD-L1 are the only predictive biomarkers for patient assessment. Although around 30% of patients receiving immunotherapy achieve 5-year survival, a significant number does not benefit from this novel therapeutic approach. Therefore, there is a need for novel strategies to improve clinical outcomes. The expression level of choline kinase α (ChoKα) is increased in a large number of human tumors, including NSCLC tumors, and constitutes an independent prognostic factor for early-stage NSCLC patients. Thus, ChoKα has been postulated as a new target drug in cancer therapy. The combination of cisplatin with novel targeted drugs such as choline kinase inhibitors may improve both the survival rates and the quality of life of NSCLC patients and may serve as the basis for the development of new therapeutic approaches. To that aim, we developed several in vitro and in vivo approaches to assess the antitumor activity of a novel combination regimen using cisplatin and ChoKα inhibitors. Our results suggest that a proper combination of specific inhibitors of the NSCLC prognostic factor ChoKα and platinum-based conventional chemotherapy might constitute a new, efficient treatment approach for NSCLC patients. This novel approach may help reduce the toxicity profile associated with cisplatin since, despite the advances in NSCLC management in recent years, the overall 5-year survival rate is still poor.
Self-Organization Dynamics of Collagen-like Peptides Crosslinking Is Driven by Rose-Bengal-Mediated Electrostatic Bridges
Authors: Rosales-Rojas Roberto , Zuñiga-Bustos Matías , Salas-Sepúlveda Francisca , Galaz-Araya Constanza , Zamora Ricardo A. , Poblete Horacio
Published: May 2022

The present work focuses on the computational study of the structural micro-organization of hydrogels based on collagen-like peptides (CLPs) in complex with Rose Bengal (RB). In previous studies, these hydrogels computationally and experimentally demonstrated that when RB was activated by green light, it could generate forms of stable crosslinked structures capable of regenerating biological tissues such as the skin and cornea. Here, we focus on the structural and atomic interactions of two collagen-like peptides (collagen-like peptide I (CLPI), and collagen-like peptide II, (CLPII)) in the presence and absence of RB, highlighting the acquired three-dimensional organization and going deep into the stabilization effect caused by the dye. Our results suggest that the dye could generate a ternary ground-state complex between collagen-like peptide fibers, specifically with positively charged amino acids (Lys in CLPI and Arg in CLPII), thus stabilizing ordered three-dimensional structures. The discoveries generated in this study provide the structural and atomic bases for the subsequent rational development of new synthetic peptides with improved characteristics for applications in the regeneration of biological tissues during photochemical tissue bonding therapies.