bluuebunny/crossref_metadata_2025 huggingface dataset:
In Silico and In Vitro Screening of 50 Curcumin Compounds as EGFR and NF-κB Inhibitors
Authors: Saeed Mohamed E. M. , Yücer Rümeysa , Dawood Mona , Hegazy Mohamed-Elamir F. , Drif Assia , Ooko Edna , Kadioglu Onat , Seo Ean-Jeong , Kamounah Fadhil S. , Titinchi Salam J. , Bachmeier Beatrice , Efferth Thomas
Published: April 2022

The improvement of cancer chemotherapy remains a major challenge, and thus new drugs are urgently required to develop new treatment regimes. Curcumin, a polyphenolic antioxidant derived from the rhizome of turmeric (Curcuma longa L.), has undergone extensive preclinical investigations and, thereby, displayed remarkable efficacy in vitro and in vivo against cancer and other disorders. However, pharmacological limitations of curcumin stimulated the synthesis of numerous novel curcumin analogs, which need to be evaluated for their therapeutic potential. In the present study, we calculated the binding affinities of 50 curcumin derivatives to known cancer-related target proteins of curcumin, i.e., epidermal growth factor receptor (EGFR) and nuclear factor κB (NF-κB) by using a molecular docking approach. The binding energies for EGFR were in a range of −12.12 (±0.21) to −7.34 (±0.07) kcal/mol and those for NF-κB ranged from −12.97 (±0.47) to −6.24 (±0.06) kcal/mol, indicating similar binding affinities of the curcumin compounds for both target proteins. The predicted receptor-ligand binding constants for EGFR and curcumin derivatives were in a range of 0.00013 (±0.00006) to 3.45 (±0.10) µM and for NF-κB in a range of 0.0004 (±0.0003) to 10.05 (±4.03) µM, indicating that the receptor-ligand binding was more stable for EGFR than for NF-κB. Twenty out of 50 curcumin compounds showed binding energies to NF-κB smaller than −10 kcal/mol, while curcumin as a lead compound revealed free binding energies of >−10 kcal/mol. Comparable data were obtained for EGFR: 15 out of 50 curcumin compounds were bound to EGFR with free binding energies of <−10 kcal/mol, while the binding affinity of curcumin itself was >−10 kcal/mol. This indicates that the derivatization of curcumin may indeed be a promising strategy to improve targe specificity and to obtain more effective anticancer drug candidates. The in silico results have been exemplarily validated using microscale thermophoresis. The bioactivity has been further investigated by using resazurin cell viability assay, lactate dehydrogenase assay, flow cytometric measurement of reactive oxygen species, and annexin V/propidium iodide assay. In conclusion, molecular docking represents a valuable approach to facilitate and speed up the identification of novel targeted curcumin-based drugs to treat cancer.
Bioinformatics Screening of Potential Biomarkers from mRNA Expression Profiles to Discover Drug Targets and Agents for Cervical Cancer
Authors: Reza Md. Selim , Harun-Or-Roshid Md. , Islam Md. Ariful , Hossen Md. Alim , Hossain Md. Tofazzal , Feng Shengzhong , Xi Wenhui , Mollah Md. Nurul Haque , Wei Yanjie
Published: April 2022

Bioinformatics analysis has been playing a vital role in identifying potential genomic biomarkers more accurately from an enormous number of candidates by reducing time and cost compared to the wet-lab-based experimental procedures for disease diagnosis, prognosis, and therapies. Cervical cancer (CC) is one of the most malignant diseases seen in women worldwide. This study aimed at identifying potential key genes (KGs), highlighting their functions, signaling pathways, and candidate drugs for CC diagnosis and targeting therapies. Four publicly available microarray datasets of CC were analyzed for identifying differentially expressed genes (DEGs) by the LIMMA approach through GEO2R online tool. We identified 116 common DEGs (cDEGs) that were utilized to identify seven KGs (AURKA, BRCA1, CCNB1, CDK1, MCM2, NCAPG2, and TOP2A) by the protein–protein interaction (PPI) network analysis. The GO functional and KEGG pathway enrichment analyses of KGs revealed some important functions and signaling pathways that were significantly associated with CC infections. The interaction network analysis identified four TFs proteins and two miRNAs as the key transcriptional and post-transcriptional regulators of KGs. Considering seven KGs-based proteins, four key TFs proteins, and already published top-ranked seven KGs-based proteins (where five KGs were common with our proposed seven KGs) as drug target receptors, we performed their docking analysis with the 80 meta-drug agents that were already published by different reputed journals as CC drugs. We found Paclitaxel, Vinorelbine, Vincristine, Docetaxel, Everolimus, Temsirolimus, and Cabazitaxel as the top-ranked seven candidate drugs. Finally, we investigated the binding stability of the top-ranked three drugs (Paclitaxel, Vincristine, Vinorelbine) by using 100 ns MD-based MM-PBSA simulations with the three top-ranked proposed receptors (AURKA, CDK1, TOP2A) and observed their stable performance. Therefore, the proposed drugs might play a vital role in the treatment against CC.
Emerging Role of Phospholipids and Lysophospholipids for Improving Brain Docosahexaenoic Acid as Potential Preventive and Therapeutic Strategies for Neurological Diseases
Authors: Hachem Mayssa , Nacir Houda
Published: April 2022

Docosahexaenoic acid (DHA, 22:6n-3) is an omega-3 polyunsaturated fatty acid (PUFA) essential for neural development, learning, and vision. Although DHA can be provided to humans through nutrition and synthesized in vivo from its precursor alpha-linolenic acid (ALA, 18:3n-3), deficiencies in cerebral DHA level were associated with neurodegenerative diseases including Parkinson’s and Alzheimer’s diseases. The aim of this review was to develop a complete understanding of previous and current approaches and suggest future approaches to target the brain with DHA in different lipids’ forms for potential prevention and treatment of neurodegenerative diseases. Since glycerophospholipids (GPs) play a crucial role in DHA transport to the brain, we explored their biosynthesis and remodeling pathways with a focus on cerebral PUFA remodeling. Following this, we discussed the brain content and biological properties of phospholipids (PLs) and Lyso-PLs with omega-3 PUFA focusing on DHA’s beneficial effects in healthy conditions and brain disorders. We emphasized the cerebral accretion of DHA when esterified at sn-2 position of PLs and Lyso-PLs. Finally, we highlighted the importance of DHA-rich Lyso-PLs’ development for pharmaceutical applications since most commercially available DHA formulations are in the form of PLs or triglycerides, which are not the preferred transporter of DHA to the brain.
Membrane Interactivity of Capsaicin Antagonized by Capsazepine
Authors: Mizogami Maki , Tsuchiya Hironori
Published: April 2022

Although the pharmacological activity of capsaicin has been explained by its specific binding to transient receptor potential vanilloid type 1, the amphiphilic structure of capsaicin may enable it to act on lipid bilayers. From a mechanistic point of view, we investigated whether capsaicin and its antagonist capsazepine interact with biomimetic membranes, and how capsazepine influences the membrane effect of capsaicin. Liposomal phospholipid membranes and neuro-mimetic membranes were prepared with 1,2-dipalmitoylphosphatidylcholine and with 1-palmitoyl-2-oleoylphosphatidylcholine and sphingomyelin plus cholesterol, respectively. These membrane preparations were subjected to reactions with capsaicin and capsazepine at 0.5–250 μM, followed by measuring fluorescence polarization to determine the membrane interactivity to modify the fluidity of membranes. Both compounds acted on 1,2-dipalmitoylphosphatidylcholine bilayers and changed membrane fluidity. Capsaicin concentration-dependently interacted with neuro-mimetic membranes to increase their fluidity at low micromolar concentrations, whereas capsazepine inversely decreased the membrane fluidity. When used in combination, capsazepine inhibited the effect of capsaicin on neuro-mimetic membranes. In addition to the direct action on transmembrane ion channels, capsaicin and capsazepine share membrane interactivity, but capsazepine is likely to competitively antagonize capsaicin’s interaction with neuro-mimetic membranes at pharmacokinetically-relevant concentrations. The structure-specific membrane interactivity may be partly responsible for the analgesic effect of capsaicin.
Vitamin D3 Metabolic Enzymes in the Porcine Uterus: Expression, Localization and Autoregulation by 1,25(OH)2D3 In Vitro
Authors: Grzesiak Malgorzata , Kaminska Kinga , Bodzioch Aleksandra , Drzewiecka Ewa M. , Franczak Anita , Knapczyk-Stwora Katarzyna
Published: April 2022

The role of vitamin D3 has been confirmed in female reproductive organs. This study aimed to examine vitamin D3 metabolic enzymes, i.e., CYP27B1 and CYP24A1, mRNA transcript and protein abundance, and protein localization in the uterus of pigs on days 2–5, 10–12, 15–16 and 18–20 of the estrous cycle. Additionally, we determined 1,25(OH)2D3 concentration in uterine flushings and the effect of 1,25(OH)2D3 (10, 50 and 100 ng/mL) in vitro on CYP27B1 and CYP24A1 mRNA transcript abundance in endometrial and myometrial slices. In the endometrium, a greater CYP27B1 mRNA transcript abundance was noted on days 10–12 and 18–20 than on days 15–16, whereas encoded protein abundance was greater on days 18–20 when compared to days 15–16. Endometrial CYP24A1 mRNA transcript abundance was greater on days 18–20 than on days 10–12 and 15–16. In the myometrium, CYP27B1 mRNA transcript abundance was greater on days 18–20 than on days 2–5 and 15–16, while protein abundance was larger in slices collected on days 18–20 than on days 15–16. Neither CYP24A1 mRNA transcript nor encoded protein abundance were detected in the myometrium. The highest 1,25(OH)2D3 concentration in uterine flushings was observed on days 18–20. Furthermore, the 1,25(OH)2D3 increased the abundance of the CYP24A1 mRNA transcript in endometrial slices. Overall, our results suggest that porcine uterus is an extra-renal site of vitamin D3 metabolism. Both the endometrium and the myometrium possess the ability to synthesize vitamin D3, while only the endometrium contributes to its catabolism.
Cruciform DNA Structures Act as Legible Templates for Accelerating Homologous Recombination in Transgenic Animals
Authors: Ou-Yang Huan , Yang Shiao-Hsuan , Chen Wei , Yang Shang-Hsun , Cidem Abdulkadir , Sung Li-Ying , Chen Chuan-Mu
Published: April 2022

Inverted repeat (IR) DNA sequences compose cruciform structures. Some genetic disorders are the result of genome inversion or translocation by cruciform DNA structures. The present study examined whether exogenous DNA integration into the chromosomes of transgenic animals was related to cruciform DNA structures. Large imperfect cruciform structures were frequently predicted around predestinated transgene integration sites in host genomes of microinjection-based transgenic (Tg) animals (αLA-LPH Tg goat, Akr1A1eGFP/eGFP Tg mouse, and NFκB-Luc Tg mouse) or CRISPR/Cas9 gene-editing (GE) animals (αLA-AP1 GE mouse). Transgene cassettes were imperfectly matched with their predestinated sequences. According to the analyzed data, we proposed a putative model in which the flexible cruciform DNA structures acted as a legible template for DNA integration into linear DNAs or double-strand break (DSB) alleles. To demonstrate this model, artificial inverted repeat knock-in (KI) reporter plasmids were created to analyze the KI rate using the CRISPR/Cas9 system in NIH3T3 cells. Notably, the KI rate of the 5′ homologous arm inverted repeat donor plasmid (5′IR) with the ROSA gRNA group (31.5%) was significantly higher than the knock-in reporter donor plasmid (KIR) with the ROSA gRNA group (21.3%, p < 0.05). However, the KI rate of the 3′ inverted terminal repeat/inverted repeat donor plasmid (3′ITRIR) group was not different from the KIR group (23.0% vs. 22.0%). These results demonstrated that the legibility of the sequence with the cruciform DNA existing in the transgene promoted homologous recombination (HR) with a higher KI rate. Our findings suggest that flexible cruciform DNAs folded by IR sequences improve the legibility and accelerate DNA 3′-overhang integration into the host genome via homologous recombination machinery.
Isolation and Functional Characterization of a LEAFY Gene in Mango (Mangifera indica L.)
Authors: Wang Yihan , Yu Haixia , He Xinhua , Lu Tingting , Huang Xing , Luo Cong
Published: April 2022

LEAFY (LFY) plays an important role in the flowering process of plants, controlling flowering time and mediating floral meristem differentiation. Owing to its considerable importance, the mango LFY gene (MiLFY; GenBank accession no. HQ585988) was isolated, and its expression pattern and function were characterized in the present study. The cDNA sequence of MiLFY was 1152 bp, and it encoded a 383 amino acid protein. MiLFY was expressed in all tested tissues and was highly expressed in flowers and buds. Temporal expression analysis showed that MiLFY expression was correlated with floral development stage, and two relative expression peaks were detected in the early stages of floral transition and floral organ differentiation. Moreover, 35S::GFP-MiLFY fusion protein was shown to be localized to the nucleus of cells. Overexpression of MiLFY in Arabidopsis promoted early flowering and the conversion of lateral meristems into terminal flowers. In addition, transgenic plants exhibited obvious morphological changes, such as differences in cauline leaf shape, and the number of lateral branches. When driven by the MiLFY promoter, GFP was highly expressed in leaves, floral organs, stems, and roots, during the flowering period. Exogenous gibberellin (GA3) treatment downregulated MiLFY promoter expression, but paclobutrazol (PPP333) upregulated it. Bimolecular fluorescence complementation (BiFC) assays showed that the MiLFY protein can interact with zinc-finger protein 4 (ZFP4) and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (MiSOC1D). Taken together, these results indicate that MiLFY plays a pivotal role in controlling mango flowering, and that it is regulated by gibberellin and paclobutrazol.
Genetics Matters: Voyaging from the Past into the Future of Humanity and Sustainability
Authors: Cheng Acga , Harikrishna Jennifer Ann , Redwood Charles S. , Lit Lei Cheng , Nath Swapan K. , Chua Kek Heng
Published: April 2022

The understanding of how genetic information may be inherited through generations was established by Gregor Mendel in the 1860s when he developed the fundamental principles of inheritance. The science of genetics, however, began to flourish only during the mid-1940s when DNA was identified as the carrier of genetic information. The world has since then witnessed rapid development of genetic technologies, with the latest being genome-editing tools, which have revolutionized fields from medicine to agriculture. This review walks through the historical timeline of genetics research and deliberates how this discipline might furnish a sustainable future for humanity.
Ghrelin Represses Thymic Stromal Lymphopoietin Gene Expression through Activation of Glucocorticoid Receptor and Protein Kinase C Delta in Inflamed Skin Keratinocytes
Authors: Jeong Hayan , Chong Hyo-Jin , So Jangho , Jo Yejin , Yune Tae-Young , Ju Bong-Gun
Published: April 2022

Ghrelin, a peptide hormone secreted from enteroendocrine cells of the gastrointestinal tract, has anti-inflammatory activity in skin diseases, including dermatitis and psoriasis. However, the molecular mechanism underlying the beneficial effect of ghrelin on skin inflammation is not clear. In this study, we found that ghrelin alleviates atopic dermatitis (AD)-phenotypes through suppression of thymic stromal lymphopoietin (TSLP) gene activation. Knockdown or antagonist treatment of growth hormone secretagogue receptor 1a (GHSR1a), the receptor for ghrelin, suppressed ghrelin-induced alleviation of AD-like phenotypes and suppression of TSLP gene activation. We further found that ghrelin induces activation of the glucocorticoid receptor (GR), leading to the binding of GR with histone deacetylase 3 (HDAC3) and nuclear receptor corepressor (NCoR) NCoR corepressor to negative glucocorticoid response element (nGRE) on the TSLP gene promoter. In addition, ghrelin-induced protein kinase C δ (PKCδ)-mediated phosphorylation of p300 at serine 89 (S89), which decreased the acetylation and DNA binding activity of nuclear factor- κB (NF-κB) p65 to the TSLP gene promoter. Knockdown of PKCδ abolished ghrelin-induced suppression of TSLP gene activation. Our study suggests that ghrelin may help to reduce skin inflammation through GR and PKCδ-p300-NF-κB-mediated suppression of TSLP gene activation.
Cone Photoreceptor Loss in Light-Damaged Albino Rats
Authors: Benthal Molly C. , McKeown Alex S. , Kraft Timothy W.
Published: April 2022

We investigated the etiology of decreased cone-driven vision in a light damage (LD) model of retinal degeneration. To induce slow, moderate degeneration, albino rats underwent low-intensity light exposure for 10 days. Electroretinography was utilized to assess physiologic function of the rod- and cone-driven retinal function in LD and control rats. Immunohistochemistry targeting cone arrestin allowed for quantification of cone density and for comparison of the decline in function. Photoreceptor loss was quantified by outer nuclear layer thickness decreases, as observed by optical coherence tomography and histology. The LD rats showed decreased rod- and cone-driven function with partial recovery 30 days after cessation of light exposure. In addition, LD rats showed decreased cone photoreceptor densities in the central retinal region compared to control rats. Our results demonstrate that the loss of cone-driven visual function induced by light damage is at least partially due to the death of cone photoreceptors.
The Multiverse of Plant Small RNAs: How Can We Explore It?
Authors: Ivanova Zdravka , Minkov Georgi , Gisel Andreas , Yahubyan Galina , Minkov Ivan , Toneva Valentina , Baev Vesselin
Published: April 2022

Plant small RNAs (sRNAs) are a heterogeneous group of noncoding RNAs with a length of 20–24 nucleotides that are widely studied due to their importance as major regulators in various biological processes. sRNAs are divided into two main classes—microRNAs (miRNAs) and small interfering RNAs (siRNAs)—which differ in their biogenesis and functional pathways. Their identification and enrichment with new structural variants would not be possible without the use of various high-throughput sequencing (NGS) techniques, allowing for the detection of the total population of sRNAs in plants. Classifying sRNAs and predicting their functional role based on such high-performance datasets is a nontrivial bioinformatics task, as plants can generate millions of sRNAs from a variety of biosynthetic pathways. Over the years, many computing tools have been developed to meet this challenge. Here, we review more than 35 tools developed specifically for plant sRNAs over the past few years and explore some of their basic algorithms for performing tasks related to predicting, identifying, categorizing, and quantifying individual sRNAs in plant samples, as well as visualizing the results of these analyzes. We believe that this review will be practical for biologists who want to analyze their plant sRNA datasets but are overwhelmed by the number of tools available, thus answering the basic question of how to choose the right one for a particular study.
Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls
Authors: Mammoli Andrea , Bianconi Elisa , Ruta Luana , Riccio Alessandra , Bigiotti Carlo , Souma Maria , Carotti Andrea , Rossini Sofia , Suvieri Chiara , Pallotta Maria Teresa , Grohmann Ursula , Camaioni Emidio , Macchiarulo Antonio
Published: April 2022

Over the last two decades, indoleamine 2,3-dioxygenase 1 (IDO1) has attracted wide interest as a key player in immune regulation, fostering the design and development of small molecule inhibitors to restore immune response in tumor immunity. In this framework, biochemical, structural, and pharmacological studies have unveiled peculiar structural plasticity of IDO1, with different conformations and functional states that are coupled to fine regulation of its catalytic activity and non-enzymic functions. The large plasticity of IDO1 may affect its ligand recognition process, generating bias in structure-based drug design campaigns. In this work, we report a screening campaign of a fragment library of compounds, grounding on the use of three distinct conformations of IDO1 that recapitulate its structural plasticity to some extent. Results are instrumental to discuss tips and pitfalls that, due to the large plasticity of the enzyme, may influence the identification of novel and differentiated chemical scaffolds of IDO1 ligands in structure-based screening campaigns.
Trimethylamine N-Oxide (TMAO) Impairs Purinergic Induced Intracellular Calcium Increase and Nitric Oxide Release in Endothelial Cells
Authors: Querio Giulia , Antoniotti Susanna , Geddo Federica , Levi Renzo , Gallo Maria Pia
Published: April 2022

Trimethylamine N-oxide (TMAO) is a diet derived compound directly introduced through foodstuff, or endogenously synthesized from its precursors, primarily choline, L-carnitine, and ergothioneine. New evidence outlines high TMAO plasma concentrations in patients with overt cardiovascular disease, but its direct role in pathological development is still controversial. The purpose of the study was to evaluate the role of TMAO in affecting key intracellular factors involved in endothelial dysfunction development, such as reactive oxygen species, mitochondrial health, calcium balance, and nitric oxide release using bovine aortic endothelial cells (BAE-1). Cell viability and oxidative stress indicators were monitored after acute and prolonged TMAO treatment. The role of TMAO in interfering with the physiological purinergic vasodilatory mechanism after ATP stimulation was defined through measurements of the rise of intracellular calcium, nitric oxide release, and eNOS phosphorylation at Ser1179 (eNOSSer1179). TMAO was not cytotoxic for BAE-1 and it did not induce the rise of reactive oxygen species and impairment of mitochondrial membrane potential, either in the basal condition or in the presence of a stressor. In contrast, TMAO modified the purinergic response affecting intracellular ATP-induced calcium increase, nitric oxide release, and eNOSSer1179. Results obtained suggest a possible implication of TMAO in impairing the endothelial-dependent vasodilatory mechanism.
Suppression of CCT3 Inhibits Tumor Progression by Impairing ATP Production and Cytoplasmic Translation in Lung Adenocarcinoma
Authors: Chen Shuohua , Tian Yang , Ju Anji , Li Boya , Fu Yan , Luo Yongzhang
Published: April 2022

Heat shock proteins are highly expressed in various cancers and exert critical functions in tumor progression. However, their expression patterns and functions in lung adenocarcinoma (LUAD) remain largely unknown. We identified that chaperonin-containing T-complex protein-1 subunit 3 (CCT3) was highly expressed in LUAD cells and was positively correlated with LUAD malignancy in the clinical samples. Animal studies showed that silencing CCT3 dramatically inhibited tumor growth and metastasis of LUAD. Proliferation and migration were markedly suppressed in CCT3-deficient LUAD cells. Moreover, the knockdown of CCT3 promoted apoptosis and cell cycle arrest. Mechanistically, the function of glycolysis was significantly inhibited and the total intracellular ATP levels were reduced by at least 25% in CCT3-deficient cells. In addition, the knockdown of CCT3 decreased the protein translation and led to a significant reduction in eukaryotic translation initiation factor 3 (EIF3G) protein, which was identified as a protein that interacts with CCT3. Impaired protein synthesis and cell growth in EIF3G-deficient cells were consistent with those caused by CCT3 knockdown in LUAD cells. Taken together, our study demonstrated in multiple ways that CCT3 is a critical factor for supporting growth and metastasis of LUAD, and for the first time, its roles in maintaining intracellular ATP levels and cytoplasmic translation are reported. Our novel findings provide a potential therapeutic target for lung adenocarcinoma.
Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation
Authors: Philippe Aurélie , Kleinau Gunnar , Gruner Jason , Wu Sumin , Postpieszala Daniel , Speck David , Heidecke Harald , Dowell Simon , Riemekasten Gabriela , Hildebrand Peter , Kamhieh-Milz Julian , Catar Rusan , Szczepek Michal , Dragun Duska , Scheerer Patrick
Published: April 2022

The angiotensin II (Ang II) type 1 receptor (AT1R) is involved in the regulation of blood pressure (through vasoconstriction) and water and ion homeostasis (mediated by interaction with the endogenous agonist). AT1R can also be activated by auto-antibodies (AT1R-Abs), which are associated with manifold diseases, such as obliterative vasculopathy, preeclampsia and systemic sclerosis. Knowledge of the molecular mechanisms related to AT1R-Abs binding and associated signaling cascade (dys-)regulation remains fragmentary. The goal of this study was, therefore, to investigate details of the effects of AT1R-Abs on G-protein signaling and subsequent cell proliferation, as well as the putative contribution of the three extracellular receptor loops (ELs) to Abs-AT1R signaling. AT1R-Abs induced nuclear factor of activated T-cells (NFAT) signaling, which reflects Gq/11 and Gi activation. The impact on cell proliferation was tested in different cell systems, as well as activation-triggered receptor internalization. Blockwise alanine substitutions were designed to potentially investigate the role of ELs in AT1R-Abs-mediated effects. First, we demonstrate that Ang II-mediated internalization of AT1R is impeded by binding of AT1R-Abs. Secondly, exclusive AT1R-Abs-induced Gq/11 activation is most significant for NFAT stimulation and mediates cell proliferation. Interestingly, our studies also reveal that ligand-independent, baseline AT1R activation of Gi signaling has, in turn, a negative effect on cell proliferation. Indeed, inhibition of Gi basal activity potentiates proliferation triggered by AT1R-Abs. Finally, although AT1R containing EL1 and EL3 blockwise alanine mutations were not expressed on the human embryonic kidney293T (HEK293T) cell surface, we at least confirmed that parts of EL2 are involved in interactions between AT1R and Abs. This current study thus provides extended insights into the molecular action of AT1R-Abs and associated mechanisms of interrelated pathogenesis.
Mesh Ti6Al4V Material Manufactured by Selective Laser Melting (SLM) as a Promising Intervertebral Fusion Cage
Authors: Przekora Agata , Kazimierczak Paulina , Wojcik Michal , Chodorski Emil , Kropiwnicki Jacek
Published: April 2022

Intervertebral cages made of Ti6Al4V alloy show excellent osteoconductivity, but also higher stiffness, compared to commonly used polyether-ether-ketone (PEEK) materials, that may lead to a stress-shielding effect and implant subsidence. In this study, a metallic intervertebral fusion cage, with improved mechanical behavior, was manufactured by the introduction of a three-dimensional (3D) mesh structure to Ti6Al4V material, using an additive manufacturing method. Then, the mechanical and biological properties of the following were compared: (1) PEEK, with a solid structure, (2) 3D-printed Ti6Al4V, with a solid structure, and (3) 3D-printed Ti6Al4V, with a mesh structure. A load-induced subsidence test demonstrated that the 3D-printed mesh Ti6Al4V cage had significantly lower tendency (by 15%) to subside compared to the PEEK implant. Biological assessment of the samples proved that all tested materials were biocompatible. However, both titanium samples (solid and mesh) were characterized by significantly higher bioactivity, osteoconductivity, and mineralization ability, compared to PEEK. Moreover, osteoblasts revealed stronger adhesion to the surface of the Ti6Al4V samples compared to PEEK material. Thus, it was clearly shown that the 3D-printed mesh Ti6Al4V cage possesses all the features for optimal spinal implant, since it carries low risk of implant subsidence and provides good osseointegration at the bone-implant interface.
Anti-Inflammatory Activities of an Anti-Histamine Drug, Loratadine, by Suppressing TAK1 in AP-1 Pathway
Authors: Jang Jiwon , Hunto Stephanie Triseptya , Kim Ji Won , Lee Hwa Pyoung , Kim Han Gyung , Cho Jae Youl
Published: April 2022

Loratadine is an anti-histamine routinely used for treating allergies. However, recent findings have shown that Loratadine may also have anti-inflammatory functions, while their exact mechanisms have not yet been fully uncovered. In this paper, we investigated whether Loratadine can be utilized as an anti-inflammatory drug through a series of in vitro and in vivo experiments using a murine macrophage cell line and an acute gastritis mouse model. Loratadine was found to dramatically reduce the expression of pro-inflammatory genes, including MMP1, MMP3, and MMP9, and inhibit AP-1 transcriptional activation, as demonstrated by the luciferase assay. Therefore, we decided to further explore its role in the AP-1 signaling pathway. The expression of c-Jun and c-Fos, AP-1 subunits, was repressed by Loratadine and, correspondingly, the expression of p-JNK, p-MKK7, and p-TAK1 was also inhibited. In addition, Loratadine was able to reduce gastric bleeding in acute gastritis-induced mice; Western blotting using the stomach samples showed reduced p-c-Fos protein levels. Loratadine was shown to effectively suppress inflammation by specifically targeting TAK1 and suppressing consequent AP-1 signaling pathway activation and inflammatory cytokine production.
Comparative Proteomic Profiling of Secreted Extracellular Vesicles from Breast Fibroadenoma and Malignant Lesions: A Pilot Study
Authors: Pane Katia , Quintavalle Cristina , Nuzzo Silvia , Ingenito Francesco , Roscigno Giuseppina , Affinito Alessandra , Scognamiglio Iolanda , Pattanayak Birlipta , Gallo Enrico , Accardo Antonella , Thomas Guglielmo , Minic Zoran , Berezovski Maxim V. , Franzese Monica , Condorelli Gerolama
Published: April 2022

Extracellular vesicles (EVs) shuttle proteins, RNA, DNA, and lipids crucial for cell-to-cell communication. Recent findings have highlighted that EVs, by virtue of their cargo, may also contribute to breast cancer (BC) growth and metastatic dissemination. Indeed, EVs are gaining great interest as non-invasive cancer biomarkers. However, little is known about the biological and physical properties of EVs from malignant BC lesions, and even less is understood about EVs from non-malignant lesions, such as breast fibroadenoma (FAD), which are clinically managed using conservative approaches. Thus, for this pilot study, we attempted to purify and explore the proteomic profiles of EVs from benign breast lesions, HER2+ BCs, triple–negative BCs (TNBCs), and continuous BC cell lines (i.e., BT-549, MCF–10A, and MDA-MB-231), combining experimental and semi-quantitative approaches. Of note, proteome-wide analyses showed 49 common proteins across EVs harvested from FAD, HER2+ BCs, TNBCs, and model BC lines. This is the first feasibility study evaluating the physicochemical composition and proteome of EVs from benign breast cells and primary and immortalized BC cells. Our preliminary results hold promise for possible implications in precision medicine for BC.
In Vitro One-Pot 3-Hydroxypropanal Production from Cheap C1 and C2 Compounds
Authors: Ju Su-Bin , Seo Min-Ju , Yeom Soo-Jin
Published: April 2022

One- or two-carbon (C1 or C2) compounds have been considered attractive substrates because they are inexpensive and abundant. Methanol and ethanol are representative C1 and C2 compounds, which can be used as bio-renewable platform feedstocks for the biotechnological production of value-added natural chemicals. Methanol-derived formaldehyde and ethanol-derived acetaldehyde can be converted to 3-hydroxypropanal (3-HPA) via aldol condensation. 3-HPA is used in food preservation and as a precursor for 3-hydroxypropionic acid and 1,3-propanediol that are starting materials for manufacturing biocompatible plastic and polytrimethylene terephthalate. In this study, 3-HPA was biosynthesized from formaldehyde and acetaldehyde using deoxyribose-5-phosphate aldolase from Thermotoga maritima (DERATma) and cloned and expressed in Escherichia coli for 3-HPA production. Under optimum conditions, DERATma produced 7 mM 3-HPA from 25 mM substrate (formaldehyde and acetaldehyde) for 60 min with 520 mg/L/h productivity. To demonstrate the one-pot 3-HPA production from methanol and ethanol, we used methanol dehydrogenase from Lysinibacillus xylanilyticus (MDHLx) and DERATma. One-pot 3-HPA production via aldol condensation of formaldehyde and acetaldehyde from methanol and ethanol, respectively, was investigated under optimized reaction conditions. This is the first report on 3-HPA production from inexpensive alcohol substrates (methanol and ethanol) by cascade reaction using DERATma and MDHLx.
Coriloxin Exerts Antitumor Effects in Human Lung Adenocarcinoma Cells
Authors: Kuo Yu-Hsuan , Wang Yi-Xuan , Peng Wan-Hua , Chi Nian-Yu , Lee Tzong-Huei , Wang Chi-Chung
Published: April 2022

Both in Taiwan and around the world, lung cancer is a primary cause of cancer-related deaths. In Taiwan, the most prevalent form of lung cancer is lung adenocarcinoma, a type of non-small-cell lung carcinoma. Although numerous lung cancer therapies are available, their clinical outcomes are unsatisfactory. Natural products, including fungal metabolites, are excellent sources of pharmaceutical compounds used in cancer treatment. We employed in vitro cell invasion, cell proliferation, cell migration, cell viability, and colony formation assays with the aim of evaluating the effects of coriloxin, isolated from fermented broths of Nectria balsamea YMJ94052402, on human lung adenocarcinoma CL1-5 and/or A549 cells. The potential targets regulated by coriloxin were examined through Western blot analysis. The cytotoxic effect of coriloxin was more efficiently exerted on lung adenocarcinoma cells than on bronchial epithelial cells. Moreover, low-concentration coriloxin significantly suppressed adenocarcinoma cells’ proliferative, migratory, and clonogenic abilities. These inhibitory effects were achieved through ERK/AKT inactivation, epithelial–mesenchymal transition regulation, and HLJ1 expression. Our findings suggest that coriloxin can be used as a multitarget anticancer agent. Further investigations of the application of coriloxin as an adjuvant therapy in lung cancer treatment are warranted.
Microbial Transformation of Yakuchinone A and Cytotoxicity Evaluation of Its Metabolites
Authors: Huo Chen , Han Fubo , Xiao Yina , Kim Hyun Jung , Lee Ik-Soo
Published: April 2022

Yakuchinone A (1) is a bioactive diarylheptanoid isolated from the dried fruits of Alpinia oxyphylla. Microbial transformation has been recognized as an efficient method to produce new biologically active derivatives from natural products. In the present study, microbial transformation of yakuchinone A was performed with the fungus Mucor hiemalis KCTC 26779, which led to the isolation of nine new metabolites (2, 3a, 3b, and 4–9). Their structures were elucidated as (3S)-oxyphyllacinol (2), (3S,7R)- and (3S,7S)-7-hydroxyoxyphyllacinol (3a and 3b), (3S)-oxyphyllacinol-4′-O-β-d-glucopyranoside (4), (3S)-4″-hydroxyoxyphyllacinol (5), (3S)-3″-hydroxyoxyphyllacinol (6), (3S)-2″-hydroxyoxyphyllacinol (7), (3S)-2″-hydroxyoxyphyllacinol-2″-O-β-d-glucopyranoside (8), and (3S)-oxyphyllacinol-3-O-β-d-glucopyranoside (9) based on the comprehensive spectroscopic analyses and the application of modified Mosher’s method. All compounds were evaluated for their cytotoxic activities against melanoma, as well as breast, lung, and colorectal cancer cell lines. Compound 9, which was O-glucosylated on the diarylheptanoid alkyl chain, exhibited the most selective cytotoxic activities against melanoma cell lines with the IC50 values ranging from 6.09 to 9.74 μM, indicating that it might be considered as a possible anti-cancer lead compound.
Fabrication, DFT Calculation, and Molecular Docking of Two Fe(III) Imine Chelates as Anti-COVID-19 and Pharmaceutical Drug Candidate
Authors: El-Lateef Hany , Khalaf Mai , Shehata Mohamed , Abu-Dief Ahmed
Published: April 2022

Two tetradentate dibasic chelating Schiff base iron (III) chelates were prepared from the reaction of 2,2′-((1E,1′E)-(1,2-phenylenebis(azanylylidene))bis(methanylylidene))bis(4-bromophenol) (PDBS) and 2,2′-((1E,1′E)-((4-chloro-1,2-phenylene)bis(azanylylidene))-bis(methanylylidene))bis(4-bromophenol) (CPBS) with Fe3+ ions. The prepared complexes were fully characterized with spectral and physicochemical tools such as IR, NMR, CHN analysis, TGA, UV-visible spectra, and magnetic moment measurements. Moreover, geometry optimizations for the synthesized ligands and complexes were conducted using the Gaussian09 program through the DFT approach, to find the best structures and key parameters. The prepared compounds were tested as antimicrobial agents against selected strains of bacteria and fungi. The results suggests that the CPBSFe complex has the highest activity, which is close to the reference. An MTT assay was used to screen the newly synthesized compounds against a variety of cell lines, including colon cancer cells, hepatic cellular carcinoma cells, and breast carcinoma cells. The results are expressed by IC50 value, in which the 48 µg/mL value of the CPBSFe complex indicates its success as a potential anticancer agent. The antioxidant behavior of the two imine chelates was studied by DPPH assay. All the tested imine complexes show potent antioxidant activity compared to the standard Vitamin C. Furthermore, the in vitro assay and the mechanism of binding and interaction efficiency of the tested samples with the receptor of COVID-19 core protease viral protein (PDB ID: 6lu7) and the receptor of Gram-negative bacteria (Escherichia coli, PDB ID: 1fj4) were investigated using molecular docking experiments.
Two-Dimensional Investigation of the Fundamentals of OGV Buffeting
Authors: Harris Jonah , Lad Bharat , Stapelfeldt Sina
Published: April 2022

The increased demands of compact modern aero engine architectures have highlighted the problem of outlet guide vane (OGV) buffeting in off-design conditions. This structural response to aerodynamic excitations is characterised by increased vibration, risking structural fatigue. Investigations focused on understanding, mitigation and avoidance are therefore of high priority. OGV buffet is a type of transonic buffet caused by unsteady shock movement, but the exact parameters driving it are not fully understood. To try and understand them, this paper examines the buffet of a quasi-2D OGV geometry. Parametric studies of the incidence angle and inlet Mach number were performed. Forcing frequencies for both studies were found to be close to the experimentally detected frequency of vibration in the first bow mode, which demonstrates that buffet is driven by quasi-2D flow features. Increasing the inlet Mach number increased the dominant forcing frequency, whereas increasing the incidence yielded little change. Profiles of unsteady pressure amplitudes were shown to smoothly increase in magnitude with an increasing incidence and inlet Mach number.
Deep Learning with Word Embedding Improves Kazakh Named-Entity Recognition
Authors: Haisa Gulizada , Altenbek Gulila
Published: April 2022

Named-entity recognition (NER) is a preliminary step for several text extraction tasks. In this work, we try to recognize Kazakh named entities by introducing a hybrid neural network model that leverages word semantics with multidimensional features and attention mechanisms. There are two major challenges: First, Kazakh is an agglutinative and morphologically rich language that presents a challenge for NER due to data sparsity. The other is that Kazakh named entities have unclear boundaries, polysemy, and nesting. A common strategy to handle data sparsity is to apply subword segmentation. Thus, we combined the semantics of words and stems by stemming from the Kazakh morphological analysis system. Additionally, we constructed a graph structure of entities, with words, entities, and entity categories as nodes and inclusion relations as edges, and updated nodes using a gated graph neural network (GGNN) with an attention mechanism. Finally, through the conditional random field (CRF), we extracted the final results. Experimental results show that our method consistently outperforms all previous methods by 88.04% in terms of F1 scores.
Multicriteria Approach for Design Optimization of Lightweight Piezoelectric Energy Harvesters Subjected to Stress Constraints
Authors: Foutsitzi Georgia , Gogos Christos , Antoniadis Nikolaos , Magklaras Aris
Published: April 2022

In this work a multicriteria optimization approach to minimize weight and maximize power output in piezoelectric energy harvesting systems for aerospace applications is studied. The design variables are the geometric and electric circuit parameters of the vibration-based piezoelectric energy harvester (PEH). A finite element model is developed to model the dynamic behavior of the composite plate-type harvester with embedded piezoelectric layers. The cantilever PEH structure is subjected to constraints in the bending stresses which must be lower than or equal to the tensile yield strength of the piezoelectric material. For solving the multi-objective optimization problem, the Non-dominated Sorting Genetic Algorithm II (NSGA-II), the Non-dominated Sorting Genetic Algorithm III (NSGA-III) and the Generalized Differential Evolution 3 (GDE3) algorithm are employed. It is shown that the proposed algorithms are effective in developing optimal Pareto front curves for maximum electrical power output and minimum mass of the PEH system. A comparative assessment of the solutions generated on the Pareto Front show that GDE3 achieved solutions that generate higher maximum power output and performs better compared to the two other algorithms.
A Game Theory Approach for Assisting Humans in Online Information-Sharing
Authors: Hirschprung Ron S. , Alkoby Shani
Published: April 2022

Contemporary information-sharing environments such as Facebook offer a wide range of social and practical benefits. These environments, however, may also lead to privacy and security violations. Moreover, there is usually a trade-off between the benefits gained and the accompanying costs. Due to the uncertain nature of the information-sharing environment and the lack of technological literacy, the layperson user often fails miserably in balancing this trade-off. In this paper, we use game theory concepts to formally model this problem as a “game”, in which the players are the users and the pay-off function is a combination of the benefits and costs of the information-sharing process. We introduce a novel theoretical framework called Online Information-Sharing Assistance (OISA) to evaluate the interactive nature of the information-sharing trade-off problem. Using these theoretical foundations, we develop a set of AI agents that attempt to calculate a strategy for balancing this trade-off. Finally, as a proof of concept, we conduct an empirical study in a simulated Facebook environment in which human participants compete against OISA-based AI agents, showing that significantly higher utility can be achieved using OISA.
Fast Tracking Algorithm Based on Spatial Regularization Correlation Filter
Authors: Liu Caihong , Ibrayim Mayire , Hamdulla Askar
Published: April 2022

To solve the problem of the redundant number of training samples in a correlation filter-based tracking algorithm, the training samples were implicitly extended by circular shifts of the given target patches, and all the extended samples were used as negative samples for the fast online learning of the filter. Since all these shifted patches were not true negative samples of the target, the tracking process suffered from boundary effects, especially in challenging situations such as occlusion and background clutter, which can significantly impair the tracking performance of the tracker. Spatial regularization in the SRDCF tracking algorithm is an effective way to mitigate boundary effects, but it comes at the cost of highly increased time complexity, resulting in a very slow tracking speed of the SRDCF algorithm that cannot achieve a real-time tracking effect. To address this issue, we proposed a fast-tracking algorithm based on spatially regularized correlation filters that efficiently optimized the solved filters by replacing the Gauss–Seidel method in the SRDCF algorithm with the alternating direction multiplier method. The problem of slow speed in the SRDCF tracking algorithm improved, and the improved FSRCF algorithm achieved real-time tracking. An adaptive update mechanism was proposed by using the feedback from the high confidence tracking results to avoid model corruption. That is, a robust confidence evaluation criterion was introduced in the model update phase, which combined the maximum response criterion and the average peak correlation energy APCE criterion to determine whether to update the filter, thereby avoiding filter model drift and improving the target tracking accuracy and speed. We conducted extensive experiments on datasets OTB-2015, OTB-2013, UAV123, and TC128, and the experimental results show that the proposed algorithm exhibits a more stable and accurate tracking performance in the presence of occlusion and background clutter during tracking.
The Flower-like Co3O4 Hierarchical Microspheres for Methane Catalytic Oxidation
Authors: Lv Changpeng , Du Dan , Wang Chao , Qin Yingyue , Ge Jinlong , Han Yansong , Zhu Junjie , Liu Muxin
Published: April 2022

The development of non-noble Co3O4 catalysts exposing highly active crystal planes to low-temperature methane oxidation is still a challenge. Hence, a facile solvothermal method was adapted to construe flower-like Co3O4 hierarchical microspheres (Co3O4-FL), which are composed of nanosheets with dominantly exposed {112} crystal planes. The flower-like hierarchical structure not only promotes the desorption of high levels of active surface oxygen and enhances reducibility, but also facilitates an increase in lattice oxygen as the active species. As a result, Co3O4-FL catalysts offer improved methane oxidation, with a half methane conversion temperature (T50) of 380 °C (21,000 mL g−1 h−1), which is much lower than that of commercial Co3O4 catalysts (Co3O4-C). This study will provide guidance for non-noble metal catalyst design and preparation for methane oxidation and other oxidative reactions.
Exploring Growth of Mycobacterium smegmatis Treated with Anticarcinogenic Vanadium Compounds
Authors: Arhouma Zeyad , Murakami Heide A. , Koehn Jordan T. , Li Xiaorong , Roess Deborah A. , Crick Dean C. , Crans Debbie C.
Published: April 2022

A major problem with patient treatments using anticancer compounds is accompanying bacterial infections, which makes more information on how such compounds impact bacterial growth desirable. In the following study, we investigated the growth effects of an anticancerous non-toxic Schiff base oxidovanadium(V) complex (N-(salicylideneaminato)-N′-(2-hydroxyethyl)ethane-1,2-diamine) coordinated to the 3,5-di-tert-butylcatecholato ligand on a representative bacterium, Mycobacterium smegmatis (M. smeg). We prepared the Schiff base V-complexes as reported previously and selected a few complexes to develop a V-complex series. Biological studies of M. smeg growth inhibition were complemented by spectroscopic studies using UV-Vis spectrophotometry and NMR spectroscopy to determine which complexes were intact under biologically relevant conditions. We specifically chose to examine (1) the growth effects of Schiff base oxidovanadium complexes coordinated to a catechol, (2) the growth effects of respective free catecholates on M. smeg, and (3) to identify complexes where the metal coordination complex was more potent than the ligand alone under biological conditions. Results from these studies showed that the observed effects of Schiff base V-catecholate complex are a combination of catechol properties including toxicity, hydrophobicity, and sterics.