bluuebunny/crossref_metadata_2025 huggingface dataset:
Antioxidant Activity, Phenolic Profile, and Nephroprotective Potential of Anastatica hierochuntica Ethanolic and Aqueous Extracts against CCl4-Induced Nephrotoxicity in Rats
Authors: Almundarij Tariq I. , Alharbi Yousef M. , Abdel-Rahman Hassan A. , Barakat Hassan
Published: August 2021

Kaff-e-Maryam (Anastatica hierochuntica L.) is extensively used to treat a range of health problems, most notably to ease childbirth and alleviate reproductive system-related disorders. This study aimed to evaluate the effect of A. hierochuntica ethanolic (KEE), and aqueous (KAE) extracts on CCl4-induced oxidative stress and nephrotoxicity in rats using the biochemical markers for renal functions and antioxidant status as well as histopathological examinations of kidney tissue. A. hierochuntica contained 67.49 mg GAE g−1 of total phenolic compounds (TPC), 3.51 µg g−1 of total carotenoids (TC), and 49.78 and 17.45 mg QE g−1 of total flavonoids (TF) and total flavonols (TFL), respectively. It resulted in 128.71 µmol of TE g−1 of DPPH-RSA and 141.92 µmol of TE g−1 of ABTS-RSA. A. hierochuntica presented superior antioxidant activity by inhibiting linoleic acid radicals and chelating oxidation metals. The HPLC analysis resulted in 9 and 21 phenolic acids and 6 and 2 flavonoids in KEE and KAE with a predominance of sinapic and syringic acids, respectively. Intramuscular injection of vit. E + Se and oral administration of KEE, KAE, and KEE + KAE at 250 mg kg−1 body weight significantly restored serum creatinine, urea, K, total protein, and albumin levels. Additionally, they reduced malondialdehyde (MOD), restored reduced-glutathione (GSH), and enhanced superoxide dismutase (SOD) levels. KEE, KAE, and KEE + KAE protected the kidneys from CCl4-nephrotoxicity as they mainly attenuated induced oxidative stress. Total nephroprotection was about 83.27%, 97.62%, and 78.85% for KEE, KAE, and KEE + KAE, respectively. Both vit. E + Se and A. hierochuntica extracts attenuated the histopathological alteration in CCl4-treated rats. In conclusion, A. hierochuntica, especially KAE, has the potential capability to restore oxidative stability and improve kidney function after CCl4 acute kidney injury better than KEE. Therefore, A. hierochuntica has the potential to be a useful therapeutic agent in the treatment of drug-induced nephrotoxicity.
Potential Roles of Iridoid Glycosides and Their Underlying Mechanisms against Diverse Cancer Growth and Metastasis: Do They Have an Inhibitory Effect on Cancer Progression?
Authors: Kim Cho-Won , Choi Kyung-Chul
Published: August 2021

Iridoids are glycosides found in plants, having inherent roles in defending them against infection by viruses and microorganisms, and in the rapid repair of damaged areas. The emerging roles of iridoid glycosides on pharmacological properties have aroused the curiosity of many researchers, and studies undertaken indicate that iridoid glycosides exert inhibitory effects in numerous cancers. This review focuses on the roles and the potential mechanism of iridoid glycosides at each stage of cancer development such as proliferation, epithelial mesenchymal transition (EMT), migration, invasion and angiogenesis. Overall, the reviewed literature indicates that iridoid glycosides inhibit cancer growth by inducing cell cycle arrest or by regulating apoptosis-related signaling pathways. In addition, iridoid glycosides suppress the expression and activity of matrix metalloproteinases (MMPs), resulting in reduced cancer cell migration and invasiveness. The antiangiogenic mechanism of iridoid glycosides was found to be closely related to the transcriptional regulation of pro-angiogenic factors, i.e., vascular endothelial growth factors (VEGFs) and cluster of differentiation 31 (CD31). Taken together, these results indicate the therapeutic potential of iridoid glycosides to alleviate or prevent rapid cancer progression and metastasis.
Methodological Development of a Multi-Readout Assay for the Assessment of Antiviral Drugs against SARS-CoV-2
Authors: Hahn Friedrich , Häge Sigrun , Herrmann Alexandra , Wangen Christina , Kicuntod Jintawee , Jungnickl Doris , Tillmanns Julia , Müller Regina , Fraedrich Kirsten , Überla Klaus , Kohlhof Hella , Ensser Armin , Marschall Manfred
Published: August 2021

Currently, human infections with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are accelerating the ongoing spread of the pandemic. Several innovative types of vaccines have already been developed, whereas effective options of antiviral treatments still await a scientific implementation. The development of novel anti-SARS-CoV-2 drug candidates demands skillful strategies and analysis systems. Promising results have been achieved with first generation direct-acting antivirals targeting the viral polymerase RdRp or the protease 3CLpro. Such recently approved or investigational drugs like remdesivir and GC376 represent a basis for further development and optimization. Here, we establish a multi-readout assay (MRA) system that enables the antiviral assessment and mechanistic characterization of novel test compounds, drug repurposing and combination treatments. Our SARS-CoV-2-specific MRA combines the quantitative measurement of several parameters of virus infection, such as the intracellular production of proteins and genomes, enzymatic activities and virion release, as well as the use of reporter systems. In this regard, the antiviral efficacy of remdesivir and GC376 has been investigated in human Caco-2 cells. The readouts included the use of spike- and double-strand RNA-specific monoclonal antibodies for in-cell fluorescence imaging, a newly generated recombinant SARS-CoV-2 reporter virus d6YFP, the novel 3CLpro-based FRET CFP::YFP and the previously reported FlipGFP reporter assays, as well as viral genome-specific RT-qPCR. The data produced by our MRA confirm the high antiviral potency of these two drugs in vitro. Combined, this MRA approach may be applied for broader analyses of SARS-CoV-2-specific antivirals, including compound screenings and the characterization of selected drug candidates.
Coagulation Status in Dogs Naturally Infected with Angiostrongylus vasorum
Authors: Sigrist Nadja E. , Tritten Lucienne , Kümmerle-Fraune Claudia , Hofer-Inteeworn Natalie , Jud Schefer Rahel , Schnyder Manuela , Kutter Annette P. N.
Published: August 2021

Angiostrongylus vasorum infection has been associated with coagulopathies including hyperfibrinolysis. We compared coagulation status including thromboelastometry (ROTEM) parameters in dogs naturally infected with A. vasorum versus healthy dogs to determine clinicopathological parameters associated with bleeding, hypocoagulopathy, and hyperfibrinolysis. Clinical signs, white blood cell count, platelet count, hematocrit, plasmatic coagulation tests (PT, aPTT, fibrinogen concentration), D-dimer, and ROTEM S parameters (Ex-tem, In-tem, Fib-tem, Ap-tem) were analysed and compared between bleeding, nonbleeding, and control dogs and between hypo- and normocoagulable animals. Clinical signs of bleeding were present in 6/9 (67%) hypocoagulable and 1/9 (11%) normocoagulable dogs. PT, fibrinogen concentration, and several ROTEM parameters were significantly different between hypocoagulable and normocoagulabe A. vasorum infected dogs. Hyperfibrinolysis was identified in 44% of infected dogs and was significantly more common in bleeding and hypocoagulable dogs. Hyperfibrinolysis was significantly associated with low MCFFib-tem but not with low fibrinogen concentration or increased D-dimers. CFTEx-tem > 248 swas 100% sensitive and 89% specific to predict hyperfibrinolysis. Hyperfibrinolysis, hypocoagulability and bleeding are common in A. vasorum infected dogs. Only Ex-tem and Fib-tem parameters and potentially PT were associated with bleeding or hypocoagulability. Ex-tem analysis enables detection of bleeding, hypocoagulability and hyperfibrinolysis within minutes.
Evaluation of a Live Attenuated S. sonnei Vaccine Strain in the Human Enteroid Model
Authors: Pilla Giulia , Wu Tao , Grassel Christen , Moon Jonathan , Foulke-Abel Jennifer , Tang Christoph M. , Barry Eileen M.
Published: August 2021

Shigella is a leading cause of bacillary dysentery worldwide, responsible for high death rates especially among children under five in low–middle income countries. Shigella sonnei prevails in high-income countries and is becoming prevalent in industrializing countries, where multi-drug resistant strains have emerged, as a significant public health concern. One strategy to combat drug resistance in S. sonnei is the development of effective vaccines. There is no licensed vaccine against Shigella, and development has been hindered by the lack of an effective small-animal model. In this work, we used human enteroids, for the first time, as a model system to evaluate a plasmid-stabilized S. sonnei live attenuated vaccine strain, CVD 1233-SP, and a multivalent derivative, CVD 1233-SP::CS2-CS3, which expresses antigens from enterotoxigenic Escherichia coli. The strains were also tested for immunogenicity and protective capacity in the guinea pig model, demonstrating their ability to elicit serum and mucosal antibody responses as well as protection against challenge with wild-type S. sonnei. These promising results highlight the utility of enteroids as an innovative preclinical model to evaluate Shigella vaccine candidates, constituting a significant advance for the development of preventative strategies against this important human pathogen.
Brazilian Dengue Virus Type 2-Associated Renal Involvement in a Murine Model: Outcomes after Infection by Two Lineages of the Asian/American Genotype
Authors: Jácome Fernanda Cunha , Caldas Gabriela Cardoso , Rasinhas Arthur da Costa , de Almeida Ana Luisa Teixeira , de Souza Daniel Dias Coutinho , Paulino Amanda Carlos , da Silva Marcos Alexandre Nunes , Barth Ortrud Monika , dos Santos Flávia Barreto , Barreto-Vieira Debora Ferreira
Published: August 2021

Dengue virus type 2 (DENV-2) is, traditionally, the most studied serotype due to its association with explosive outbreaks and severe cases. In Brazil, almost 20 years after the first introduction in the 1990s, a new lineage (Lineage II) of the DENV-2 Asian/American genotype emerged and caused an epidemic with severe cases and hospitalizations. Severe dengue includes multiple organ failure, and renal involvement can be potentially related to increased mortality. In order to better understand the role of DENV infection in renal injury, here we aimed to investigate the outcomes of infection with two distinct lineages of DENV-2 Asian/American genotype in the kidney of a murine model. BALB/c mice were infected with Lineages I and II and tissues were submitted to histopathology, immunohistochemistry, histomorphometry and ultrastructural analysis. Blood urea nitrogen (BUN) was detected in blood sample accessed by cardiac puncture. A tendency in kidney weight increase was observed in mice infected with both lineages, but urea levels, on average, were increased only in mice infected with Lineage II. The DENV antigen was detected in the tissue of mice infected with Lineage II and morphological changes were similar to those observed in human dengue cases. Furthermore, the parameters such as organ weight, urea levels and morphometric analysis, showed significant differences between the two lineages in the infected BALB/c, which was demonstrated to be a suitable experimental model for dengue pathophysiology studies in kidneys.
Aspergillus Section Fumigati Pneumonia and Oxalate Nephrosis in a Foal
Authors: Hattab Jasmine , Vulcano Antonella , D’Arezzo Silvia , Verni Fabiana , Tiscar Pietro Giorgio , Lanteri Giovanni , Gjurcevic Emil , Tosi Umberto , Marruchella Giuseppe
Published: August 2021

Equine pulmonary aspergillosis is a rare deep mycosis often due to the hematogenous spread of hyphae after gastrointestinal tract disease. We describe herein the main clinic-pathological findings observed in a foal, which spontaneously died after showing diarrhea and respiratory distress. Necropsy and histopathological investigations allowed to diagnose pulmonary aspergillosis, which likely developed after necrotic typhlitis-colitis. Biomolecular studies identified Aspergillus section Fumigati strain as the causative agent. Notably, severe oxalate nephrosis was concurrently observed. Occasionally, oxalate nephropathy can be a sequela of pulmonary aspergillosis in humans. The present case report suggests that the renal precipitation of oxalates can occur also in horses affected by pulmonary aspergillosis and could likely contribute to the fatal outcome of the disease.
Development, Characterization, and Stability Evaluation of the Anti-Cellulite Emgel Containing Herbal Extracts and Essential Oils
Authors: Ngamdokmai Ngamrayu , Ingkaninan Kornkanok , Chaichamnong Nattiya , Chootip Krongkarn , Neungchamnong Nitra , Waranuch Neti
Published: August 2021

Recently, the herbal compress was successfully developed and applied for cellulite treatment. The aim of this study was to formulate a more convenient dosage form of herbal application from the original formula. In addition, we aimed to characterize and evaluate the stability of the developed dosage form. A gelled emulsion, or an “emgel,” incorporated with 0.1 wt% tea and coffee extracts (1:1 ratio) plus 5 wt% essential oils (mixed oil) was prepared. The caffeine content in the finished product obtained from tea and coffee extracts analyzed by HPLC was 48.1 ± 2.3 µg/g. The bio-active marker monoterpenes of mixed oil characterized by headspace GCMS were camphene 50.8 ± 1.8 µg/mg, camphor 251.0 ± 3.2 µg/mg, 3-carene 46.7 ± 1.8 µg/mg, α-citral 75.0 ± 2.1 µg/mg, β-citral 65.6 ± 1.3 µg/mg, limonene 36.8 ± 6.7 µg/mg, myrcene 53.3 ± 4.5 µg/mg, α-pinene 85.2 ± 0.6 µg/mg, β-pinene 88.4 ± 1.1 µg/mg, and terpinene-4-ol 104.3 ± 2.6 µg/mg. The stability study was carried out over a period of 3 months at 4, 25, and 50 °C. The caffeine content showed no significant changes and passed the acceptance criteria of ≥80% at all tested temperatures. However, monoterpenes showed their stability for only 2 months at 50 °C. Therefore, the shelf-life of the emgel was, consequently, calculated to be 31 months using the Q10 method. Thus, the anti-cellulite emgel was successfully formulated. The characterization methods and stability evaluation for caffeine and monoterpenes in an emgel matrix were also successfully developed and validated.
Utility of suPAR and NGAL for AKI Risk Stratification and Early Optimization of Renal Risk Medications among Older Patients in the Emergency Department
Authors: Walls Anne Byriel , Bengaard Anne Kathrine , Iversen Esben , Nguyen Camilla Ngoc , Kallemose Thomas , Juul-Larsen Helle Gybel , Jawad Baker Nawfal , Hornum Mads , Andersen Ove , Eugen-Olsen Jesper , Houlind Morten Baltzer
Published: August 2021

Diagnosis of acute kidney injury (AKI) based on plasma creatinine often lags behind actual changes in renal function. Here, we investigated early detection of AKI using the plasma soluble urokinase plasminogen activator receptor (suPAR) and neutrophil gelatinase-sssociated lipocalin (NGAL) and observed the impact of early detection on prescribing recommendations for renally-eliminated medications. This study is a secondary analysis of data from the DISABLMENT cohort on acutely admitted older (≥65 years) medical patients (n = 339). Presence of AKI according to kidney disease: improving global outcomes (KDIGO) criteria was identified from inclusion to 48 h after inclusion. Discriminatory power of suPAR and NGAL was determined by receiver-operating characteristic (ROC). Selected medications that are contraindicated in AKI were identified in Renbase®. A total of 33 (9.7%) patients developed AKI. Discriminatory power for suPAR and NGAL was 0.69 and 0.78, respectively, at a cutoff of 4.26 ng/mL and 139.5 ng/mL, respectively. The interaction of suPAR and NGAL yielded a discriminatory power of 0.80, which was significantly higher than for suPAR alone (p = 0.0059). Among patients with AKI, 22 (60.6%) used at least one medication that should be avoided in AKI. Overall, suPAR and NGAL levels were independently associated with incident AKI and their combination yielded excellent discriminatory power for risk determination of AKI.
Prevalence and Determinants of Multimorbidity, Polypharmacy, and Potentially Inappropriate Medication Use in the Older Outpatients: Findings from EuroAgeism H2020 ESR7 Project in Ethiopia
Authors: Bhagavathula Akshaya Srikanth , Seid Mohammed Assen , Adane Aynishet , Gebreyohannes Eyob Alemayehu , Brkic Jovana , Fialová Daniela
Published: August 2021

Few studies have been conducted on multimorbidity (two or more chronic diseases) and rational geriatric prescribing in Africa. This study examined the prevalence and determinants of multimorbidity, polypharmacy (five or more long-term medications), and potentially inappropriate medication (PIM) use according to the 2019 Beers criteria among the older adults attending chronic care clinics from a single institution in Ethiopia. A hospital-based cross-sectional study was conducted among 320 randomly selected older adults from 12 March 2020 to 30 August 2020. A multivariable logistic regression analysis was performed to identify the predictor variables. The prevalence of multimorbidity, polypharmacy, and PIM exposure was 59.1%, 24.1%, and 47.2%, respectively. Diuretics (10%), insulin sliding scale (8.8%), amitriptyline (7.8%), and aspirin (6.9%) were among the most frequently prescribed PIMs. Older patients experiencing pain flare-ups were more likely to have multimorbidity (adjusted odds ratio (AOR): 1.64, 95% confidence intervals: 1.13–2.39). Persistent anger (AOR: 3.33; 1.71–6.47) and use of mobility aids (AOR: 2.41, 1.35–4.28) were associated with polypharmacy. Moreover, cognitive impairment (AOR: 1.65, 1.15–2.34) and health deterioration (AOR: 1.61, 1.11–2.32) increased the likelihood of PIM exposure. High prevalence of multimorbidity and PIM use was observed in Ethiopia. Several important determinants that can be modified by applying PIM criteria in routine practice were also identified.
Preparation of Solid Dispersions of Simvastatin and Soluplus Using a Single-Step Organic Solvent-Free Supercritical Fluid Process for the Drug Solubility and Dissolution Rate Enhancement
Authors: Nandi Uttom , Ajiboye Adejumoke Lara , Patel Preksha , Douroumis Dennis , Trivedi Vivek
Published: August 2021

The study was designed to investigate the feasibility of supercritical carbon dioxide (scCO2) processing for the preparation of simvastatin (SIM) solid dispersions (SDs) in Soluplus® (SOL) at temperatures below polymer’s glass transition. The SIM content in the SDs experimental design was kept at 10, 20 and 30% to study the effect of the drug–polymer ratio on the successful preparation of SDs. The SIM–SOL formulations, physical mixtures (PMs) and SDs were evaluated using X-ray diffraction (XRD), differential scanning calorimetry (DSC), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), and dissolution studies. The scCO2 processing conditions and drug–polymer ratio were found to influence the physicochemical properties of the drug in formulated SDs. SIM is a highly crystalline drug; however, physicochemical characterisation carried out by SEM, DSC, and XRD demonstrated the presence of SIM in amorphous nature within the SDs. The SIM–SOL SDs showed enhanced drug dissolution rates, with 100% being released within 45 min. Moreover, the drug dissolution from SDs was faster and higher in comparison to PMs. In conclusion, this study shows that SIM–SOL dispersions can be successfully prepared using a solvent-free supercritical fluid process to enhance dissolution rate of the drug.
Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes
Authors: Cruz Lucas , Soares Paula , Correia Marcelo
Published: August 2021

Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs.
Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues
Authors: Bieszczad Bartosz , Garbicz Damian , Świtalska Marta , Dudek Marta K. , Warszycki Dawid , Wietrzyk Joanna , Grzesiuk Elżbieta , Mieczkowski Adam
Published: August 2021

Histone deacetylase (HDAC) inhibitors are a class of drugs used in the cancer treatment. Here, we developed a library of 19 analogues of Vorinostat, an HDAC inhibitor used in lymphomas treatment. In Vorinostat, we replaced the hydrophobic phenyl group with various tricyclic ‘caps’ possessing a central, eight-membered, heterocyclic ring, and investigated the HDAC activity and cytotoxic effect on the cancer and normal cell lines. We found that 3 out of the 19 compounds, based on dibenzo[b,f]azocin-6(5H)-one, 11,12-dihydrodibenzo[b,f]azocin-6(5H)-one, and benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)-dione scaffolds, showed better HDACs inhibition than the referenced Vorinostat. In leukemic cell line MV4-11 and in the lymphoma cell line Daudi, three compounds showed lower IC50 values than Vorinostat. These compounds had higher activity and selectivity against MV4-11 and Daudi cell lines than reference Vorinostat. We also observed a strong correlation between HDACs inhibition and the cytotoxic effect. Cell lines derived from solid tumours: A549 (lung carcinoma) and MCF-7 (breast adenocarcinoma) as well as reference BALB/3T3 (normal murine fibroblasts) were less susceptible to compounds tested. Developed derivatives show improved properties than Vorinostat, thus they could be considered as possible agents for leukemia and lymphoma treatment.
Doxycycline Attenuates Cancer Cell Growth by Suppressing NLRP3-Mediated Inflammation
Authors: Alsaadi Mohammad , Tezcan Gulcin , Garanina Ekaterina E. , Hamza Shaimaa , McIntyre Alan , Rizvanov Albert A. , Khaiboullina Svetlana F.
Published: August 2021

NLR family pyrin domain containing 3 (NLRP3) inflammasome formation is triggered by the damaged mitochondria releasing reactive oxygen species. Doxycycline was shown to regulate inflammation; however, its effect on NLRP3 in cancer remains largely unknown. Therefore, we sought to determine the effect of doxycycline on NLRP3 regulation in cancer using an in vitro model. NLRP3 was activated in a prostate cancer cell line (PC3) and a lung cancer cell line (A549) before treatment with doxycycline. Inflammasome activation was assessed by analyzing RNA expression of NLRP3, Pro-CASP-1, and Pro-IL1β using RT-qPCR. Additionally, NLPR3 protein expression and IL-1β secretion were analyzed using Western blot and ELISA, respectively. Tumor cell viability was determined using Annexin V staining and a cell proliferation assay. Cytokine secretion was analyzed using a 41Plex assay for human cytokines. Data were analyzed using one-way ANOVA model with Tukey’s post hoc tests. Doxycycline treatment decreased NLRP3 formation in PC3 and A549 cells compared to untreated and LPS only treated cells (p < 0.05). Doxycycline also decreased proliferation and caused cell death through apoptosis, a response that differed to the LPS-Nigericin mediated pyroptosis. Our findings suggest that doxycycline inhibits LPS priming of NLRP3 and reduces tumor progression through early apoptosis in cancer.
Retinoids Delivery Systems in Cancer: Liposomal Fenretinide for Neuroectodermal-Derived Tumors
Authors: Bensa Veronica , Calarco Enzo , Giusto Elena , Perri Patrizia , Corrias Maria Valeria , Ponzoni Mirco , Brignole Chiara , Pastorino Fabio
Published: August 2021

Retinoids are a class of natural and synthetic compounds derived from vitamin A. They are involved in several biological processes like embryogenesis, reproduction, vision, growth, inflammation, differentiation, proliferation, and apoptosis. In light of their important functions, retinoids have been widely investigated for their therapeutic applications. Thus far, their use for the treatment of several types of cancer and skin disorders has been reported. However, these therapeutic agents present several limitations for their widespread clinical translatability, i.e., poor solubility and chemical instability in water, sensitivity to light, heat, and oxygen, and low bioavailability. These characteristics result in internalization into target cells and tissues only at low concentration and, consequently, at an unsatisfactory therapeutic dose. Furthermore, the administration of retinoids causes severe side-effects. Thus, in order to improve their pharmacological properties and circulating half-life, while minimizing their off-target uptake, various retinoids delivery systems have been recently developed. This review intends to provide examples of retinoids-loaded nano-delivery systems for cancer treatment. In particular, the use and the therapeutic results obtained by using fenretinide-loaded liposomes against neuroectodermal-derived tumors, such as melanoma, in adults, and neuroblastoma, the most common extra-cranial solid tumor of childhood, will be discussed.
Inulin and Its Application in Drug Delivery
Authors: Afinjuomo Franklin , Abdella Sadikalmahdi , Youssef Souha H. , Song Yunmei , Garg Sanjay
Published: August 2021

Inulin’s unique and flexible structure, stabilization/protective effects, and organ targeting ability make it an excellent drug delivery carrier compared to other biodegradable polysaccharides. The three hydroxyl groups attached to each fructose unit serve as an anchor for chemical modification. This, in turn, helps in increasing bioavailability, improving cellular uptake, and achieving targeted, sustained, and controlled release of drugs and biomolecules. This review focuses on the various types of inulin drug delivery systems such as hydrogel, conjugates, nanoparticles, microparticles, micelles, liposomes, complexes, prodrugs, and solid dispersion. The preparation and applications of the different inulin drug delivery systems are further discussed. This work highlights the fact that modification of inulin allows the use of this polymer as multifunctional scaffolds for different drug delivery systems.
Hypoglycemic Activity of Aqueous Extract of Latex from Hancornia speciosa Gomes: A Study in Zebrafish and In Silico
Authors: Tomazi Rosana , Figueira Ângela Costa , Ferreira Adriana Maciel , Ferreira Diego Quaresma , de Souza Gisele Custódio , de Souza Pinheiro Wandson Braamcamp , Pinheiro Neto José Rodrigues , da Silva Geilson Alcantara , de Lima Henrique Barros , da Silva Hage-Melim Lorane Izabel , Pereira Arlindo César Matias , Carvalho José Carlos Tavares , da Silva de Almeida Sheylla Susan Moreira
Published: August 2021

Hancornia speciosa Gomes is a tree native to Brazil and has therapeutic potential for several diseases. Ethnopharmacological surveys have reported that the plant is used as a hypoglycemic agent and to lose weight. This study aimed to evaluate the effects of the aqueous extract from H. speciosa latex (LxHs) in a zebrafish model of diabetes. The extract was evaluated through high-performance thin-layer chromatography (HTPLC), nuclear magnetic resonance (NMR), and Fourier-transform infrared spectroscopy (FT-IR). We then tested treatments with LxHs (500, 1000, and 1500 mg/kg) by assessing blood glucose levels in alloxan-induced diabetic animals, and metformin was used as a control. The toxicity was evaluated through histopathology of the pancreas and biochemical assessment of serum levels of AST, ALT, creatinine, and urea. The extract was also assessed for acute toxicity through several parameters in embryos and adult animals. Finally, we performed in silico analysis through the SEA server and docking using the software GOLD. The phytochemical study showed the compounds cornoside, dihydrocornoide, and 1-O-methyl-myoinositol (bornesitol). The treatment with all doses of LxHs significantly decreased alloxan-induced hyperglycemia without any significant histological or biochemical abnormalities. No significant frequency of teratogenesis was observed in the embryos exposed to the extract, and no significant behavioral changes or deaths were observed in adult animals. In silico, the results showed a potential interaction between inositol and enzymes involved in carbohydrates’ metabolism. Overall, the results show a hypoglycemic activity of the extract in vivo, with no apparent toxicity. The computational studies suggest this could be at least partially due to the presence of bornesitol, since inositols can interact with carbohydrates’ enzymes.
A Novel Chitosan Nanosponge as a Vehicle for Transepidermal Drug Delivery
Authors: Lee Jin Sil , Oh Hyeryeon , Kim Sunghyun , Lee Jeung-Hoon , Shin Yong Chul , Choi Won Il
Published: August 2021

Transepidermal drug delivery achieves high drug concentrations at the action site and ensures continuous drug delivery and better patient compliance with fewer adverse effects. However, drug delivery through topical application is still limited in terms of drug penetration. Chitosan is a promising enhancer to overcome this constraint, as it can enhance drug diffusion by opening the tight junctions of the stratum corneum. Therefore, here, we developed a novel chitosan nanosponge (CNS) with an optimal ratio and molecular weight of chitosan to improve drug penetration through skin. To prepare the CNS, two types of chitosan (3 and 10 kDa) were each conjugated with poloxamer 407 using para-nitrophenyl chloroformate, and the products were mixed with poloxamer 407 at ratios of 5:5, 8:2, and 10:0. The resulting mixtures were molded to produce flexible soft nanosponges by simple nanoprecipitation. The CNSs were highly stable in biological buffer for four weeks and showed no toxicity in human dermal fibroblasts. The CNSs increased drug permeability through human cadaver skin in a Franz-type diffusion cell, with substantially higher permeability with 3 kDa chitosan at a ratio of 8:2. This suggests the applicability of the novel CNS as a promising carrier for efficient transepidermal drug delivery.
A Traffic Light System to Maximize Carbohydrate Cryoprotectants’ Effectivity in Nanostructured Lipid Carriers’ Lyophilization
Authors: Rouco Helena , Diaz-Rodriguez Patricia , Guillin Alba , Remuñán-López Carmen , Landin Mariana
Published: August 2021

Lyophilization is often employed to transform nanoparticle suspensions to stable solid forms. This work proposed Neurofuzzy Logic (NFL) to better understand the lyophilization process of Nanostructured Lipid Carriers’ (NLCs) dispersions and the carbohydrate cryoprotectants’ (CPs) performance in these processes. NLCs were produced by hot homogenization, frozen at different speeds, and lyophilized using several CPs at variable concentrations. NLCs were characterized, and results were expressed as increase in particle size (Δ size), polydispersity (Δ PdI), and zeta potential (Δ ZP) of lyophilized powders (LP) regarding initial dispersions. CPs were classified according to their molecular weights (MW), and the osmolarities (Π) of CPs solutions were also determined. Databases obtained were finally modelled through FormRules® (Intelligensys Ltd., Kirkwall, Scotland, UK), an NFL software. NFL models revealed that CPs’ MW determines the optimal freezing conditions and CPs’ proportions. The knowledge generated allowed the establishment of a traffic light system intended to successfully select and apply sugars for nanoparticles lyophilization.
Reparation of an Inflamed Air-Liquid Interface Cultured A549 Cells with Nebulized Nanocurcumin
Authors: Altube Maria Julia , Caimi Lilen Ivonne , Huck-Iriart Cristian , Morilla Maria Jose , Romero Eder Lilia
Published: August 2021

The anti-inflammatory, antifibrotic and antimicrobial activities of curcumin (CUR) are missed because of its low solubility in aqueous media, low bioavailability, and structural lability upon oral intake. Soft nanoparticles such as nanoliposomes are not efficient as CUR carriers, since crystalline CUR is expelled from them to physiological media. Nanostructures to efficiently trap and increase the aqueous solubility of CUR are needed to improve both oral or nebulized delivery of CUR. Here we showed that SRA1 targeted nanoarchaeosomes (nATC) [1:0.4 w:w:0.04] archaeolipids, tween 80 and CUR, 155 ± 16 nm sized of −20.7 ± 3.3 z potential, retained 0.22 mg CUR ± 0.09 per 12.9 mg lipids ± 4.0 (~600 μM CUR) in front to dilution, storage, and nebulization. Raman and fluorescence spectra and SAXS patterns were compatible with a mixture of enol and keto CUR tautomers trapped within the depths of nATC bilayer. Between 20 and 5 µg CUR/mL, nATC was endocytosed by THP1 and A549 liquid–liquid monolayers without noticeable cytotoxicity. Five micrograms of CUR/mL nATC nebulized on an inflamed air–liquid interface of A549 cells increased TEER, normalized the permeation of LY, and decreased il6, tnfα, and il8 levels. Overall, these results suggest the modified pharmacodynamics of CUR in nATC is useful for epithelia repair upon inflammatory damage, deserving further deeper exploration, particularly related to its targeting ability.
Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions
Authors: Correia José H. , Rodrigues José A. , Pimenta Sara , Dong Tao , Yang Zhaochu
Published: August 2021

Photodynamic therapy (PDT) is a minimally invasive therapeutic modality that has gained great attention in the past years as a new therapy for cancer treatment. PDT uses photosensitizers that, after being excited by light at a specific wavelength, react with the molecular oxygen to create reactive oxygen species in the target tissue, resulting in cell death. Compared to conventional therapeutic modalities, PDT presents greater selectivity against tumor cells, due to the use of photosensitizers that are preferably localized in tumor lesions, and the precise light irradiation of these lesions. This paper presents a review of the principles, mechanisms, photosensitizers, and current applications of PDT. Moreover, the future path on the research of new photosensitizers with enhanced tumor selectivity, featuring the improvement of PDT effectiveness, has also been addressed. Finally, new applications of PDT have been covered.
Gene Expression and Protein Abundance of Hepatic Drug Metabolizing Enzymes in Liver Pathology
Authors: Drozdzik Marek , Lapczuk-Romanska Joanna , Wenzel Christoph , Szelag-Pieniek Sylwia , Post Mariola , Skalski Łukasz , Kurzawski Mateusz , Oswald Stefan
Published: August 2021

Hepatic drug metabolizing enzymes (DMEs) markedly affect drug pharmacokinetics. Because liver diseases may alter enzymatic function and in turn drug handling and clinical efficacy, we investigated DMEs expression in dependence on liver pathology and liver failure state. In 5 liver pathologies (hepatitis C, alcoholic liver disease, autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis) and for the first time stratified according to the Child–Pugh score, 10 CYPs (CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) and 4 UGTs (UGT1A1, UGT1A3, UGT2B7 and UGT2B) enzymes were quantified for protein abundance (LC-MS/MS) and gene expression (qRT-PCR). CYP2E1 was the most vulnerable enzyme, and its protein levels were significantly reduced just in Child–Pugh class A livers. The protein abundance of CYP1A1, CYP2B6, CYP2C19, CYP2D6 as well as UGT1A1, UGT1A3 and UGT2B15 was relatively stable in the course of progression of liver function deterioration. Alcoholic liver disease and primary biliary cholangitis were involved in the most prominent changes in the protein abundances, with downregulation of 6 (CYP1A2, CYP2C8, CYP2D6, CYP2E1, CYP3A4, UGT2B7) and 5 (CYP1A1, CYP2B6, CYP2C8, CYP2E1, CYP3A4) significantly downregulated enzymes, respectively. The results of the study demonstrate that DMEs protein abundance is affected both by the type of liver pathology as well as functional state of the organ.
Firing up the Tumor Microenvironment with Nanoparticle-Based Therapies
Authors: Pan Yunfeng , Song Xueru , Wang Yue , Wei Jia
Published: August 2021

Therapies mobilizing host immunity against cancer cells have profoundly improved prognosis of cancer patients. However, efficacy of immunotherapies depends on local immune conditions. The “cold” tumor, which is characterized by lacking inflamed T cells, is insensitive to immunotherapy. Current strategies of improving the “cold” tumor microenvironment are far from satisfying. Nanoparticle-based therapies provide novel inspiration in firing up the tumor microenvironment. In this review, we presented progress and limitations of conventional immunotherapies. Then, we enumerate advantages of nanoparticle-based therapies in remodeling the “cold” tumor microenvironment. Finally, we discuss the prospect of nanoparticle-based therapies in clinical application.
Comprehensive Evidence of Carrier-Mediated Distribution of Amantadine to the Retina across the Blood–Retinal Barrier in Rats
Authors: Shinozaki Yusuke , Akanuma Shin-ichi , Mori Yuika , Kubo Yoshiyuki , Hosoya Ken-ichi
Published: August 2021

Amantadine, a drug used for the blockage of NMDA receptors, is well-known to exhibit neuroprotective effects. Accordingly, assessment of amantadine transport at retinal barriers could result in the application of amantadine for retinal diseases such as glaucoma. The objective of this study was to elucidate the retinal distribution of amantadine across the inner and outer blood–retinal barrier (BRB). In vivo blood-to-retina [3H]amantadine transport was investigated by using the rat retinal uptake index method, which was significantly reduced by unlabeled amantadine. This result indicated the involvement of carrier-mediated processes in the retinal distribution of amantadine. In addition, in vitro model cells of the inner and outer BRB (TR-iBRB2 and RPE-J cells) exhibited saturable kinetics (Km in TR-iBRB2 cells, 79.4 µM; Km in RPE-J cells, 90.5 and 9830 µM). The inhibition of [3H]amantadine uptake by cationic drugs/compounds indicated a minor contribution of transport systems that accept cationic drugs (e.g., verapamil), as well as solute carrier (SLC) organic cation transporters. Collectively, these outcomes suggest that carrier-mediated transport systems, which differ from reported transporters and mechanisms, play a crucial role in the retinal distribution of amantadine across the inner/outer BRB.
Nanoparticles to Target and Treat Macrophages: The Ockham’s Concept?
Authors: Medrano-Bosch Mireia , Moreno-Lanceta Alazne , Melgar-Lesmes Pedro
Published: August 2021

Nanoparticles are nanomaterials with three external nanoscale dimensions and an average size ranging from 1 to 1000 nm. Nanoparticles have gained notoriety in technological advances due to their tunable physical, chemical, and biological characteristics. However, the administration of functionalized nanoparticles to living beings is still challenging due to the rapid detection and blood and tissue clearance by the mononuclear phagocytic system. The major exponent of this system is the macrophage. Regardless the nanomaterial composition, macrophages can detect and incorporate foreign bodies by phagocytosis. Therefore, the simplest explanation is that any injected nanoparticle will be probably taken up by macrophages. This explains, in part, the natural accumulation of most nanoparticles in the spleen, lymph nodes, and liver (the main organs of the mononuclear phagocytic system). For this reason, recent investigations are devoted to design nanoparticles for specific macrophage targeting in diseased tissues. The aim of this review is to describe current strategies for the design of nanoparticles to target macrophages and to modulate their immunological function involved in different diseases with special emphasis on chronic inflammation, tissue regeneration, and cancer.
Towards a Trait-Based Approach to Potentiate Yield under Drought in Legume-Rich Annual Forage Mixtures
Authors: Leitão Susana T. , Alves Mara Lisa , Pereira Priscila , Zerrouk Aziza , Godinho Bruno , Barradas Ana , Vaz Patto Maria Carlota
Published: August 2021

Mediterranean annual forage mixtures are facing the impact of climate change, especially higher frequencies of winter-time drought. Increased mixture plasticity to climate variability is needed to mitigate this impact. However, little information exists regarding the specificities and complementarities of each forage species component to potentiate mixture resilience under drought. In this study, we identified traits with breeding potential under water scarcity through a detailed characterization of leaf and root-related parameters of 10 legume and grass species components of Mediterranean annual forage mixtures, complemented by their photosynthetic response evaluation under well-watered and water deficit conditions. This integrated approach also allowed us to identify the most resilient species to water deficit. In particular, we found that the highest canopy height and root to shoot ratio of grass components complemented well the highest aerial and root biomass and superior photosynthetic performance of the legume components. Trifolium squarrosum and Triticosecale showed the most adequate combination of traits and the best photosynthetic performance under water deficit within each species family. Although some of these traits are not commonly used in annual forage selection, they may in part explain the potential higher resilience of the grass–legume mixture under water deficit and should be considered in forage breeding.
Genetic Variation of Native Perilla Germplasms Collected from South Korea Using Simple Sequence Repeat (SSR) Markers and Morphological Characteristics
Authors: Oh Jun Seok , Sa Kyu Jin , Park Hyeon , Hyun Do Yoon , Lee Sookyeong , Rhee Ju Hee , Lee Ju Kyong
Published: August 2021

Using morphological characteristics and simple sequence repeat (SSR) markers, we evaluated the morphological variation and genetic diversity of 200 Perilla accessions collected from the five regions of South Korea and another region. In morphological characteristics analysis, particularly leaf color, stem color, degree of pubescence, and leaf size have been found to help distinguish the morphological features of native Perilla accessions cultivated in South Korea. Twenty SSR primer sets confirmed a total of 137 alleles in the 200 Perilla accessions. The number of alleles per locus ranged from 3 to 13, with an average number of alleles per locus of 6.85. The average genetic diversity (GD) was 0.649, with a range of 0.290–0.828. From analysis of SSR markers, accessions from the Jeolla-do and Gyeongsang-do regions showed comparatively high genetic diversity values compared with those from other regions in South Korea. In the unweighted pair group method with arithmetic mean (UPGMA) analysis, the 200 Perilla accessions were found to cluster into three main groups and an outgroup with 42% genetic similarity, and did not show a clear geographic structure from the five regions of South Korea. Therefore, it is believed that landrace Perilla seeds are frequently exchanged by farmers through various routes between the five regions of South Korea. The results of this study are expected to provide interesting information on the conservation of these genetic resources and selection of useful resources for the development of varieties for seeds and leafy vegetables of cultivated Perilla frutescens var. frutescens in South Korea.
The Micromorphology and Histochemistry of Foliar Mixed Indumentum of Leucas lavandulaefolia (Lamiaceae)
Authors: Naidoo Yougasphree , Dladla Thobekile , Dewir Yaser Hassan , Gangaram Serisha , Naidoo Clarissa Marcelle , Rihan Hail Z.
Published: August 2021

Leucas lavandulaefolia Sm. (Lamiaceae) is an important medicinal plant with a broad spectrum of pharmacological activities. This study aimed at characterizing the morphology, distribution, and chemical composition of the secretions of trichomes at different developmental stages on the leaves of L. lavandulaefolia, using light and electron microscopy. Morphological observations revealed the presence of bicellular non-glandular, glandular peltate, and capitate trichomes on both adaxial and abaxial leaf surfaces. The density of both non-glandular and glandular trichomes decreased with the progression of leaf development. Heads of peltate and short-stalked capitate trichomes were between 20.78–42.80 µm and 14.98–18.93 µm at different developmental stages. Furthermore, long-stalked capitate trichomes were rare and infrequent. Leaf sections revealed the presence of important secondary metabolites in glandular trichomes, i.e., terpenoids. This study represents the first report on the morphology and histochemistry of trichomes of L. lavandulaefolia; therefore, there is a great scope for further research in this field.
Variation in Ribosomal DNA in the Genus Trifolium (Fabaceae)
Authors: Vozárová Radka , Macková Eliška , Vlk David , Řepková Jana
Published: August 2021

The genus Trifolium L. is characterized by basic chromosome numbers 8, 7, 6, and 5. We conducted a genus-wide study of ribosomal DNA (rDNA) structure variability in diploids and polyploids to gain insight into evolutionary history. We used fluorescent in situ hybridization to newly investigate rDNA variation by number and position in 30 Trifolium species. Evolutionary history among species was examined using 85 available sequences of internal transcribed spacer 1 (ITS1) of 35S rDNA. In diploid species with ancestral basic chromosome number (x = 8), one pair of 5S and 26S rDNA in separate or adjacent positions on a pair of chromosomes was prevalent. Genomes of species with reduced basic chromosome numbers were characterized by increased number of signals determined on one pair of chromosomes or all chromosomes. Increased number of signals was observed also in diploids Trifolium alpestre and Trifolium microcephalum and in polyploids. Sequence alignment revealed ITS1 sequences with mostly single nucleotide polymorphisms, and ITS1 diversity was greater in diploids with reduced basic chromosome numbers compared to diploids with ancestral basic chromosome number (x = 8) and polyploids. Our results suggest the presence of one 5S rDNA site and one 26S rDNA site as an ancestral state.