bluuebunny/crossref_metadata_2025 huggingface dataset:
The bHLH Transcription Factors in Neural Development and Therapeutic Applications for Neurodegenerative Diseases
Authors: Lee Dong Gi , Kim Young-Kwang , Baek Kwang-Hyun
Published: November 2022

The development of functional neural circuits in the central nervous system (CNS) requires the production of sufficient numbers of various types of neurons and glial cells, such as astrocytes and oligodendrocytes, at the appropriate periods and regions. Hence, severe neuronal loss of the circuits can cause neurodegenerative diseases such as Huntington’s disease (HD), Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Treatment of such neurodegenerative diseases caused by neuronal loss includes some strategies of cell therapy employing stem cells (such as neural progenitor cells (NPCs)) and gene therapy through cell fate conversion. In this report, we review how bHLH acts as a regulator in neuronal differentiation, reprogramming, and cell fate determination. Moreover, several different researchers are conducting studies to determine the importance of bHLH factors to direct neuronal and glial cell fate specification and differentiation. Therefore, we also investigated the limitations and future directions of conversion or transdifferentiation using bHLH factors.
Metabolomics Analysis Revealed Significant Metabolic Changes in Brain Cancer Cells Treated with Paclitaxel and/or Etoposide
Authors: Semreen Ahlam M. , Alsoud Leen Oyoun , El-Huneidi Waseem , Ahmed Munazza , Bustanji Yasser , Abu-Gharbieh Eman , El-Awady Raafat , Ramadan Wafaa S. , Alqudah Mohammad A.Y. , Shara Mohd , Abuhelwa Ahmad Y. , Soares Nelson C. , Semreen Mohammad H. , Alzoubi Karem H.
Published: November 2022

Cancer of the central nervous system (CNS) is ranked as the 19th most prevalent form of the disease in 2020. This study aims to identify candidate biomarkers and metabolic pathways affected by paclitaxel and etoposide, which serve as potential treatments for glioblastoma, and are linked to the pathogenesis of glioblastoma. We utilized an untargeted metabolomics approach using the highly sensitive ultra-high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS) for identification. In this study, 92 and 94 metabolites in U87 and U373 cell lines were profiled, respectively. The produced metabolites were then analyzed utilizing t-tests, volcano plots, and enrichment analysis modules. Our analysis revealed distinct metabolites to be significantly dysregulated (nutriacholic acid, L-phenylalanine, L-arginine, guanosine, ADP, hypoxanthine, and guanine), and to a lesser extent, mevalonic acid in paclitaxel and/or etoposide treated cells. Furthermore, both urea and citric acid cycles, and metabolism of polyamines and amino acids (aspartate, arginine, and proline) were significantly enriched. These findings can be used to create a map that can be utilized to assess the antitumor effect of paclitaxel and/or etoposide within the studied cancer cells.
B Cell Kinetics upon Therapy Commencement for Active Extrarenal Systemic Lupus Erythematosus in Relation to Development of Renal Flares: Results from Three Phase III Clinical Trials of Belimumab
Authors: Parodis Ioannis , Gomez Alvaro , Lindblom Julius , Chow Jun Weng , Sjöwall Christopher , Sciascia Savino , Gatto Mariele
Published: November 2022

Renal flares constitute major determinants of poor prognosis in people living with systemic lupus erythematosus (SLE). The aim of the present study was to investigate changes in B cell subsets in relation to renal flares upon initiation of standard therapy (ST) plus belimumab or placebo in patients with SLE. Using data from the BLISS-76, BLISS-SC, and BLISS Northeast Asia trials, we investigated associations of relative to baseline rapid (through week 8) and early (through week 24) percentage changes in circulating CD19+ B cell subsets characterised through flow cytometry, anti-dsDNA antibodies, and complement levels with the occurrence of renal flares over one year. Patients who developed renal flares showed more prominent rapid decreases in CD19+CD20+CD138+ short-lived plasma cells (−50.4% vs. −16.7%; p = 0.019) and CD19+CD20-CD27bright plasmablasts (−50.0% vs. −29.9%; p = 0.020) compared to non-flaring patients, followed by a subsequent return. Less prominent rapid reductions in CD19+CD27-CD24brightCD38bright transitional B cells (−42.9% vs. −75.0%; p = 0.038) and CD19+CD20-CD138+ peripheral long-lived plasma cells (−11.3% vs. −29.2%; p = 0.019) were seen in belimumab-treated—but not placebo-treated—patients who developed renal flares compared to belimumab-treated patients who did not. Rapid and early changes in anti-dsDNA or complement levels showed no clear association with renal flares. In summary, a rapid drop followed by a subsequent return in circulating short-lived plasma cells and plasmablasts upon treatment for active extra-renal SLE portended renal flares, indicating a need for therapeutic adjustments in patients showing such B cell patterns. Rapid decreases in transitional B cells and peripheral long-lived plasma cells upon belimumab therapy commencement may signify a greater protection against renal flares. B cell kinetics may prove useful in early drug evaluation.
Identification of Active Compounds against Melanoma Growth by Virtual Screening for Non-Classical Human DHFR Inhibitors
Authors: Vásquez Andrés Felipe , Gómez Luis Alberto , González Barrios Andrés , Riaño-Pachón Diego M.
Published: November 2022

Antifolates such as methotrexate (MTX) have been largely known as anticancer agents because of their role in blocking nucleic acid synthesis and cell proliferation. Their mechanism of action lies in their ability to inhibit enzymes involved in the folic acid cycle, especially human dihydrofolate reductase (hDHFR). However, most of them have a classical structure that has proven ineffective against melanoma, and, therefore, inhibitors with a non-classical lipophilic structure are increasingly becoming an attractive alternative to circumvent this clinical resistance. In this study, we conducted a protocol combining virtual screening (VS) and cell-based assays to identify new potential non-classical hDHFR inhibitors. Among 173 hit compounds identified (average logP = 3.68; average MW = 378.34 Da), two—herein, called C1 and C2—exhibited activity against melanoma cell lines B16 and A375 by MTT and Trypan-Blue assays. C1 showed cell growth arrest (39% and 56%) and C2 showed potent cytotoxic activity (77% and 51%) in a dose-dependent manner. The effects of C2 on A375 cell viability were greater than MTX (98% vs 60%) at equivalent concentrations and times. Our results indicate that the integrated in silico/in vitro approach provided a benchmark to identify novel promising non-classical DHFR inhibitors showing activity against melanoma cells.
Cirsilineol Treatment Attenuates PM2.5-Induced Lung Injury in Mice
Authors: Kim Chaeyeong , Kim Go Oun , Bae Jong-Sup
Published: November 2022

Ultrafine particulate matter with less than 2.5 μm diameter (PM2.5) is an air pollutant that causes severe lung damage. Currently, effective treatment and preventive methods for PM2.5-induced lung damage are limited. Cirsilineol (CSL) is a small natural compound isolated from Artemisia vestita. In this study, the efficacy of CSL on PM2.5-induced lung toxicity was tested, and its mechanism was identified. Lung injury was caused by intratracheal administration of PM2.5 suspension in animal models. Two days after PM2.5 pretreatment, CSL was injected via mouse tail vein for two days. The effects of CSL on PM2.5-induced lung damage, autophagy, apoptosis, and pulmonary inflammation in a mouse model and their mechanisms were investigated. CSL significantly suppressed histological lung damage and lung wet/dry weight proportion. CSL also significantly reduced PM2.5-induced autophagy dysfunction, apoptosis, lymphocyte suppression, and inflammatory cytokine levels in bronchoalveolar fluid (BALF). Furthermore, CSL increased mammalian target of rapamycin (mTOR) phosphorylation and significantly inhibited the expression of Toll-like receptors (TLR) 2 and 4, MyD88, and the autophagy proteins, Beclin1 and LC3II. Thus, CSL exerts protective effects on pulmonary damage by regulating mTOR and TLR2,4–myD88 autophagy pathways. Therefore, CSL can be used as an effective treatment for PM2.5-induced lung damage.
Adaptive Immunity to Viruses: What Did We Learn from SARS-CoV-2 Infection?
Authors: Vályi-Nagy István , Uher Ferenc , Rákóczi Éva , Szekanecz Zoltán
Published: November 2022

The SARS-CoV-2 virus causes various conditions, from asymptomatic infection to the fatal coronavirus disease 2019 (COVID-19). An intact immune system can overcome SARS-CoV-2 and other viral infections. Defective natural, mainly interferon I- and III-dependent, responses may lead to the spread of the virus to multiple organs. Adaptive B- and T-cell responses, including memory, highly influence the severity and outcome of COVID-19. With respect to B-cell immunity, germinal centre formation is delayed or even absent in the most severe cases. Extrafollicular low-affinity anti-SARS-CoV-2 antibody production will occur instead of specific, high-affinity antibodies. Helper and CD8+ cytotoxic T-cells become hyperactivated and then exhausted, leading to ineffective viral clearance from the body. The dysregulation of neutrophils and monocytes/macrophages, as well as lymphocyte hyperreactivity, might lead to the robust production of inflammatory mediators, also known as cytokine storm. Eventually, the disruption of this complex network of immune cells and mediators leads to severe, sometimes fatal COVID-19 or another viral disease.
Nitro Dihydrocapsaicin, a Non-Pungent Capsaicin Analogue, Inhibits Cellular Senescence of Lens Epithelial Cells via Upregulation of SIRT1
Authors: Paensuwan Pussadee , Laorob Thanet , Ngoenkam Jatuporn , Wichai Uthai , Pongcharoen Sutatip
Published: November 2022

Diabetic cataracts are a common complication that can cause blindness among patients with diabetes mellitus. A novel nitro dihydrocapsaicin (NDHC), a capsaicin analog, was constructed to have a non-pungency effect. The objective of this research was to study the effect of NDHC on human lens epithelial (HLE) cells that lost function from hyperglycemia. HLE cells were pretreated with NDHC before an exposure to high glucose (HG) conditions. The results show that NDHC promoted a deacceleration of cellular senescence in HLE cells. This inhibition of cellular senescence was characterized by a delayed cell growth and lower production of reactive oxygen species (ROS) as well as decreased SA-β-galactosidase activity. Additionally, the expression of Sirt1 protein sharply increased, while the expression of p21 and phospho-p38 proteins decreased. These findings provide evidence that NDHC could exert a pharmacologically protective effect by inhibiting the senescence program of lens cells during diabetic cataracts.
A Novel 3D Culture Scaffold to Shorten Development Time for Multicellular Tumor Spheroids
Authors: Yang Cian-Ru , Liang Chu-Ting , Tsai Shih-Chieh , Wu Yu-Chun , Liu Ching-Wen , Yang Hui-Hua , Tu Ting-Yuan , Lee Yueh-Chun , Hsiao Kuei-Yang , Chang Wei-Chun , Ma Wen-Lung
Published: November 2022

Multicellular tumor spheroids and tumoroids are considered ideal in vitro models that reflect the features of the tumor microenvironment. Biomimetic components resembling the extracellular matrix form scaffolds to provide structure to 3-dimensional (3D) culture systems, supporting the growth of both spheroids and tumoroids. Although Matrigel has long been used to support 3D culture systems, batch variations, component complexity, and the use of components derived from tumors are complicating factors. To address these issues, we developed the ACD 3D culture system to provide better control and consistency. We evaluated spheroid and tumoroid formation using the ACD 3D culture system, including the assessment of cell viability and cancer marker expression. Under ACD 3D culture conditions, spheroids derived from cancer cell lines exhibited cancer stem cell characteristics, including a sphere-forming size and the expression of stem cell marker genes. The ACD 3D culture system was also able to support patient-derived primary cells and organoid cell cultures, displaying adequate cell growth, appropriate morphology, and resistance to oxaliplatin treatment. These spheroids could also be used for drug screening purposes. In conclusion, the ACD 3D culture system represents an efficient tool for basic cancer research and therapeutic development.
Adaptation of Saccharomyces Species to High-Iron Conditions
Authors: Sorribes-Dauden Raquel , Jordá Tania , Peris David , Martínez-Pastor María Teresa , Puig Sergi
Published: November 2022

Iron is an indispensable element that participates as an essential cofactor in multiple biological processes. However, when present in excess, iron can engage in redox reactions that generate reactive oxygen species that damage cells at multiple levels. In this report, we characterized the response of budding yeast species from the Saccharomyces genus to elevated environmental iron concentrations. We have observed that S. cerevisiae strains are more resistant to high-iron concentrations than Saccharomyces non-cerevisiae species. Liquid growth assays showed that species evolutionarily closer to S. cerevisiae, such as S. paradoxus, S. jurei, S. mikatae, and S. arboricola, were more resistant to high-iron levels than the more distant species S. eubayanus and S. uvarum. Remarkably, S. kudriavzevii strains were especially iron sensitive. Growth assays in solid media suggested that S. cerevisiae and S. paradoxus were more resistant to the oxidative stress caused by elevated iron concentrations. When comparing iron accumulation and sensitivity, different patterns were observed. As previously described for S. cerevisiae, S. uvarum and particular strains of S. kudriavzevii and S. paradoxus became more sensitive to iron while accumulating more intracellular iron levels. However, no remarkable changes in intracellular iron accumulation were observed for the remainder of species. These results indicate that different mechanisms of response to elevated iron concentrations exist in the different species of the genus Saccharomyces.
Insight into the Spatial Arrangement of the Lysine Tyrosylquinone and Cu2+ in the Active Site of Lysyl Oxidase-like 2
Authors: Meier Alex A. , Moon Hee-Jung , Sabuncu Sinan , Singh Priya , Ronnebaum Trey A. , Ou Siyu , Douglas Justin T. , Jackson Timothy A. , Moënne-Loccoz Pierre , Mure Minae
Published: November 2022

Lysyl oxidase-2 (LOXL2) is a Cu2+ and lysine tyrosylquinone (LTQ)-dependent amine oxidase that catalyzes the oxidative deamination of peptidyl lysine and hydroxylysine residues to promote crosslinking of extracellular matrix proteins. LTQ is post-translationally derived from Lys653 and Tyr689, but its biogenesis mechanism remains still elusive. A 2.4 Å Zn2+-bound precursor structure lacking LTQ (PDB:5ZE3) has become available, where Lys653 and Tyr689 are 16.6 Å apart, thus a substantial conformational rearrangement is expected to take place for LTQ biogenesis. However, we have recently shown that the overall structures of the precursor (no LTQ) and the mature (LTQ-containing) LOXL2s are very similar and disulfide bonds are conserved. In this study, we aim to gain insights into the spatial arrangement of LTQ and the active site Cu2+ in the mature LOXL2 using a recombinant LOXL2 that is inhibited by 2-hydrazinopyridine (2HP). Comparative UV-vis and resonance Raman spectroscopic studies of the 2HP-inhibited LOXL2 and the corresponding model compounds and an EPR study of the latter support that 2HP-modified LTQ serves as a tridentate ligand to the active site Cu2. We propose that LTQ resides within 2.9 Å of the active site of Cu2+ in the mature LOXL2, and both LTQ and Cu2+ are solvent-exposed.
The Interplay between ESIPT and TADF for the 2,2′-Bipyridine-3,3′-diol: A Theoretical Reconsideration
Authors: Zhao Xin , Zhu Lixia , Li Qi , Yin Hang , Shi Ying
Published: November 2022

Organic molecules with excited-state intramolecular proton transfer (ESIPT) and thermally activated delayed fluorescence (TADF) properties have great potential for realizing efficient organic light-emitting diodes (OLEDs). Furthermore, 2,2′-bipyridine-3,3′-diol (BP(OH)2) is a typical molecule with ESIPT and TADF properties. Previously, the double ESIPT state was proved to be a luminescent state, and the T2 state plays a dominant role in TADF for the molecule. Nevertheless, whether BP(OH)2 undergoes a double or single ESIPT process is controversial. Since different ESIPT channels will bring different TADF mechanisms, the previously proposed TADF mechanism based on the double ESIPT structure for BP(OH)2 needs to be reconsidered. Herein, reduced density gradient, potential energy surface, IR spectra and exited-state hydrogen-bond dynamics computations confirm that BP(OH)2 undergoes the barrierless single ESIPT process rather than the double ESIPT process with a barrier. Moreover, based on the single ESIPT structure, we calculated spin-orbit coupling matrix elements, nonradiative rates and electron-hole distributions. These results disclose that the T3 state plays a predominant role in TADF. Our investigation provides a better understanding on the TADF mechanism in hydrogen-bonded molecular systems and the interaction between ESIPT and TADF, which further provides a reference for developing efficient OLEDs.
Computational Analysis of SAM Analogs as Methyltransferase Inhibitors of nsp16/nsp10 Complex from SARS-CoV-2
Authors: Balieiro Alessandra M. , Anunciação Eduarda L. S. , Costa Clauber H. S. , Qayed Wesam S. , Silva José Rogério A.
Published: November 2022

Methyltransferases (MTases) enzymes, responsible for RNA capping into severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are emerging important targets for the design of new anti-SARS-CoV-2 agents. Here, analogs of S-adenosylmethionine (SAM), obtained from the bioisosteric substitution of the sulfonium and amino acid groups, were evaluated by rigorous computational modeling techniques such as molecular dynamics (MD) simulations followed by relative binding free analysis against nsp16/nsp10 complex from SARS-CoV-2. The most potent inhibitor (2a) shows the lowest binding free energy (–58.75 Kcal/mol) and more potency than Sinefungin (SFG) (–39.8 Kcal/mol), a pan-MTase inhibitor, which agrees with experimental observations. Besides, our results suggest that the total binding free energy of each evaluated SAM analog is driven by van der Waals interactions which can explain their poor cell permeability, as observed in experimental essays. Overall, we provide a structural and energetic analysis for the inhibition of the nsp16/nsp10 complex involving the evaluated SAM analogs as potential inhibitors.
Rational Design of a Peptidomimetic Inhibitor of Gelsolin Amyloid Aggregation
Authors: Bollati Michela , Peqini Kaliroi , Barone Luigi , Natale Carmina , Beeg Marten , Gobbi Marco , Diomede Luisa , Trucchi Michelangelo , de Rosa Matteo , Pellegrino Sara
Published: November 2022

Gelsolin amyloidosis (AGel) is characterized by multiple systemic and ophthalmic features resulting from pathological tissue deposition of the gelsolin (GSN) protein. To date, no cure is available for the treatment of any form of AGel. More than ten single-point substitutions in the GSN gene are responsible for the occurrence of the disease and, among them, D187N/Y is the most widespread variant. These substitutions undergo an aberrant proteolytic cascade, producing aggregation-prone peptides of 5 and 8 kDa, containing the Gelsolin Amyloidogenic Core, spanning residues 182–192 (GAC182–192). Following a structure-based approach, we designed and synthesized three novel sequence-specific peptidomimetics (LB-5, LB-6, and LB-7) built on a piperidine-pyrrolidine unnatural amino acid. LB-5 and LB-6, but not LB-7, efficiently inhibit the aggregation of the GAC182–192 amyloidogenic peptides at sub-stoichiometric concentrations. These peptidomimetics resulted also effective in vivo, in a C. elegans-based assay, in counteracting the proteotoxicity of aggregated GAC182–192. These data pave the way to a novel pharmacological strategy against AGel and also validate a toolbox exploitable in other amyloidogenic diseases.
Chromosomally Unstable Gastric Cancers Overexpressing Claudin-6 Disclose Cross-Talk between HNF1A and HNF4A, and Upregulated Cholesterol Metabolism
Authors: Dwivedi Sanyog , Hernández-Montes Georgina , Montaño Luis Felipe , Rendón-Huerta Erika Patricia
Published: November 2022

(1) Abnormally increased expression of claudin-6 in gastric cancer is considered a prognostic marker of the chromosomal unstable molecular subtype. However, a detailed molecular profile analysis of differentially expressed genes and affected pathways associated with claudin-6 increased (Cldn6high) expression has not been assessed. (2) The TCGA Stomach Adenocarcinoma Pan-Cancer Atlas Data was evaluated using Cytoscape’s Gene Mania, MCODE, and Cytohubba bioinformatic software. (3) 96.88% of Cldn6high gastric cancer tumors belonging to the chromosomal unstable molecular subtype are associated with a worse prognosis. Cldn6expression coincided with higher mutations in TP53, MIEN1, STARD3, PGAP3, and CCNE1 genes compared to Cldn6low expression. In Cldn6high cancers, 1316 genes were highly expressed. Cholesterol metabolism was the most affected pathway as APOA1, APOA2, APOH, APOC2, APOC3, APOB-100, LDL receptor-related protein 1/2, Sterol O-acyltransferase, STARD3, MAGEA-2, -3, -4, -6, -9B, and -12 genes were overexpressed in Cldn6high gastric cancers; interestingly, APOA2 and MAGEA9b were identified as top hub genes. Functional enrichment of DEGs linked HNF-4α and HNF-1α genes as highly expressed in Cldn6high gastric cancer. (4) Our results suggest that APOA2 and MAGEA9b could be considered as prognostic markers for Cldn6high gastric cancers.
Investigation of the Anticancer and Drug Combination Potential of Brominated Coelenteramines toward Breast and Prostate Cancer
Authors: Magalhães Carla M. , González-Berdullas Patricia , Pereira Mariana , Duarte Diana , Vale Nuno , Esteves da Silva Joaquim C. G. , Pinto da Silva Luís
Published: November 2022

Cancer is a very challenging disease to treat, both in terms of therapeutic efficiency and harmful side effects, which continues to motivate the pursuit for novel molecules with potential anticancer activity. Herein, we have designed, synthesized, and evaluated the cytotoxicity of different brominated coelenteramines, which are metabolic products and synthesis precursors of the chemi-/bioluminescent system of marine coelenterazine. The evaluation of the anticancer potential of these molecules was carried out for both prostate and breast cancer, while also exploring their potential for use in combination therapy. Our results provided further insight into the structure–activity relationship of this type of molecule, such as their high structural specificity, as well highlighting the 4-bromophenyl moiety as essential for the anticancer activity. The obtained data also indicated that, despite their similarity, the anticancer activity displayed by both brominated coelenteramines and coelenterazines should arise from independent mechanisms of action. Finally, one of the studied coelenteramines was able to improve the profile of a known chemotherapeutic agent, even at concentrations in which its anticancer activity was not relevant. Thus, our work showed the potential of different components of marine chemi-/bioluminescent systems as novel anticancer molecules, while providing useful information for future optimizations.
Choline Improves Neonatal Hypoxia-Ischemia Induced Changes in Male but Not Female Rats
Authors: Adeyemo Tayo , Jaiyesimi Ayodele , Bumgardner Jill G. , Lohr Charity , Banerjee Aditi , McKenna Mary C. , Waddell Jaylyn
Published: November 2022

Choline is an essential nutrient with many roles in brain development and function. Supplementation of choline in early development can have long-lasting benefits. Our experiments aimed to determine the efficacy of choline supplementation in a postnatal day (PND) 10 rat model of neonatal hypoxia ischemia (HI) at term using both male and female rat pups. Choline (100 mg/kg) or saline administration was initiated the day after birth and given daily for 10 or 14 consecutive days. We determined choline’s effects on neurite outgrowth of sex-specific cultured cerebellar granule cells after HI with and without choline. The magnitude of tissue loss in the cerebrum was determined at 72 h after HI and in adult rats. The efficacy of choline supplementation in improving motor ability and learning, tested using eyeblink conditioning, were assessed in young adult male and female rats. Overall, we find that choline improves neurite outgrowth, short-term histological measures and learning ability in males. Surprisingly, choline did not benefit females, and appears to exacerbate HI-induced changes.
Transcriptome Profiling of Stem-Differentiating Xylem in Response to Abiotic Stresses Based on Hybrid Sequencing in Cunninghamia lanceolata
Authors: Wei Wentao , Wang Huiyuan , Liu Xuqing , Kou Wenjing , Liu Ziqi , Wang Huihui , Yang Yongkang , Zhao Liangzhen , Zhang Hangxiao , Liu Bo , Ma Xiangqing , Gu Lianfeng
Published: November 2022

Cunninghamia lanceolata (C. lanceolata) belongs to Gymnospermae, which are fast-growing and have desirable wood properties. However, C. lanceolata’s stress resistance is little understood. To unravel the physiological and molecular regulation mechanisms under environmental stresses in the typical gymnosperm species of C. lanceolata, three-year-old plants were exposed to simulated drought stress (polyethylene glycol 8000), salicylic acid, and cold treatment at 4 °C for 8 h, 32 h, and 56 h, respectively. Regarding the physiological traits, we observed a decreased protein content and increased peroxidase upon salicylic acid and polyethylene glycol treatment. Superoxide dismutase activity either decreased or increased at first and then returned to normal under the stresses. Regarding the molecular regulation, we used both nanopore direct RNA sequencing and short-read sequencing to reveal a total of 5646 differentially expressed genes in response to different stresses, of which most had functions in lignin catabolism, pectin catabolism, and xylan metabolism, indicating that the development of stem-differentiating xylem was affected upon stress treatment. Finally, we identified a total of 51 AP2/ERF, 29 NAC, and 37 WRKY transcript factors in C. lanceolata. The expression of most of the NAC TFs increased under cold stress, and the expression of most of the WRKY TFs increased under cold and SA stress. These results revealed the transcriptomics responses in C. lanceolata to short-term stresses under this study’s experimental conditions and provide preliminary clues about stem-differentiating xylem changes associated with different stresses.
The Discovery of Novel Ferulic Acid Derivatives Incorporating Substituted Isopropanolamine Moieties as Potential Tobacco Mosaic Virus Helicase Inhibitors
Authors: Li Zhenxing , Yang Binxin , Liu Hongwu , Ding Yue , Fang Zimian , Shao Wubin , Qi Puying , Zhou Xiang , Liu Liwei , Yang Song
Published: November 2022

Target-based drug design, a high-efficiency strategy used to guide the development of novel pesticide candidates, has attracted widespread attention. Herein, various natural-derived ferulic acid derivatives incorporating substituted isopropanolamine moieties were designed to target the tobacco mosaic virus (TMV) helicase. Bioassays demonstrating the optimized A19, A20, A29, and A31 displayed excellent in vivo antiviral curative abilities, affording corresponding EC50 values of 251.1, 336.2, 347.1, and 385.5 μg/mL, which visibly surpassed those of commercial ribavirin (655.0 μg/mL). Moreover, configurational analysis shows that the R-forms of target compounds were more beneficial to aggrandize antiviral profiles. Mechanism studies indicate that R-A19 had a strong affinity (Kd = 5.4 μM) to the TMV helicase and inhibited its ability to hydrolyze ATP (50.61% at 200 μM). Meanwhile, A19 could down-regulate the expression of the TMV helicase gene in the host to attenuate viral replication. These results illustrate the excellent inhibitory activity of A19 towards the TMV helicase. Additionally, docking simulations uncovered that R-A19 formed more hydrogen bonds with the TMV helicase in the binding pocket. Recent studies have unambiguously manifested that these designed derivatives could be considered as promising potential helicase-based inhibitors for plant disease control.
Tumor-Derived Exosomes and Their Role in Breast Cancer Metastasis
Authors: Huang Shaojuan , Dong Ming , Chen Qiang
Published: November 2022

Breast cancer has been the most common cancer in women worldwide, and metastasis is the leading cause of death from breast cancer. Even though the study of breast cancer metastasis has been extensively carried out, the molecular mechanism is still not fully understood, and diagnosis and prognosis need to be improved. Breast cancer metastasis is a complicated process involving multiple physiological changes, and lung, brain, bone and liver are the main metastatic targets. Exosomes are membrane-bound extracellular vesicles that contain secreted cellular constitutes. The biogenesis and functions of exosomes in cancer have been intensively studied, and mounting studies have indicated that exosomes play a crucial role in cancer metastasis. In this review, we summarize recent findings on the role of breast cancer-derived exosomes in metastasis organotropism and discuss the potential promising clinical applications of targeting exosomes as novel strategies for breast cancer diagnosis and therapy.
Integrative and Comprehensive Pan-Cancer Analysis of Lymphocyte-Specific Protein Tyrosine Kinase in Human Tumors
Authors: Han Mingwei , Li Yiming , Guo Yixiao , Zhu Wanwan , Jiang Jianli
Published: November 2022

Lymphocyte-specific protein tyrosine kinase (LCK) is common in a variety of hematologic malignancies but comparatively less common in solid tumors. This study aimed to explore the potential diagnostic and prognostic value of LCK across tumors through integrative and comprehensive pan-cancer analysis, as well as experimental validation. Multiple databases were used to explore the expression, alteration, prognostic value, association with immune infiltration, and potential functional pathways of LCK in pan-cancers. The results were further validated by western blotting and qPCR of patient samples as well as tumor cell lines. High LCK expression typically represents a better prognosis. Notably, drug sensitivity prediction of LCK identified P-529 as a candidate for drug development. Gene Annotations (GO) and KEGG analyses showed significant enrichment of PD-L1 and the T-cell receptor pathway. The results from patient samples and tumor cell lines confirmed these conclusions in LIHC. In conclusion, LCK is differentially expressed in multiple tumors and normal tissues. Further analysis highlighted its association with prognostic implications, pan-cancer genetic alterations, and immune signatures. Our data provide evidence for a diagnostic marker of LCK and the possible use of LCK as a target for the treatment of tumors.
Therapeutic Textiles Functionalized with Keratin-Based Particles Encapsulating Terbinafine for the Treatment of Onychomycosis
Authors: Costa André F. , Luís Salomé , Noro Jennifer , Silva Sónia , Silva Carla , Ribeiro Artur
Published: November 2022

Onychomycosis is the most common nail fungal infection worldwide. There are several therapy options available for onychomycosis, such as oral antifungals, topicals, and physical treatments. Terbinafine is in the frontline for the treatment of onychomycosis; however, several adverse effects are associated to its oral administration. In this work, innovative keratin-based carriers encapsulating terbinafine were designed to overcome the drawbacks related to the use this drug. Therapeutic textiles functionalized with keratin-based particles (100% keratin; 80% keratin/20% keratin-PEG) encapsulating terbinafine were developed. The controlled release of terbinafine from the functionalized textiles was evaluated against different mimetic biologic solutions (PBS buffer—pH = 7.4, micellar solution and acidic sweat solution—pH = 4.3). The modification of keratin with polyethylene glycol (PEG) moieties favored the release of terbinafine at the end of 48 h for all the solution conditions. When the activity of functionalized textiles was tested against Trichophyton rubrum, a differentiated inhibition was observed. Textiles functionalized with 80% keratin/20% keratin-PEG encapsulating terbinafine showed a 2-fold inhibition halo compared with the textiles containing 100% keratin-encapsulating terbinafine. No activity was observed for the textiles functionalized with keratin-based particles without terbinafine. The systems herein developed revealed therapeutic potential towards nail fungal infections, taking advantage of keratin-based particles affinity to keratin structures and of the keratinase activity of T. rubrum.
Mast Cells and Interleukins
Authors: Solimando Antonio Giovanni , Desantis Vanessa , Ribatti Domenico
Published: November 2022

Mast cells play a critical role in inflammatory diseases and tumor growth. The versatility of mast cells is reflected in their ability to secrete a wide range of biologically active cytokines, including interleukins, chemokines, lipid mediators, proteases, and biogenic amines. The aim of this review article is to analyze the complex involvement of mast cells in the secretion of interleukins and the role of interleukins in the regulation of biological activities of mast cells.
Preparation of Nano/Microcapsules of Ozonated Olive Oil in Hyaluronan Matrix and Analysis of Physicochemical and Microbiological (Biological) Properties of the Obtained Biocomposite
Authors: Khachatryan Gohar , Khachatryan Lusine , Krystyjan Magdalena , Lenart-Boroń Anna , Krzan Marcel , Kulik Klaudia , Białecka Anna , Grabacka Maja , Nowak Nikola , Khachatryan Karen
Published: November 2022

Hydrogels, based on natural polymers, such as hyaluronic acid, are gaining an increasing popularity because of their biological activity. The antibacterial effect of ozone is widely known and used, but the instability the gas causes, severely limits its application. Ozone entrapment in olive oil by its reaction with an unsaturated bond, allows for the formation of stable, therapeutically active ozone derivatives. In this study, we obtained an innovative hydrogel, based on hyaluronic acid containing micro/nanocapsules of ozonated olive oil. By combination of the biocompatible polymer with a high regenerative capacity and biologically active ingredients, we obtained a hydrogel with regenerative properties and a very weak inhibitory effect against both bacterial commensal skin microbiota and pathogenic Candida-like yeasts. We assessed the stability and rheological properties of the gel, determined the morphology of the composite, using scanning electron microscopy (SEM) and particle size by the dynamic light scattering (DLS) method. We also performed Attenuated total reflectance Fourier transform infrared (FTIR-ATR) spectroscopy. The functional properties, including the antimicrobial potential were assessed by the microbiological analysis and in vitro testing on the HaCat human keratinocyte cell line. The studies proved that the obtained emulsions were rheologically stable, exhibited an antimicrobial effect and did not show cytotoxicity in the HaCat keratinocyte model.
Circulating Inflammatory, Mitochondrial Dysfunction, and Senescence-Related Markers in Older Adults with Physical Frailty and Sarcopenia: A BIOSPHERE Exploratory Study
Authors: Picca Anna , Calvani Riccardo , Coelho-Júnior Hélio José , Marini Federico , Landi Francesco , Marzetti Emanuele
Published: November 2022

Multisystem derangements encompassing musculoskeletal, stress, and metabolic response have been described in older adults with physical frailty and sarcopenia (PF&S). Whether PF&S is also associated with markers of cellular senescence has yet to be explored. To address this research question, we quantified the serum levels of selected inflammatory, mitochondrial, and senescence-associated secretory phenotype (SASP)-related factors in 22 older adults with PF&S (mean age 75.5 ± 4.7 years; 81.8% women) and 27 nonPF&S controls (mean age 75.0 ± 4.4 years; 62.9% women) and evaluated their association with PF&S. Markers of inflammation (interleukin (IL)1-β, IL6, and tumor necrosis factor α (TNF-α)), matrix remodeling (Serpin E1, intercellular adhesion molecule 1 (ICAM-1), and tissue inhibitor of metalloproteinases 1 (TIMP-1)), mitochondrial dysfunction (growth/differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21)), Activin A, and glial fibrillary acidic protein (GFAP) were assayed. Serum levels of TNF-α and those of the SASP-related factors ICAM-1 and TIMP-1 were found to be higher, while IL1-β and IL6 were lower in PF&S participants compared with controls. Partial least squares discriminant analysis allowed discrimination of PF&S from nonPF&S participants with 74.0 ± 3.4% accuracy. Markers that significantly contributed to the classification were ICAM-1, TIMP-1, TNF-α, GFAP, and IL6. Future studies are warranted to establish whether inflammatory and SASP-related pathways are causally linked to the development and progression of PF&S, and may represent new targets for interventions.
Cocaine and Its Abstinence Condition Modulate Striatal and Hippocampal Wnt Signaling in a Male Rat Model of Drug Self-Administration
Authors: Gawliński Dawid , Gawlińska Kinga , Frankowska Małgorzata , Filip Małgorzata
Published: November 2022

Recent years have provided more and more evidence confirming the important role of Wnt/β-catenin signaling in the pathophysiology of mental illnesses, including cocaine use disorder. High relapse rates, which is a hallmark of drug addiction, prompt the study of changes in Wnt signaling elements (Wnt5a, Wnt7b, and Ctnnb1) in the motivational aspects of cocaine use and early drug-free period (3 days after the last exposure to cocaine). For this purpose, an animal model of intravenous cocaine self-administration and two types of drug-free period (extinction training and abstinence in the home cage) were used. The studies showed that chronic cocaine self-administration mainly disturbs the expression of Wnt5a and Ctnnb1 (the gene encoding β-catenin) in the examined brain structures (striatum and hippocampus), and the examined types of early abstinence are characterized by a different pattern of changes in the expression of these genes. At the same time, in cocaine self-administrated animals, there were no changes in the level of Wnt5a and β-catenin proteins at the tested time points. Moreover, exposure to cocaine induces a significant reduction in the striatal and hippocampal expression of miR-374 and miR-544, which can regulate Wnt5a levels post-transcriptionally. In summary, previous observations from experimenter-administered cocaine have not been fully validated in the cocaine self-administration model. Yoked cocaine administration appears to disrupt Wnt signaling more than cocaine self-administration. The condition of the cocaine-free period, the routes of drug administration, and the motivational aspect of drug administration play an important role in the type of drug-induced molecular changes observed. Furthermore, in-depth research involving additional brain regions is needed to determine the exact role of Wnt signaling in short-term and long-lasting plasticity as well as in the motivational aspects of cocaine use, and thus to assess its potential as a target for new drug therapy for cocaine use disorder.
Justifying Arabic Text Sentiment Analysis Using Explainable AI (XAI): LASIK Surgeries Case Study
Authors: Abdelwahab Youmna , Kholief Mohamed , Sedky Ahmed Ahmed Hesham
Published: November 2022

With the increasing use of machine learning across various fields to address several aims and goals, the complexity of the ML and Deep Learning (DL) approaches used to provide solutions has also increased. In the last few years, Explainable AI (XAI) methods to further justify and interpret deep learning models have been introduced across several domains and fields. While most papers have applied XAI to English and other Latin-based languages, this paper aims to explain attention-based long short-term memory (LSTM) results across Arabic Sentiment Analysis (ASA), which is considered an uncharted area in previous research. With the use of Local Interpretable Model-agnostic Explanation (LIME), we intend to further justify and demonstrate how the LSTM leads to the prediction of sentiment polarity within ASA in domain-specific Arabic texts regarding medical insights on LASIK surgery across Twitter users. In our research, the LSTM reached an accuracy of 79.1% on the proposed data set. Throughout the representation of sentiments using LIME, it demonstrated accurate results regarding how specific words contributed to the overall sentiment polarity classification. Furthermore, we compared the word count with the probability weights given across the examples, in order to further validate the LIME results in the context of ASA.
Laser Powder Bed Fusion Tool Repair: Statistical Analysis of 1.2343/H11 Tool Steel Process Parameters and Microstructural Analysis of the Repair Interface
Authors: Megahed Sandra , Koch Raphael , Schleifenbaum Johannes Henrich
Published: November 2022

High pressure die casting (HPDC) tools undergo several repairs during their life cycle. Traditional repair methods (e.g., welding) cannot always be applied on damaged tools, necessitating complete replacement. Usually, direct energy deposition (DED) is considered and applied to repair tools. In this study, the potential of laser powder bed fusion (LPBF) for HPDC tool repair is investigated. LPBF of the hot work tool steel 1.2343/H11 normally requires preheating temperatures above 200 °C to overcome cracking. Therefore, a process window for the crack-susceptible hot work tool steel 1.2343/H11 with no preheating was developed to avoid preheating an entire preform. Laser power, hatch distance, and scan speed are varied to maximize relative density. Since the correlation of LPBF process parameters and resulting build quality is not fully understood yet, the relationship between process parameters and surface roughness is statistically determined. The identification of suitable process parameters with no preheating allowed crack-free processing of 1.2343/H11 tool steel via LPBF in this study. The LPBF repair of a volume of ~2000 cm3 was successfully carried out and microstructurally and mechanically characterized. A special focus lays on the interface between the worn HPDC tool and additive reconstruction, since it must withstand the mechanical and thermal loads during the HPDC process.
Study of Electric and Magnetic Properties of Iron-Modified MFI Zeolite Prepared by a Mechanochemical Method
Authors: Murrieta-Rico Fabian N. , Antúnez-García Joel , Yocupicio-Gaxiola Rosario I. , Zamora Jonathan , Reyes-Serrato Armando , Pestryakov Alexey , Petranovskii Vitalii
Published: November 2022

Zeolites are materials of undeniable importance for science and technology. Since the properties of zeolites can be tuned after the inclusion of additional chemical species into the zeolitic framework, it is necessary to study the nature of zeolites after modification with transition metals to understand the new properties that were obtained, and with this information, novel applications can be proposed. This paper reports a solvent-free approach for the rapid synthesis of zeolites modified with iron and/or iron oxide particles. The samples were characterized, and their electrical and magnetic properties were investigated.
New Mesoporous Silica Materials Loaded with Polyphenols: Caffeic Acid, Ferulic Acid and p-Coumaric Acid as Dietary Supplements for Oral Administration
Authors: Petrisor Gabriela , Motelica Ludmila , Ficai Denisa , Trusca Roxana Doina , Surdu Vasile-Adrian , Voicu Georgeta , Oprea Ovidiu Cristian , Ficai Anton , Andronescu Ecaterina
Published: November 2022

In this study, two types of mesoporous silica with different pore structures and volumes were synthesized by the soft-templating method. The two types of mesoporous silica, type MCM-41 and MCM-48, were loaded with three polyphenols—caffeic acid, p-coumaric acid and trans-ferulic acid—in the same ratio of mesoporous silica:polyphenol (1:0.4 w/w). The materials obtained were characterized from a morphological and structural point of view through different analysis techniques. Through X-ray diffraction (XRD), the crystallization plane and the ordered structure of the mesoporous silica were observed. The difference between the two types of materials containing MCM-41 and MCM-48 was observed through the different morphologies of the silica particles through scanning electron microscopy (SEM) and also through the Brunauer–Emmet–Teller (BET) analysis, that the surface areas and volumes of pores was different between the two types of mesoporous silica, and, after loading with polyphenols, the values were reduced. The characteristic bands of silica and of polyphenols were easily observed by Fourier-transform infrared spectroscopy (FTIR), and, through thermogravimetric analysis (TGA), the residual mass was determined and the estimated amount of polyphenol in the materials and the efficient loading of mesoporous silica with polyphenols could be determined. The in vitro study was performed in two types of simulated biological fluids with different pH—simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). The obtained materials could be used in various biomedical applications as systems with controlled release of natural polyphenols and the most suitable application could be as food supplements especially when a mixture of such materials is used or when the polyphenols are co-loaded within the mesoporous silica.
Swelled Mechanism of Crumb Rubber and Technical Properties of Crumb Rubber Modified Bitumen
Authors: Zhu Hongbin , Zhang Min , Li Yuanyuan , Zou Yingxue , Chen Anqi , Wang Fu , Liu Langrun , Gu Dengjun , Zhou Shaoyun
Published: November 2022

Crumb rubber modified bitumen (CRMB) has excellent high-temperature performance and fatigue resistance, and is widely used in asphalt pavement to cope with increasing traffic axle load and changing climate. Under conventional preparation conditions, the swelling degree of CR can directly impact the comprehensive properties of CRMB; however, physical and chemical properties research on swelling crumb rubber (SCR) and crumb rubber recycled bitumen (CRRB) in CRMB is relatively lacking. In this paper, the working performance of CRMB and CRRB in high-temperature and low-temperature conditions were studied through physical and working performance testing of bitumen. The CR and SCR were tested by scanning electron microscope (SEM), Fourier transform infrared spectrometer (FTIR), gel permeation chromatography (GPC), and particle size distribution (PSD) tests to study the physicochemical behavior and microscopic effects before and after CR swelling. The results showed that CR dosage was in the range of 10%, 15%, and 20%, as well as that CR dosages have a positive effect on the high- and low-temperature performance, storage stability, and elastic recovery of bitumen. The high-temperature PG grades of bitumen were directly improved by four grades, and the elastic recovery rate increased by 339.9%. CR improved the ultra-low temperature crack resistance of bitumen. Due to the absorption of lighter components by CR, the relative content of the heavy component of bitumen increased; however, its low-temperature performance decreased significantly. After swelling, the CR particle size increased and the range became wider, the surface complexity of CR became higher, and the specific surface area was larger. At the same time, CR carried out the transformation process from large and medium molecules to small molecules. During the swelling process, a new benzene ring structure appeared in the CR, and the C–C bond and C–S bond of CR broke, forming part of the C=C bond.