bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comprehensive Analysis and Anti-Cancer Activities of Quercetin in ROS-Mediated Cancer and Cancer Stem Cells
Authors: Biswas Partha , Dey Dipta , Biswas Polash Kumar , Rahaman Tanjim Ishraq , Saha Shuvo , Parvez Anwar , Khan Dhrubo Ahmed , Lily Nusrat Jahan , Saha Konka , Sohel Md , Hasan Mohammad Mehedi , Al Azad Salauddin , Bibi Shabana , Hasan Md. Nazmul , Rahmatullah Mohammed , Chun Jaemoo , Rahman Md. Ataur , Kim Bonglee
Published: October 2022

Reactive oxygen species (ROS) induce carcinogenesis by causing genetic mutations, activating oncogenes, and increasing oxidative stress, all of which affect cell proliferation, survival, and apoptosis. When compared to normal cells, cancer cells have higher levels of ROS, and they are responsible for the maintenance of the cancer phenotype; this unique feature in cancer cells may, therefore, be exploited for targeted therapy. Quercetin (QC), a plant-derived bioflavonoid, is known for its ROS scavenging properties and was recently discovered to have various antitumor properties in a variety of solid tumors. Adaptive stress responses may be induced by persistent ROS stress, allowing cancer cells to survive with high levels of ROS while maintaining cellular viability. However, large amounts of ROS make cancer cells extremely susceptible to quercetin, one of the most available dietary flavonoids. Because of the molecular and metabolic distinctions between malignant and normal cells, targeting ROS metabolism might help overcome medication resistance and achieve therapeutic selectivity while having little or no effect on normal cells. The powerful bioactivity and modulatory role of quercetin has prompted extensive research into the chemical, which has identified a number of pathways that potentially work together to prevent cancer, alongside, QC has a great number of evidences to use as a therapeutic agent in cancer stem cells. This current study has broadly demonstrated the function-mechanistic relationship of quercetin and how it regulates ROS generation to kill cancer and cancer stem cells. Here, we have revealed the regulation and production of ROS in normal cells and cancer cells with a certain signaling mechanism. We demonstrated the specific molecular mechanisms of quercetin including MAPK/ERK1/2, p53, JAK/STAT and TRAIL, AMPKα1/ASK1/p38, RAGE/PI3K/AKT/mTOR axis, HMGB1 and NF-κB, Nrf2-induced signaling pathways and certain cell cycle arrest in cancer cell death, and how they regulate the specific cancer signaling pathways as long-searched cancer therapeutics.
Celiac Disease and Possible Dietary Interventions: From Enzymes and Probiotics to Postbiotics and Viruses
Authors: Wagh Sandip K. , Lammers Karen M. , Padul Manohar V. , Rodriguez-Herrera Alfonso , Dodero Veronica I.
Published: October 2022

Celiac Disease (CeD) is a chronic small intestinal immune-mediated enteropathy caused by the ingestion of dietary gluten proteins in genetically susceptible individuals. CeD is one of the most common autoimmune diseases, affecting around 1.4% of the population globally. To date, the only acceptable treatment for CeD is strict, lifelong adherence to a gluten-free diet (GFD). However, in some cases, GFD does not alter gluten-induced symptoms. In addition, strict adherence to a GFD reduces patients’ quality of life and is often a socio-economic burden. This narrative review offers an interdisciplinary overview of CeD pathomechanism and the limitations of GFD, focusing on current research on possible dietary interventions. It concentrates on the recent research on the degradation of gluten through enzymes, the modulation of the microbiome, and the different types of “biotics” strategies, from probiotics to the less explored “viromebiotics” as possible beneficial complementary interventions for CeD management. The final aim is to set the context for future research that may consider the role of gluten proteins and the microbiome in nutritional and non-pharmacological interventions for CeD beyond the sole use of the GFD.
From Solution Studies of Pharmaceuticals (Aspirin and Related Compounds) to the Thermodynamics of Aspirin-β-Cyclodextrin Interaction in water and N,N-Dimethylformamide
Authors: Danil de Namor Angela F. , Cambanis Alexandros , Al Hakawati Nawal , Khalife Rasha
Published: October 2022

The solution behavior of pharmaceuticals (acetylsalicylic acid, 4-acetoxybenzoic acid and 5-acetylsalicylic acid) in water and N,N-Dimethylformamide (DMF) at 298.15 K were investigated through solubility, conductance and calorimetric measurements. Taking into account the formation of ion pairs of these pharmaceuticals in water, the solution Gibbs energies of the dissociated electrolytes in this solvent were calculated. Thus, the solution thermodynamics of these compounds in water are reported using enthalpy data obtained by calorimetry. These pharmaceuticals undergo solvation when exposed to a saturated atmosphere of DMF. As the composition of the solid is not the same as that in solution, the Gibbs energy of the solutions of these compounds could not be obtained; only enthalpy data are reported. The thermodynamics of the interaction of acetylsalicylic acid (aspirin) with β-cyclodextrin in water and DMF is fully discussed, emphasizing the two different processes that take place in water at the two different pHs. In all cases, the favorable Gibbs energies for these processes are entropically controlled, mainly resulting from the higher dehydration/desolvation that the receptor undergoes upon interaction with the guest.
A Tale of Two Lobsters—Transcriptomic Analysis Reveals a Potential Gap in the RNA Interference Pathway in the Tropical Rock Lobster Panulirus ornatus
Authors: Banks Thomas M. , Wang Tianfang , Fitzgibbon Quinn P. , Smith Gregory G. , Ventura Tomer
Published: October 2022

RNA interference (RNAi) has been widely utilised in many invertebrate models since its discovery, and in a majority of instances presents as a highly efficient and potent gene silencing mechanism. This is emphasized in crustaceans with almost all taxa having the capacity to trigger effective silencing, with a notable exception in the spiny lobsters where repeated attempts at dsRNA induced RNAi have demonstrated extremely ineffective gene knockdown. A comparison of the core RNAi machinery in transcriptomic data from spiny lobsters (Panulirus ornatus) and the closely related slipper lobsters (Thenus australiensis, where silencing is highly effective) revealed that both lobsters possess all proteins involved in the small interfering and microRNA pathways, and that there was little difference at both the sequence and domain architecture level. Comparing the expression of these genes however demonstrated that T. australiensis had significantly higher expression in the transcripts encoding proteins which directly interact with dsRNA when compared to P. ornatus, validated via qPCR. These results suggest that low expression of the core RNAi genes may be hindering the silencing response in P. ornatus, and suggest that it may be critical to enhance the expression of these genes to induce efficient silencing in spiny lobsters.
HOTAIR/miR-203/CAV1 Crosstalk Influences Proliferation, Migration, and Invasion in the Breast Cancer Cell
Authors: Shi Fuxiu , Chen Xinyue , Wang Yi , Xie Yujie , Zhong Junpei , Su Kangtai , Li Miao , Li Yuqiu , Lin Qing , Zhou Youjia , Wang Jie , Xiong Lixia
Published: October 2022

In recent years, malignant breast cancer metastasis has caused a great increase in mortality. Research on the genetic and molecular mechanisms of malignant breast cancer has continued to deepen, and targeted therapy has become the general trend. Among them, competing endogenous RNA (ceRNA)-related molecules have received much attention. Homeobox transcript antisense RNA (HOTAIR) has been reported to function extensively as a ceRNA in breast cancer. Notably, miR-203 and Caveolin 1 (CAV1) have also been found to play a role in breast cancer. However, the relationship between the three remains unclear. In this study, we present a new mechanic through bioinformatics tool and basic experiments: the HOTAIR/miR-203/CAV1 axis, which complemented the role network of HOTAIR as a ceRNA, thus, it will provide a novel potential idea for breast cancer research and therapy.
Pharmacogenetic Variation and Its Clinical Relevance in a Latin American Rural Population
Authors: Olloquequi Jordi , Castro-Santos Patricia , Díaz-Peña Roberto
Published: October 2022

Latin-American populations have been largely underrepresented in genomic studies of drug response and disease susceptibility. In this paper, we present a genome-wide Chilean dataset from Talca based on the Illumina Global Screening Array. This let us to compare the frequency of gene variants involved in response to drugs among our population and others, taking data from the 1000 Genomes Project. We found four single-nucleotide polymorphisms with low prevalence in Chileans when compared with African, Amerindian, East and South Asian, and European populations: rs2819742 (RYR2), rs2631367 (SLC22A5), rs1063320 (HLA-G), and rs1042522 (TP53). Moreover, two markers showed significant differences between lower and higher proportion of Mapuche ancestry groups: rs1719247 (located in an intergenic region in chromosome 15; p-value = 6.17 × 10−5, Bonferroni corrected p-value = 0.02) and rs738409 (A nonsynonymous gene variant in the PNPLA3 gene; p-value = 9.02 × 10−5, Bonferroni corrected p-value = 0.04). All of these polymorphisms have been shown to be associated with diverse pathologies, such as asthma, cancer, or chronic hepatitis B, or to be involved in a different response to drugs, such as metformin, HMG-CoA reductase inhibitors, or simvastatin. The present work provides a pharmacogenetic landscape of an understudied Latin American rural population and supports the notion that pharmacogenetic studies in admixed populations should consider ancestry for a higher accuracy of the results. Our study stresses the relevance of the pharmacogenomic research to provide guidance for a better choice of the best treatment for each individual in a population with admixed ancestry.
The Role of Small Heat Shock Proteins in Protein Misfolding Associated Motoneuron Diseases
Authors: Tedesco Barbara , Ferrari Veronica , Cozzi Marta , Chierichetti Marta , Casarotto Elena , Pramaggiore Paola , Mina Francesco , Galbiati Mariarita , Rusmini Paola , Crippa Valeria , Cristofani Riccardo , Poletti Angelo
Published: October 2022

Motoneuron diseases (MNDs) are neurodegenerative conditions associated with death of upper and/or lower motoneurons (MNs). Proteostasis alteration is a pathogenic mechanism involved in many MNDs and is due to the excessive presence of misfolded and aggregated proteins. Protein misfolding may be the product of gene mutations, or due to defects in the translation process, or to stress agents; all these conditions may alter the native conformation of proteins making them prone to aggregate. Alternatively, mutations in members of the protein quality control (PQC) system may determine a loss of function of the proteostasis network. This causes an impairment in the capability to handle and remove aberrant or damaged proteins. The PQC system consists of the degradative pathways, which are the autophagy and the proteasome, and a network of chaperones and co-chaperones. Among these components, Heat Shock Protein 70 represents the main factor in substrate triage to folding, refolding, or degradation, and it is assisted in this task by a subclass of the chaperone network, the small heat shock protein (sHSPs/HSPBs) family. HSPBs take part in proteostasis by bridging misfolded and aggregated proteins to the HSP70 machinery and to the degradative pathways, facilitating refolding or clearance of the potentially toxic proteins. Because of its activity against proteostasis alteration, the chaperone system plays a relevant role in the protection against proteotoxicity in MNDs. Here, we discuss the role of HSPBs in MNDs and which HSPBs may represent a valid target for therapeutic purposes.
NCAPG Promotes Pulmonary Artery Smooth Muscle Cell Proliferation as a Promising Therapeutic Target of Idiopathic Pulmonary Hypertension: Bioinformatics Analysis and Experiment Verification
Authors: Fu Bowen , Li You , Shi Xiaobo , Liu Peng , Zhang Yiman , Tian Hongyan
Published: October 2022

Idiopathic pulmonary arterial hypertension (IPAH) is a disease with complex etiology. Currently, IPAH treatment is limited, and patients’ prognosis is poor. This study aimed to explore new therapeutic targets in IPAH through bioinformatics. Two data sets (GSE113439 and GSE130391) meeting the requirements were obtained from the Gene Expression Omnibus (GEO) database. Then, differentially expressed genes (DEGs) were identified and analyzed by NetworkAnalyst platform. By enriching Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), we examined the function of DEGs. A protein–protein interaction (PPI) network was constructed to identify central genes using the CytoNCA plug-in. Finally, four central genes, ASPM, CENPE, NCAPG, and TOP2A, were screened out. We selected NCAPG for protein-level verification. We established an animal model of PAH and found that the expression of NCAPG was significantly increased in the lung tissue of PAH rats. In vitro experiments showed that the expression of NCAPG was significantly increased in proliferative pulmonary arterial smooth muscle cells (PASMCs). When NCAPG of PASMCs was knocked down, the cell proliferation was inhibited, which suggested that NCAPG was related to the proliferation of PASMCs. Therefore, these results may provide new therapeutic targets for IPAH.
Cardiolipin for Enhanced Cellular Uptake and Cytotoxicity of Thermosensitive Liposome-Encapsulated Daunorubicin toward Breast Cancer Cell Lines
Authors: Alrbyawi Hamad , Boddu Sai H. S. , Poudel Ishwor , Annaji Manjusha , Mita Nur , Arnold Robert D. , Tiwari Amit K. , Babu R. Jayachandra
Published: October 2022

Daunorubicin (DNR) and cardiolipin (CL) were co-delivered using thermosensitive liposomes (TSLs). 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine (MSPC), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] or DSPE-mPEG (2000) and CL were used in the formulation of liposomes at a molar ratio of 57:40:30:3:20, respectively. CL forms raft-like microdomains that may relocate and change lipid organization of the outer and inner mitochondrial membranes. Such transbilayer lipid movement eventually leads to membrane permeabilization. TSLs were prepared by thin-film hydration (drug:lipid ratio 1:5) where DNR was encapsulated within the aqueous core of the liposomes and CL acted as a component of the lipid bilayer. The liposomes exhibited high drug encapsulation efficiency (>90%), small size (~115 nm), narrow size distribution (polydispersity index ~0.12), and a rapid release profile under the influence of mild hyperthermia. The liposomes also exhibited ~4-fold higher cytotoxicity against MDA-MB-231 cells compared to DNR or liposomes similar to DaunoXome® (p < 0.001). This study provides a basis for developing a co-delivery system of DNR and CL encapsulated in liposomes for treatment of breast cancer.
Genome-Wide Identification of the DOF Gene Family Involved in Fruitlet Abscission in Areca catechu L.
Authors: Li Jia , Jia Xiaocheng , Yang Yaodong , Chen Yunche , Wang Linkai , Liu Liyun , Li Meng
Published: October 2022

Fruitlet abscission frequently occurs in Areca catechu L. and causes considerable production loss. However, the inducement mechanism of fruitlet abscission remains mysterious. In this study, we observed that the cell architecture in the abscission zone (AZ) was distinct with surrounding tissues, and varied obviously before and after abscission. Transcriptome analysis of the “about-to-abscise” and “non-abscised” AZs were performed in A. catechu, and the genes encoding the plant-specific DOF (DNA-binding with one finger) transcription factors showed a uniform up-regulation in AZ, suggesting a role of the DOF transcription in A. catechu fruitlet abscission. In total, 36 members of the DOF gene family distributed in 13 chromosomes were identified from the A. catechu genome. The 36 AcDOF genes were classified into nine subgroups based on phylogenic analysis. Six of them showed an AZ-specific expression pattern, and their expression levels varied according to the abscission process. In total, nine types of phytohormone response cis-elements and five types of abiotic stress related cis-elements were identified in the promoter regions of the AcDOF genes. In addition, histochemical staining showed that lignin accumulation of vascular bundles in AZ was significantly lower than that in pedicel and mesocarp, indicating the specific characteristics of the cell architecture in AZ. Our data suggests that the DOF transcription factors might play a role in fruitlet abscission regulation in A. catechu.
Enhanced BDNF and TrkB Activation Enhance GABA Neurotransmission in Cerebellum in Hyperammonemia
Authors: Arenas Yaiza M. , Martínez-García Mar , Llansola Marta , Felipo Vicente
Published: October 2022

Background: Hyperammonemia is a main contributor to minimal hepatic encephalopathy (MHE) in cirrhotic patients. Hyperammonemic rats reproduce the motor incoordination of MHE patients, which is due to enhanced GABAergic neurotransmission in the cerebellum as a consequence of neuroinflammation. In hyperammonemic rats, neuroinflammation increases BDNF by activating the TNFR1–S1PR2–CCR2 pathway. (1) Identify mechanisms enhancing GABAergic neurotransmission in hyperammonemia; (2) assess the role of enhanced activation of TrkB; and (3) assess the role of the TNFR1–S1PR2–CCR2–BDNF pathway. In the cerebellum of hyperammonemic rats, increased BDNF levels enhance TrkB activation in Purkinje neurons, leading to increased GAD65, GAD67 and GABA levels. Enhanced TrkB activation also increases the membrane expression of the γ2, α2 and β3 subunits of GABAA receptors and of KCC2. Moreover, enhanced TrkB activation in activated astrocytes increases the membrane expression of GAT3 and NKCC1. These changes are reversed by blocking TrkB or the TNFR1–SP1PR2–CCL2–CCR2–BDNF–TrkB pathway. Hyperammonemia-induced neuroinflammation increases BDNF and TrkB activation, leading to increased synthesis and extracellular GABA, and the amount of GABAA receptors in the membrane and chloride gradient. These factors enhance GABAergic neurotransmission in the cerebellum. Blocking TrkB or the TNFR1–SP1PR2–CCL2–CCR2–BDNF–TrkB pathway would improve motor function in patients with hepatic encephalopathy and likely with other pathologies associated with neuroinflammation.
Selective Calpain Inhibition Improves Functional and Histopathological Outcomes in a Canine Spinal Cord Injury Model
Authors: Metwally Elsayed , Al-Abbadi Hatim A. , Hashem Mohamed A. , Mahmoud Yasmina K. , Ahmed Eman A. , Maaty Ahmed I. , Helal Ibrahim E. , Ahmed Mahmoud F.
Published: October 2022

Calpain activation has been implicated in various pathologies, including neurodegeneration. Thus, calpain inhibition could effectively prevent spinal cord injury (SCI) associated with neurodegeneration. In the current study, a dog SCI model was used to evaluate the therapeutic potential of a selective calpain inhibitor (PD150606) in combination with methylprednisolone sodium succinate (MPSS) as an anti-inflammatory drug. SCI was experimentally induced in sixteen mongrel dogs through an epidural balloon compression technique. The dogs were allocated randomly into four groups: control, MPSS, PD150606, and MPSS+PD150606. Clinical evaluation, serum biochemical, somatosensory evoked potentials, histopathological, and immunoblotting analyses were performed to assess treated dogs during the study. The current findings revealed that the combined administration of MPSS+PD150606 demonstrated considerably lower neuronal loss and microglial cell infiltration than the other groups, with a significant improvement in the locomotor score. The increased levels of inflammatory markers (GFAP and CD11) and calcium-binding proteins (Iba1 and S100) were significantly reduced in the combination group and to a lesser extent in MPSS or PD150606 treatment alone. Interestingly, the combined treatment effectively inhibited the calpain-induced cleavage of p35, limited cdk5 activation, and inhibited tau phosphorylation. These results suggest that early MPSS+PD150606 therapy after acute SCI may prevent subsequent neurodegeneration via calpain inhibition.
Protective Effect of Rutin on Triethylene Glycol Dimethacrylate-Induced Toxicity through the Inhibition of Caspase Activation and Reactive Oxygen Species Generation in Macrophages
Authors: Yang Li-Chiu , Chang Yu-Chao , Yeh Kun-Lin , Huang Fu-Mei , Su Ni-Yu , Kuan Yu-Hsiang
Published: October 2022

Rutin, also called quercetin-3-rhamnosyl glucoside, is a natural flavonol glycoside present in many plants. Rutin is used to treat various diseases, such as inflammation, diabetes, and cancer. For polymeric biomaterials, triethylene glycol dimethacrylate (TEGDMA) is the most commonly used monomer and serves as a restorative resin, a dentin bonding agent and sealant, and a bone cement component. Overall, TEGDMA induces various toxic effects in macrophages, including cytotoxicity, apoptosis, and genotoxicity. The aim of this study was to investigate the protective mechanism of rutin in alleviating TEGDMA-induced toxicity in RAW264.7 macrophages. After treatment with rutin, we assessed the cell viability and apoptosis of TEGDMA-induced RAW264.7 macrophages using an methylthiazol tetrazolium (MTT) assay and Annexin V-FITC/propidium iodide assay, respectively. Subsequently, we assessed the level of genotoxicity using comet and micronucleus assays, assessed the cysteinyla aspartate specific proteinases (caspases) and antioxidant enzyme (AOE) activity using commercial kits, and evaluated the generation of reactive oxygen species (ROS) using a dichlorodihydrofluorescein diacetate (DCFH-DA) assay. We evaluated the expression of heme oxygenase (HO)-1, the expression of nuclear factor erythroid 2 related factor (Nrf-2), and phosphorylation of AMP activated protein kinase (AMPK) using the Western blot assay. The results indicated that rutin substantially reduced the level of cytotoxicity, apoptosis, and genotoxicity of TEGDMA-induced RAW264.7 macrophages. Rutin also blocked the activity of caspase-3, caspase-8, and caspase-9 in TEGDMA-stimulated RAW264.7 macrophages. In addition, it decreased TEGDMA-induced ROS generation and AOE deactivation in macrophages. Finally, we found that TEGDMA-inhibited slightly the HO-1 expression, Nrf-2 expression, and AMPK phosphorylation would be revered by rutin. In addition, the HO-1 expression, Nrf-2 expression, and AMPK phosphorylation was enhanced by rutin. These findings indicate that rutin suppresses TEGDMA-induced caspase-mediated toxic effects through ROS generation and antioxidative system deactivation through the Nrf-2/AMPK pathway. Therefore, rutin has the potential to serve as a novel antitoxicity agent for TEGDMA in RAW264.7 macrophages.
Putative Transcription Factor Genes Associated with Regulation of Carotenoid Biosynthesis in Chili Pepper Fruits Revealed by RNA-Seq Coexpression Analysis
Authors: Villa-Rivera Maria Guadalupe , Martínez Octavio , Ochoa-Alejo Neftalí
Published: October 2022

During the ripening process, the pericarp of chili pepper (Capsicum spp.) fruits accumulates large amounts of carotenoids. Although the carotenoid biosynthesis pathway in the Capsicum genus has been widely studied from different perspectives, the transcriptional regulation of genes encoding carotenoid biosynthetic enzymes has not been elucidated in this fruit. We analyzed RNA-Seq transcriptomic data from the fruits of 12 accessions of Capsicum annuum during the growth, development, and ripening processes using the R package named Salsa. We performed coexpression analyses between the standardized expression of genes encoding carotenoid biosynthetic enzymes (target genes (TGs)) and the genes of all expressed transcription factors (TFs). Additionally, we analyzed the promoter region of each biosynthetic gene to identify putative binding sequences for each selected TF candidate. We selected 83 TFs as putative regulators of the carotenogenic structural genes. From them, putative binding sites in the promoters of the carotenoid-biosynthesis-related structural genes were found for only 54 TFs. These results could guide the search for transcription factors involved in the regulation of the carotenogenic pathway in chili pepper fruits and might facilitate the collection of corresponding experimental evidence to corroborate their participation in the regulation of this biosynthetic pathway in Capsicum spp.
Methionine 274 Is Not the Determining Factor for Selective Inhibition of Histone Deacetylase 8 (HDAC8) by L-Shaped Inhibitors
Authors: Jänsch Niklas , Lang Kim Leoni , Meyer-Almes Franz-Josef
Published: October 2022

HDAC8 is an important target in several indication areas including childhood neuroblastoma. Several isozyme selective inhibitors of HDAC8 with L-shaped structures have been developed. A theoretical study has suggested that methionine 274 (M274) would act as a “switch” that controls a transient binding pocket, which is induced upon binding of L-shaped inhibitors. This hypothesis was experimentally examined in this study. The thermostability and functionality of HDAC8 wildtype and mutant variants with exchanged M274 were analyzed using biophysical methods. Furthermore, the binding kinetics of L-shaped and linear reference inhibitors of these HDAC8 variants were determined in order to elucidate the mode of interaction. Exchange of M274 has considerable impact on enzyme activity, but is not the decisive factor for selective recognition of HDAC8 by L-shaped inhibitors.
Novel In Vivo CometChip Reveals NDMA-Induced DNA Damage and Repair in Multiple Mouse Tissues
Authors: Owiti Norah A. , Corrigan Joshua J. , Pribyl Lee J. , Kay Jennifer E. , Engelward Bevin P.
Published: October 2022

The comet assay is a versatile assay for detecting DNA damage in eukaryotic cells. The assay can measure the levels of various types of damage, including DNA strand breaks, abasic sites and alkali-sensitive sites. Furthermore, the assay can also be modified to include purified DNA glycosylases so that alkylated and oxidized bases can be detected. The CometChip is a higher throughput version of the traditional comet assay and has been used to study cultured cells. Here, we have tested its utility for studies of DNA damage present in vivo. We show that the CometChip is effective in detecting DNA damage in multiple tissues of mice exposed to the direct-acting methylating agent methylmethane sulfonate (MMS) and to the metabolically activated methylating agent N-nitrosodimethylamine (NDMA), which has been found to contaminate food, water, and drugs. Specifically, results from MMS-exposed mice demonstrate that DNA damage can be detected in cells from liver, lung, kidney, pancreas, brain and spleen. Results with NDMA show that DNA damage is detectable in metabolically competent tissues (liver, lung, and kidney), and that DNA repair in vivo can be monitored over time. Additionally, it was found that DNA damage persists for many days after exposure. Furthermore, glycosylases were successfully incorporated into the assay to reveal the presence of damaged bases. Overall, this work demonstrates the efficacy of the in vivo CometChip and reveals new insights into the formation and repair of DNA damage caused by MMS and NDMA.
Revealing and Tuning the Photophysics of C=N Containing Photothermal Molecules: Excited State Dynamics Simulations
Authors: Chen Shunwei , Zhang Huajing , Li Yi , Chen Tingfeng , Liu Hao , Han Xiujun
Published: October 2022

Molecular photothermal conversion materials are recently attracting increasing attention for phototherapy applications. Herein we investigate the excitation and de-excitation processes of a photothermal molecule (C1TI) that is among the recently developed class of small-molecule-based photothermal imines with superb photothermal conversion efficiencies (PTCEs) up to 90% and a molecule (M2) that is constructed by replacing the amino group of C1TI with an H atom, via excited-state dynamics simulations based on the time-dependent density functional theory (TD-DFT). The simulations reveal fast (<150 fs of average time) nonradiative decays of the lowest excited singlet (S1) state to a conical intersection (CI) with the ground (S0) state in high yields (C1TI: 93.9% and M2: 87.1%). The fast decays, driven by C=N bond rotation to a perpendicular structural configuration, are found to be barrierless. The slight structural difference between C1TI and M2 leads to drastically different S0-S1 energy surfaces, especially M2 features a relatively much lower CI (0.8 eV in energy) and much more decay energy (1.0 eV) to approach the CI. This work provides insights into the de-excitation mechanisms and the performance tuning of C=N enabled photothermal materials.
Mini Review: Molecular Interpretation of the IGF/IGF-1R Axis in Cancer Treatment and Stem Cells-Based Therapy in Regenerative Medicine
Authors: Lin Syuan-Ling , Lin Chih-Yang , Lee Wei , Teng Chiao-Fang , Shyu Woei-Cherng , Jeng Long-Bin
Published: October 2022

In addition to the fundamental role of insulin-like growth factor (IGF)/IGF-1 receptor (IGF-1R) signaling dysregulation in cancer initiation and proliferation, the IGF/IGF-1R signaling also plays an important role in the maintenance of stem cell characteristics and enhancement of stem cell-based therapeutic efficacy. This review focused on the role of IGF/IGF-1R signaling in preclinical IGF-targeted therapies, including IGF-1R monoclonal antibodies, IGF-1R tyrosine kinase inhibitors, and neutralizing antibodies of IGFs in multiple tumors and endocrine disorders. On the other hand, the function of IGF/IGF-1R signaling in stem cell self-renewal, pluripotency and therapeutic efficacy in regenerative medicine was outlined. Finally, the review summarized ongoing studies on IGF/IGF-1R signaling blockade in multiple cancers and highlighted the IGF-1R signaling modifications in stem cells as a potential strategy to improve stem cell-based therapeutics in regenerative medicine.
Cancer Three-Dimensional Spheroids Mimic In Vivo Tumor Features, Displaying “Inner” Extracellular Vesicles and Vasculogenic Mimicry
Authors: Giusti Ilaria , Poppa Giuseppina , D’Ascenzo Sandra , Esposito Letizia , Vitale Anna Rita , Calvisi Giuseppe , Dolo Vincenza
Published: October 2022

The role of extracellular vesicles (EVs) as mediators of cell-to-cell communication in cancer progression is widely recognized. In vitro studies are routinely performed on 2D culture models, but recent studies suggest that 3D cultures could represent a more valid model. Human ovarian cancer cells CABA I were cultured by the hanging drop method to form tumor spheroids, that were moved to low adhesion supports to observe their morphology by Scanning Electron Microscopy (SEM) and to isolate the EVs. EVs release was verified by SEM and their identity confirmed by morphology (Transmission Electron Microscopy, TEM), size distribution (Nanoparticles Tracking Analysis), and markers (CD63, CD9, TSG-101, Calnexin). CABA I form spheroids with a clinically relevant size, above 400 μm; they release EVs on their external surface and also trap “inner” EVs. They also produce vasculogenic mimicry-like tubules, that bulge from the spheroid and are composed of a hollow lumen delimited by tumor cells. CABA I can be grown as multicellular spheroids to easily isolate EVs. The presence of features typical of in vivo tumors (inner entrapped EVs and vasculogenic mimicry) suggests their use as faithful experimental models to screen therapeutic drugs targeting these pro-tumorigenic processes.
The Metabolite Content of the Post-Culture Medium of the Tree Fern Cyathea delgadii Sternb. Cell Suspension Cultured in the Presence of 2,4-D and BAP
Authors: Rybczyński Jan J. , Marczak Łukasz , Stobiecki Maciej , Strugała Aleksander , Mikuła Anna
Published: October 2022

The aim of this study was to demonstrate the metabolic profile of post-culture medium as an expression of cell suspension metabolic activity of the tree fern Cyathea delgadii Sternb. The molecular profile of the tree fern’s cell culture has been never described, according to our knowledge. The cell suspension was established using ½ MS medium supplemented with various concentrations of 2,4-D and BAP. The optimal concentrations were 2.0 mg·L−1 and 0.2 mg·L−1, respectively. The cell suspension initially showed an organized system of cell division and later unorganized cell proliferation. LC-MS and GC-MS were used to identify the chemical composition of the post-culture medium. The LC-MS analysis results suggested that the color of liquid medium could be due to the presence of flavonoid derivatives, as this group of compounds was represented by eight compounds. After GC-MS analysis based on retention indexes and thanks to mass spectra comparison, 130 natural products were recognized, belonging to various classes of primary and secondary metabolites.
Event-Related Potential Study of Recovery of Consciousness during Forced Awakening from Slow-Wave Sleep and Rapid Eye Movement Sleep
Authors: Liaukovich Krystsina , Sazhin Sergei , Bobrov Pavel , Ukraintseva Yulia
Published: October 2022

This work aimed to study the recovery of consciousness during forced awakening from slow-wave sleep (SWS) and rapid eye movement sleep (REM) in healthy volunteers. To track the changes in the degree of awareness of the stimuli during the transition to wakefulness, event-related potentials (ERPs) and motor responses (MR) in the auditory local-global paradigm were analyzed. The results show that during awakening from both SWS and REM, first, alpha-activity restores in the EEG, and only 20 and 25 s (for REM and SWS awakenings, respectively) after alpha onset MR to target stimuli recovers. During REM awakening, alpha-rhythm, MR, and conscious awareness of stimuli recover faster than during SWS awakening. Moreover, pre-attentive processing of local irregularities emerges earlier, even before alpha-rhythm onset, while during SWS awakening, the local effect we registered only after alpha restoration. The P300-like response both on global and local irregularities was found only when accurate MR was restored. Thus, the appearance in EEG predominating alpha-activity is insufficient either for conscious awareness of external stimuli or for generating MR to them. This work may help to understand the pathophysiology of sleep disorders well as conditions characterized by the dissociation between behavior and various aspects of consciousness.
Hypoxia-Regulated Tumor-Derived Exosomes and Tumor Progression: A Focus on Immune Evasion
Authors: Shao Xuejun , Hua Shenghao , Feng Tao , Ocansey Dickson Kofi Wiredu , Yin Lei
Published: October 2022

Tumor cells express a high quantity of exosomes packaged with unique cargos under hypoxia, an important characteristic feature in solid tumors. These hypoxic tumor-derived exosomes are, crucially, involved in the interaction of cancer cells with their microenvironment, facilitating not only immune evasion, but increased cell growth and survival, enhanced angiogenesis, epithelial–mesenchymal transition (EMT), therapeutic resistance, autophagy, pre-metastasis, and metastasis. This paper explores the tumor microenvironment (TME) remodeling effects of hypoxic tumor-derived exosome towards facilitating the tumor progression process, particularly, the modulatory role of these factors on tumor cell immune evasion through suppression of immune cells, expression of surface recognition molecules, and secretion of antitumor soluble factor. Tumor-expressed exosomes educate immune effector cells, including macrophages, monocytes, T cells, natural killer (NK) cells, dendritic cells (DCs), γδ T lymphocytes, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), mast cells, and B cells, within the hypoxic TME through the release of factors that regulate their recruitment, phenotype, and function. Thus, both hypoxia and tumor-derived exosomes modulate immune cells, growth factors, cytokines, receptor molecules, and other soluble factors, which, together, collaborate to form the immune-suppressive milieu of the tumor environment. Exploring the contribution of exosomal cargos, such as RNAs and proteins, as indispensable players in the cross-talk within the hypoxic tumor microenvironmental provides a potential target for antitumor immunity or subverting immune evasion and enhancing tumor therapies.
Integration of QTL Mapping and Whole Genome Sequencing Identifies Candidate Genes for Alkalinity Tolerance in Rice (Oryza sativa)
Authors: Singh Lovepreet , Coronejo Sapphire , Pruthi Rajat , Chapagain Sandeep , Subudhi Prasanta K.
Published: October 2022

Soil alkalinity is an important stressor that impairs crop growth and development, resulting in reduced crop productivity. Unlike salinity stress, research efforts to understand the mechanism of plant adaptation to alkaline stress is limited in rice, a major staple food for the world population. We evaluated a population of 193 recombinant inbred lines (RIL) developed from a cross between Cocodrie and N22 under alkaline stress at the seedling stage. Using a linkage map consisting of 4849 SNP markers, 42 additive QTLs were identified. There were seven genomic regions where two or more QTLs for multiple traits colocalized. Three important QTL clusters were targeted, and several candidate genes were identified based on high impact variants using whole genome sequences (WGS) of both parents and differential expression in response to alkalinity stress. These genes included two expressed protein genes, the glucan endo-1,3-beta-glucosidase precursor, F-box domain-containing proteins, double-stranded RNA-binding motif-containing protein, aquaporin protein, receptor kinase-like protein, semialdehyde hydrogenase, and NAD-binding domain-containing protein genes. Tolerance to alkaline stress in Cocodrie was most likely due to the low Na+/K+ ratio resulting from reduced accumulation of Na+ ions and higher accumulation of K+ in roots and shoots. Our study demonstrated the utility of integrating QTL mapping with WGS to identify the candidate genes in the QTL regions. The QTLs and candidate genes originating from the tolerant parent Cocodrie should be targeted for introgression to improve alkalinity tolerance in rice and to elucidate the molecular basis of alkali tolerance.
Recent Advances in Inverted Perovskite Solar Cells: Designing and Fabrication
Authors: Yang Jiayan , Luo Xingrui , Zhou Yankai , Li Yingying , Qiu Qingqing , Xie Tengfeng
Published: October 2022

Inverted perovskite solar cells (PSCs) have been extensively studied by reason of their negligible hysteresis effect, easy fabrication, flexible PSCs and good stability. The certified photoelectric conversion efficiency (PCE) achieved 23.5% owing to the formed lead−sulfur (Pb−S) bonds through the surface sulfidation process of perovskite film, which gradually approaches the performance of traditional upright structure PSCs and indicates their industrial application potential. However, the fabricated devices are severely affected by moisture, high temperature and ultraviolet light due to the application of organic materials. Depending on nitrogen, cost of protection may increase, especially for the industrial production in the future. In addition, the inverted PSCs are found with a series of issues compared with the traditional upright PSCs, such as nonradiative recombination of carriers, inferior stability and costly charge transport materials. Thus, the development of inverted PSCs is systematically reviewed in this paper. The design and fabrication of charge transport materials and perovskite materials, enhancement strategies (e.g., interface modification and doping) and the development of all−inorganic inverted devices are discussed to present the indicator for development of efficient and stable inverted PSCs.
Magnetic Micellar Nanovehicles: Prospects of Multifunctional Hybrid Systems for Precision Theranostics
Authors: Miranda Margarida S. , Almeida Ana F. , Gomes Manuela E. , Rodrigues Márcia T.
Published: October 2022

Hybrid nanoarchitectures such as magnetic polymeric micelles (MPMs) are among the most promising nanotechnology-enabled materials for biomedical applications combining the benefits of polymeric micelles and magnetic nanoparticles within a single bioinstructive system. MPMs are formed by the self-assembly of polymer amphiphiles above the critical micelle concentration, generating a colloidal structure with a hydrophobic core and a hydrophilic shell incorporating magnetic particles (MNPs) in one of the segments. MPMs have been investigated most prominently as contrast agents for magnetic resonance imaging (MRI), as heat generators in hyperthermia treatments, and as magnetic-susceptible nanocarriers for the delivery and release of therapeutic agents. The versatility of MPMs constitutes a powerful route to ultrasensitive, precise, and multifunctional diagnostic and therapeutic vehicles for the treatment of a wide range of pathologies. Although MPMs have been significantly explored for MRI and cancer therapy, MPMs are multipurpose functional units, widening their applicability into less expected fields of research such as bioengineering and regenerative medicine. Herein, we aim to review published reports of the last five years about MPMs concerning their structure and fabrication methods as well as their current and foreseen expectations for advanced biomedical applications.
The Importance of Toll-like Receptor 9 Expression on Monocytes and Dendritic Cells in the Context of Epstein–Barr Virus Infection in the Immunopathogenesis of Primary Glomerulonephritis
Authors: Smarz-Widelska Iwona , Mertowski Sebastian , Mertowska Paulina , Korona-Głowniak Izabela , Hymos Anna , Grywalska Ewelina , Załuska Wojciech
Published: October 2022

Toll-like receptor 9 (TLR9) is activated by unmethylated cytosine-phosphate-guanosine (CpG) dinucleotides found in the genomes of pathogens such as Epstein–Barr virus (EBV). The aim of this study was to determine the role of TLR9 in the immunopathogenesis of IgA nephropathy (IgAN) and membranoproliferative glomerulonephritis (MPGN) in the context of Epstein–Barr virus (EBV) infection. For this purpose, the frequency of TLR9-positive monocytes and dendritic cells (DCs, i.e., BDCA-1; myeloid dendritic cells, and BDCA-2; plasmocytoid dendritic cells) was studied, and a quantitative analysis of the concentration of TLR9 in the serum of patients diagnosed with IgAN and MPGN was undertaken. Higher frequencies of TLR9-positive DCs and monocytes in IgAN and MPGN patients were observed as compared with the control group. Patients diagnosed with GN exhibited a higher percentage of BDCA-1+CD19− and BDCA-2+CD123+ DCs than patients in the control group. Moreover, serum TLR9 concentration was shown to be significantly correlated with EBV DNA copy number/µg DNA, IgG, IgM, serum albumin, total protein in 24-h urine collection test and the frequency of BDCA-2+CD123+ DCs in peripheral blood. Our findings confirm that TLR9 may be involved in the development of IgAN and MPGN.
First Report on the Streptococcus gallolyticus (S. bovis Biotype I) DSM 13808 Exopolysaccharide Structure
Authors: Maciejewska Anna , Lugowski Czeslaw , Lukasiewicz Jolanta
Published: October 2022

Streptococcus gallolyticus subspecies gallolyticus, known as Streptococcus bovis biotype I, is a facultative pathogen causing bacteraemia, infective endocarditis and sepsis that has been linked with colorectal cancer (CRC), but this correlation is still unclear. Bacterial surface structures, such as the major sugar antigens exposed to the outside of the microorganism, are potential virulence factors. One of the primary sugar antigens loosely attached to the cell surface is the biofilm component, exopolysaccharide (EPS). EPSs of S. bovis are poorly characterized molecules. Until now, only one S. macedonicus Sc136 EPS structure was known to the entire S. bovis group. The S. gallolyticus DSM 13808 EPS was investigated by chemical analysis, mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. The hexasaccharide repeating unit of the EPS, containing four Glc, two Rha residues and one phosphate group, has been described “ →6)-α-d-Glcp-(1→3)-β-l-Rhap-(1→4)-β-d-Glcp-(1→3)-[β-d-Glcp-(1→2)]-α-l-Rhap-(1→2)-α-d-Glcp-(1→P→”.
Soluble Epoxide Hydrolase Is Associated with Postprandial Anxiety Decrease in Healthy Adult Women
Authors: Nguyen Nhien , Morisseau Christophe , Li Dongyang , Yang Jun , Lam Eileen , Woodside D. Blake , Hammock Bruce D. , Shih Pei-an Betty
Published: October 2022

The metabolism of bioactive oxylipins by soluble epoxide hydrolase (sEH) plays an important role in inflammation, and sEH may be a risk modifier in various human diseases and disorders. The relationships that sEH has with the risk factors of these diseases remain elusive. Herein, sEH protein expression and activity in white blood cells were characterized before and after a high-fat meal in healthy women (HW) and women with anorexia nervosa (AN). sEH expression and sEH activity were significantly correlated and increased in both groups two hours after consumption of the study meal. Fasting sEH expression and activity were positively associated with body mass index (BMI) in both groups, while an inverse association with age was found in AN only (p value < 0.05). sEH was not associated with anxiety or depression in either group at the fasting timepoint. While the anxiety score decreased after eating in both groups, a higher fasting sEH was associated with a lower postprandial anxiety decrease in HW (p value < 0.05). sEH characterization using direct measurements verified the relationship between the protein expression and in vivo activity of this important oxylipin modulator, while a well-controlled food challenge study design using HW and a clinical control group of women with disordered eating elucidated sEH’s role in the health of adult women.
ECG Markers of Acute Melatonin Treatment in a Porcine Model of Acute Myocardial Ischemia
Authors: Bernikova Olesya G. , Tsvetkova Alena S. , Ovechkin Alexey O. , Demidova Marina M. , Azarov Jan E. , Platonov Pyotr G.
Published: October 2022

In myocardial ischemia, melatonin confers antiarrhythmic action, but its electrocardiographic expression is unclear. We aimed to evaluate the effects of melatonin treatment on electrocardiogram (ECG) parameters reflecting major arrhythmogenic factors and to test the association of these parameters with ventricular fibrillation (VF) incidence. Myocardial ischemia was induced by 40 min coronary artery occlusion in 25 anesthetized pigs. After induction of ischemia, 12 and 13 animals were given melatonin or placebo, respectively. Twelve-lead ECGs were recorded and durations of QRS, QT, Tpeak-Tend intervals and extrasystolic burden were measured at baseline and during occlusion. During ischemia, VF episodes clustered into early and delayed phases (<10 and >20 min, respectively), and QRS duration was associated with VF incidence. QT interval and extrasystolic burden did not differ between the groups. The Tpeak-Tend interval was progressively prolonged, and the prolongation was less pronounced in the treated animals. QRS duration increased, demonstrating two maxima (5–10 and 25 min, respectively). In the melatonin group, the earlier maximum was blunted, and VF development in this period was prevented. Thus, acute melatonin treatment prevented excessive prolongation of the QRS and Tpeak-Tend intervals in the porcine myocardial infarction model, and QRS duration can be used for the assessment of antiarrhythmic action of melatonin.