bluuebunny/crossref_metadata_2025 huggingface dataset:
Asymmetric Non-Fullerene Small Molecule Acceptor with Unidirectional Non-Fused π-Bridge and Extended Terminal Group for High-Efficiency Organic Solar Cells
Authors: Wang Kun , Guo Qing , Nie Zengkun , Wang Huiyan , Gao Jingshun , Zhang Jianqi , Yu Linfeng , Guo Xia , Zhang Maojie
Published: September 2022

We designed and synthesized an asymmetric non-fullerene small molecule acceptor (NF-SMA) IDT-TNIC with an A–D–π–A structure, based on an indacenodithiophene (IDT) central core, with a unidirectional non-fused alkylthio-thiophene (T) π-bridge, and 2-(3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-ylidene)malononitrile (NIC) extended terminal groups. IDT-TNIC molecules still maintain a good coplanar structure, which benefits from the non-covalent conformational locks (NCL) between O···S and S···S. The asymmetric structure increases the molecular dipole moment, and the extended terminal group broadens the absorption of the material, resulting in an excellent photovoltaic performance of IDT-TNIC. The photovoltaic device, based on PBDB-T:IDT-TNIC, exhibits an energetic PCE of 11.32% with a high Voc of 0.87 V, high Jsc of 19.85 mA cm−2, and a low energy loss of 0.57 eV. More importantly, IDT-TNICs with asymmetric structures show a superior property compared to symmetric IDT-Ns. The results demonstrate that it is an effectual strategy to enhance the properties of asymmetric A–D–π–A-based NF-SMAs with non-fused NCL π-bridges and extended terminal groups.
A Narrative Review of the Association between Obstructive Sleep Apnea and Glaucoma in Adults
Authors: Leggewie Barbara , Gouveris Haralampos , Bahr Katharina
Published: September 2022

Background: Obstructive sleep apnea (OSA) is a sleep disorder, primarily of the upper airway, which not only has a significant impact on quality of life but is also associated with various systemic diseases. Several ophthalmological diseases are also associated with OSA, especially glaucoma. The purpose of this review is to take a closer look at the causality and mutual influence. Methods: A systematic literature search was conducted using PubMed. A total of 19 studies with 316,178 adult participants were included. Results: Eleven of the sixteen studies concentrating on the prevalence of glaucoma in patients with OSA showed an association of both entities. One paper found a higher risk for progression of glaucoma in OSA patients. Five of the sixteen included studies failed to show a correlation between OSA and glaucoma. One study out of three surveying specific ophthalmological parameters showed an influence of OSA therapy on retinal nerve fiber layer (RNFL) thinning and vision. One study showed a rise in intraocular pressure (IOP), while two other studies showed no increase under continuous positive airway pressure (CPAP). Conclusions: Our findings suggest an association between OSA and glaucoma and, especially, between OSA and thinning of RNFL. CPAP therapy appears to be also suitable for patients with comorbid glaucoma.
Hormone-Glutamine Metabolism: A Critical Regulatory Axis in Endocrine-Related Cancers
Authors: Xu Fengyuan , Shi Jialu , Qin Xueyun , Zheng Zimeng , Chen Min , Lin Zhi , Ye Jiangfeng , Li Mingqing
Published: September 2022

The endocrine-related cancers and hormones are undoubtedly highly interconnected. How hormones support or repress tumor induction and progression has been extensively profiled. Furthermore, advances in understanding the role of glutamine metabolism in mediating tumorigenesis and development, coupled with these in-depth studies on hormone (e.g., estrogen, progesterone, androgen, prostaglandin, thyroid hormone, and insulin) regulation of glutamine metabolism, have led us to think about the relationship between these three factors, which remains to be elucidated. Accordingly, in this review, we present an updated overview of glutamine metabolism traits and its influence on endocrine oncology, as well as its upstream hormonal regulation. More importantly, this hormone/glutamine metabolism axis may help in the discovery of novel therapeutic strategies for endocrine-related cancer.
Quantum Biochemistry and MM-PBSA Description of the ZIKV NS2B-NS3 Protease: Insights into the Binding Interactions beyond the Catalytic Triad Pocket
Authors: de Paula Junior Valdir Ferreira , van Tilburg Mauricio Fraga , Morais Pablo Abreu , Júnior Francisco Franciné Maia , Lima Elza Gadelha , Oliveira Victor Tabosa dos Santos , Guedes Maria Izabel Florindo , Caetano Ewerton Wagner Santos , Freire Valder Nogueira
Published: September 2022

The Zika virus protease NS2B-NS3 has a binding site formed with the participation of a H51-D75-S135 triad presenting two forms, active and inactive. Studies suggest that the inactive conformation is a good target for the design of inhibitors. In this paper, we evaluated the co-crystallized structures of the protease with the inhibitors benzoic acid (5YOD) and benzimidazole-1-ylmethanol (5H4I). We applied a protocol consisting of two steps: first, classical molecular mechanics energy minimization followed by classical molecular dynamics were performed, obtaining stabilized molecular geometries; second, the optimized/relaxed geometries were used in quantum biochemistry and molecular mechanics/Poisson–Boltzmann surface area (MM-PBSA) calculations to estimate the ligand interactions with each amino acid residue of the binding pocket. We show that the quantum-level results identified essential residues for the stabilization of the 5YOD and 5H4I complexes after classical energy minimization, matching previously published experimental data. The same success, however, was not observed for the MM-PBSA simulations. The application of quantum biochemistry methods seems to be more promising for the design of novel inhibitors acting on NS2B-NS3.
Expression of Eosinophilic Subtype Markers in Patients with Kawasaki Disease
Authors: Chang Ling-Sai , Chen Kuang-Den , Huang Ying-Hsien , Kuo Ho-Chang
Published: September 2022

Purpose: Eosinophils may rise to a higher level in the acute phase of Kawasaki disease (KD) both before and after intravenous immunoglobulin (IVIG) therapy. A substantial body of research was carried out on the association between KD and allergic diseases. Eosinophils play an important role in type 2 inflammation. Recent studies have shown that there are two distinct subtypes of eosinophils. In addition to their role in inflammation, lung-resident eosinophils (rEOS) also regulate homeostasis. Inflammatory eosinophils (iEOS) reflect type 2 inflammation in tissues. iEOS were considered the primary eosinophils in non-severe allergic asthma, while rEOS were thought to be the primary eosinophils in severe non-allergic eosinophilic asthma. This case–control study aimed to investigate the marker expression of eosinophilic subtypes in KD patients. Materials and Methods: The marker expressions of eosinophilic subtypes in the leukocytes of patients with KD were evaluated by the recently established KDmarkers online tool, a web server including gene expression data. Finally, the results were validated with a quantitative reverse transcriptase polymerase chain reaction (RT-PCR). We analyzed the mRNA expression levels of SELL and IL10RA in leukocytes from KD patients and febrile children. Results: Included in our screening tools were transcriptome arrays, which provided clues showing the importance of rEOS, whose role was identified by three genes (lower IL10RA, higher SELL, and SERPINB1 than controls). In contrast, the iEOS representative gene CD101 was not elevated in KD. It was found that the gene IL10RA, a marker of inflammatory eosinophilic leukocytes, was more highly expressed in the leukocytes of KD patients (n = 43) than febrile controls (n = 32), especially those without coronary artery lesions (CAL) (n = 26). Before treatment, SELL expression was higher in leukocytes of CAL patients (CAL, 1.33 ± 0.18, n = 39; non-CAL, 0.87 ± 0.12, n = 55; p = 0.012). SELL was significantly higher after half a year compared to febrile controls. Conclusions: To our knowledge, this is the first study to demonstrate that KD patients have increased SELL than febrile controls after 6 months of treatment. We present evidence here that dynamically different eosinophilic involvement exists between KD patients with and without CAL. The role of eosinophilic subtypes in KD patients warrants further investigation.
The Pleiotropy of PAX5 Gene Products and Function
Authors: Nasri Nasrabadi Parinaz , Martin Danick , Gharib Ehsan , Robichaud Gilles A.
Published: September 2022

PAX5, a member of the Paired Box (PAX) transcription factor family, is an essential factor for B-lineage identity during lymphoid differentiation. Mechanistically, PAX5 controls gene expression profiles, which are pivotal to cellular processes such as viability, proliferation, and differentiation. Given its crucial function in B-cell development, PAX5 aberrant expression also correlates with hallmark cancer processes leading to hematological and other types of cancer lesions. Despite the well-established association of PAX5 in the development, maintenance, and progression of cancer disease, the use of PAX5 as a cancer biomarker or therapeutic target has yet to be implemented. This may be partly due to the assortment of PAX5 expressed products, which layers the complexity of their function and role in various regulatory networks and biological processes. In this review, we provide an overview of the reported data describing PAX5 products, their regulation, and function in cellular processes, cellular biology, and neoplasm.
Insights into Allosteric Mechanisms of the Lung-Enriched p53 Mutants V157F and R158L
Authors: Lei Jiangtao , Li Xuanyao , Cai Mengqiang , Guo Tianjing , Lin Dongdong , Deng Xiaohua , Li Yin
Published: September 2022

Lung cancer is a leading fatal malignancy in humans. p53 mutants exhibit not only loss of tumor suppressor capability but also oncogenic gain-of-function, contributing to lung cancer initiation, progression and therapeutic resistance. Research shows that p53 mutants V157F and R158L occur with high frequency in lung squamous cell carcinomas. Revealing their conformational dynamics is critical for developing novel lung therapies. Here, we used all-atom molecular dynamics (MD) simulations to investigate the effect of V157F and R158L substitutions on the structural properties of the p53 core domain (p53C). Compared to wild-type (WT) p53C, both V157F and R158L mutants display slightly lesser β-sheet structure, larger radius of gyration, larger volume and larger exposed surface area, showing aggregation-prone structural characteristics. The aggregation-prone fragments (residues 249–267 and 268–282) of two mutants are more exposed to water solution than that of WT p53C. V157F and R158L mutation sites can affect the conformation switch of loop 1 through long-range associations. Simulations also reveal that the local structure and conformation around the V157F and R158L mutation sites are in a dynamic equilibrium between the misfolded and properly folded conformations. These results provide molecular mechanistic insights into allosteric mechanisms of the lung-enriched p53 mutants.
Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA
Authors: Zhang Qianqian , Han Jianting , Zhu Yongchang , Tan Shuoyan , Liu Huanxiang
Published: September 2022

Given the current epidemic of multidrug-resistant tuberculosis, there is an urgent need to develop new drugs to combat drug-resistant tuberculosis. Direct inhibitors of the InhA target do not require activation and thus can overcome drug resistance caused by mutations in drug-activating enzymes. In this work, the binding thermodynamic and kinetic information of InhA to its direct inhibitors, phenoxyphenol derivatives, were explored through multiple computer-aided drug design (CADD) strategies. The results show that the van der Waals interactions were the main driving force for protein–ligand binding, among which hydrophobic residues such as Tyr158, Phe149, Met199 and Ile202 have high energy contribution. The AHRR pharmacophore model generated by multiple ligands demonstrated that phenoxyphenol derivatives inhibitors can form pi–pi stacking and hydrophobic interactions with InhA target. In addition, the order of residence time predicted by random acceleration molecular dynamics was consistent with the experimental values. The intermediate states of these inhibitors could form hydrogen bonds and van der Waals interactions with surrounding residues during dissociation. Overall, the binding and dissociation mechanisms at the atomic level obtained in this work can provide important theoretical guidance for the development of InhA direct inhibitors with higher activity and proper residence time.
Cottonseed Meal Protein Isolate as a New Source of Alternative Proteins: A Proteomics Perspective
Authors: Tan Chee Fan , Kwan Soon Hong , Lee Chun Shing , Soh Yan Ni Annie , Ho Ying Swan , Bi Xuezhi
Published: September 2022

Cottonseed meal (CSM) is a good source of dietary proteins but is unsuitable for human consumption due to its gossypol content. To unlock its potential, we developed a protein extraction process with a gossypol removal treatment to generate CSM protein isolate (CSMPI) with ultra-low gossypol content. This process successfully reduced the free and total gossypol content to 4.8 ppm and 147.2 ppm, respectively, far below the US FDA limit. In addition, the functional characterisation of CSMPI revealed a better oil absorption capacity and water solubility than pea protein isolate. Proteome profiling showed that the treatment improved protein identification, while SDS-PAGE analysis indicated that the treatment did not induce protein degradation. Amino acid analysis revealed that post-treated CSMPI was rich in branched-chain amino acids (BCAAs). Mass spectrometry analysis of various protein fractions obtained from an in vitro digestibility assay helped to establish the digestibility profile of CSM proteins. Several potential allergens in CSMPI were also found using allergenic prediction software, but further evaluation based on their digestibility profiles and literature reviews suggests that the likelihood of CSMPI allergenicity remains low. Overall, our results help to navigate and direct the application of CSMPIs as alternative proteins toward nutritive human food application.
Hypothermia Alleviates Reductive Stress, a Root Cause of Ischemia Reperfusion Injury
Authors: Eskla Kattri-Liis , Vellama Hans , Tarve Liisi , Eichelmann Hillar , Jagomäe Toomas , Porosk Rando , Oja Vello , Rämma Heikko , Peet Nadežda , Laisk Agu , Volke Vallo , Vasar Eero , Luuk Hendrik
Published: September 2022

Ischemia reperfusion injury is common in transplantation. Previous studies have shown that cooling can protect against hypoxic injury. To date, the protective effects of hypothermia have been largely associated with metabolic suppression. Since kidney transplantation is one of the most common organ transplant surgeries, we used human-derived renal proximal tubular cells (HKC8 cell line) as a model of normal renal cells. We performed a temperature titration curve from 37 °C to 22 °C and evaluated cellular respiration and molecular mechanisms that can counteract the build-up of reducing equivalents in hypoxic conditions. We show that the protective effects of hypothermia are likely to stem both from metabolic suppression (inhibitory component) and augmentation of stress tolerance (activating component), with the highest overlap between activating and suppressing mechanisms emerging in the window of mild hypothermia (32 °C). Hypothermia decreased hypoxia-induced rise in the extracellular lactate:pyruvate ratio, increased ATP/ADP ratio and mitochondrial content, normalized lipid content, and improved the recovery of respiration after anoxia. Importantly, it was observed that in contrast to mild hypothermia, moderate and deep hypothermia interfere with HIF1 (hypoxia inducible factor 1)-dependent HRE (hypoxia response element) induction in hypoxia. This work also demonstrates that hypothermia alleviates reductive stress, a conceptually novel and largely overlooked phenomenon at the root of ischemia reperfusion injury.
Performance Analysis Based on Sustainability Exergy Indicators of High-Temperature Proton Exchange Membrane Fuel Cell
Authors: Guo Xinjia , Xu Bing , Ma Zheshu , Li Yanju , Li Dongxu
Published: September 2022

Based on finite-time thermodynamics, an irreversible high-temperature proton exchange membrane fuel cell (HT-PEMFC) model is developed, and the mathematical expressions of exergy efficiency, exergy destruction index (EDI), and exergy sustainability indicators (ESI) of HT-PEMFC are derived. According to HT-PEMFC model, the influences of thermodynamic irreversibility on exergy sustainability of HT-PEMFC are researched under different operating parameters that include operating temperatures, inlet pressure, and current density. The results show that the higher operating temperature and inlet pressure of HT-PEMFCs is beneficial to performance improvement. In addition, the single cell performance gradually decreases with increasing current density due to the presence of the irreversibility of HT-PEMFC.
Transcriptional Regulation of Endogenous Retroviruses and Their Misregulation in Human Diseases
Authors: Zhang Qian , Pan Juan , Cong Yusheng , Mao Jian
Published: September 2022

Endogenous retroviruses (ERVs), deriving from exogenous retroviral infections of germ line cells occurred millions of years ago, represent ~8% of human genome. Most ERVs are highly inactivated because of the accumulation of mutations, insertions, deletions, and/or truncations. However, it is becoming increasingly apparent that ERVs influence host biology through genetic and epigenetic mechanisms under particular physiological and pathological conditions, which provide both beneficial and deleterious effects for the host. For instance, certain ERVs expression is essential for human embryonic development. Whereas abnormal activation of ERVs was found to be involved in numbers of human diseases, such as cancer and neurodegenerative diseases. Therefore, understanding the mechanisms of regulation of ERVs would provide insights into the role of ERVs in health and diseases. Here, we provide an overview of mechanisms of transcriptional regulation of ERVs and their dysregulation in human diseases.
Small RNA-Seq Reveals Similar miRNA Transcriptome in Children and Young Adults with T-ALL and Indicates miR-143-3p as Novel Candidate Tumor Suppressor in This Leukemia
Authors: Dawidowska Małgorzata , Maćkowska-Maślak Natalia , Drobna-Śledzińska Monika , Kosmalska Maria , Jaksik Roman , Szymczak Donata , Jarmuż-Szymczak Małgorzata , Sadowska-Klasa Alicja , Wojtaszewska Marzena , Sędek Łukasz , Wróbel Tomasz , Zaucha Jan Maciej , Szczepański Tomasz , Lewandowski Krzysztof , Giebel Sebastian , Witt Michał
Published: September 2022

We aimed to identify miRNAs and pathways specifically deregulated in adolescent and young adult (AYA) T-ALL patients. Small RNA-seq showed no major differences between AYA and pediatric T-ALL, but it revealed downregulation of miR-143-3p in T-ALL patients. Prediction algorithms identified several known and putative oncogenes targeted by this miRNA, including KRAS, FGF1, and FGF9. Pathway analysis indicated signaling pathways related to cell growth and proliferation, including FGFR signaling and PI3K-AKT signaling, with the majority of genes overrepresented in these pathways being predicted targets of hsa-miR-143-3p. By luciferase reporter assays, we validated direct interactions of this miRNA with KRAS, FGF1 and FGF9. In cell proliferation assays, we showed reduction of cell growth upon miR-143-3p overexpression in two T-ALL cell lines. Our study is the first description of the miRNA transcriptome in AYA T-ALL patients and the first report on tumor suppressor potential of miR-143-3p in T-ALL. Downregulation of this miRNA in T-ALL patients might contribute to enhanced growth and viability of leukemic cells. We also discuss the potential role of miR-143-3p in FGFR signaling. Although this requires more extensive validation, it might be an interesting direction, since FGFR inhibition proved promising in preclinical studies in various cancers.
Extracellular Vesicles in Haematological Disorders: A Friend or a Foe?
Authors: Lazana Ioanna
Published: September 2022

Extracellular vesicles (EVs) have emerged as important mediators of homeostasis, immune modulation and intercellular communication. They are released by every cell of the human body and accordingly detected in a variety of body fluids. Interestingly, their expression can be upregulated under various conditions, such as stress, hypoxia, irradiation, inflammation, etc. Their cargo, which is variable and may include lipids, proteins, RNAs and DNA, reflects that of the parental cell, which offers a significant diagnostic potential to EVs. In line with this, an increasing number of studies have reported the important contribution of cancer-derived EVs in altering the tumour microenvironment and allowing for cancer progression and metastasis. As such, cancer-derived EVs may be used to monitor the development and progression of disease and to evaluate the potential response to treatment, which has generated much excitement in the field of oncology and particularly in haemato-oncology. Finally, EVs are able to transfer their cargo to target cells, modifying the properties of the recipient cell, which offers great therapeutic potential for EVs (either by specific drug delivery or by delivery of siRNAs and other inhibitory proteins). In this manuscript, we review the potential diagnostic use and therapeutic options of EVs in the context of haematological malignancies.
Microfluidic Electroceuticals Platform for Therapeutic Strategies of Intervertebral Disc Degeneration: Effects of Electrical Stimulation on Human Nucleus Pulposus Cells under Inflammatory Conditions
Authors: Kim Tae-Won , Kim An-Gi , Lee Kwang-Ho , Hwang Min-Ho , Choi Hyuk
Published: September 2022

The degeneration of an intervertebral disc (IVD) is a major cause of lower back pain. IVD degeneration is characterized by the abnormal expression of inflammatory cytokines and matrix degradation enzymes secreted by IVD cells. In addition, macrophage-mediated inflammation is strongly associated with IVD degeneration. However, the precise pathomechanisms of macrophage-mediated inflammation in IVD are still unknown. In this study, we developed a microfluidic platform integrated with an electrical stimulation (ES) array to investigate macrophage-mediated inflammation in human nucleus pulposus (NP). This platform provides multiple cocultures of different cell types with ES. We observed macrophage-mediated inflammation and considerable migration properties via upregulated expression of interleukin (IL)-6 (p < 0.001), IL-8 (p < 0.05), matrix metalloproteinase (MMP)-1 (p < 0.05), and MMP-3 (p < 0.05) in human NP cells cocultured with macrophages. We also confirmed the inhibitory effects of ES at 10 μA due to the production of IL-6 (p < 0.05) and IL-8 (p < 0.01) under these conditions. Our findings indicate that ES positively affects degenerative inflammation in diverse diseases. Accordingly, the microfluidic electroceutical platform can serve as a degenerative IVD inflammation in vitro model and provide a therapeutic strategy for electroceuticals.
Anti-Inflammation and Anti-Pyroptosis Activities of Mangiferin via Suppressing NF-κB/NLRP3/GSDMD Signaling Cascades
Authors: Feng Min , Wei Shaoqiang , Zhang Shidong , Yang Ying
Published: September 2022

Mangiferin (MF), a xanthone that extensively exists in many herbal medicines, processes significant activities of anti-inflammation and immunomodulation. The potential regulatory effect and mechanism of mangiferin on cell pyroptosis remain unclear. In this study, mouse bone-marrow-derived macrophages (BMDMs) were stimulated with 1 μg/mL LPS to induce cell pyroptosis and were treated with 10, 50, or 100 μg/mL MF for regulating pyroptosis. The cell supernatants TNF-α, IL-1β, IL-6, and IL-18 were detected by enzyme-linked immunosorbent assay (ELISA); gene expression of TNF-α, IL-1β, IL-6, IL-18, Caspase-1, Caspase-11, and gasdermin D (GSDMD) was tested by real-time polymerase chain reaction (RT-PCR), and protein expression levels of apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), nod-like receptor protein-3 (NLRP3), caspase-1, caspase-11, GSDMD, and NF-κB were detected by Western blot. The results showed that MF significantly inhibited the secretion and gene expression of TNF-α, IL-6, IL-1β, and IL-18 that were elevated by LPS. Moreover, MF significantly suppressed the gene expression of Caspase-1, Caspase-11, and GSDMD, and decreased the protein levels of NLRP3, caspase-1, caspase-11, full-length GSDMD (GSDMD-FL), GSDMD N-terminal (GSDMD-N), and NF-κB. In conclusion, mangiferin has a multi-target regulating effect on inflammation and pyroptosis by inhibiting the NF-κB pathway, suppressing inflammatory caspase-mediated pyroptosis cascades, and reducing GSDMD cleavage in LPS-induced BMDMs.
Loss of Protein Stability and Function Caused by P228L Variation in NADPH-Cytochrome P450 Reductase Linked to Lower Testosterone Levels
Authors: Rojas Velazquez Maria Natalia , Noebauer Mathias , Pandey Amit V.
Published: September 2022

Cytochrome P450 oxidoreductase (POR) is the redox partner of steroid and drug-metabolising cytochromes P450 located in the endoplasmic reticulum. Mutations in POR cause a broad range of metabolic disorders. The POR variant rs17853284 (P228L), identified by genome sequencing, has been linked to lower testosterone levels and reduced P450 activities. We expressed the POR wild type and the P228L variant in bacteria, purified the proteins, and performed protein stability and catalytic functional studies. Variant P228L affected the stability of the protein as evidenced by lower unfolding temperatures and higher sensitivity to urea denaturation. A significant decline in the rate of electron transfer to cytochrome c and thiazolyl blue tetrazolium (MTT) was observed with POR P228L, while activities of CYP3A4 were reduced by 25% and activities of CYP3A5 and CYP2C9 were reduced by more than 40% compared with WT POR. The 17,20 lyase activity of CYP17A1, responsible for the production of the main androgen precursor dehydroepiandrosterone, was reduced to 27% of WT in the presence of the P228L variant of POR. Based on in silico and in vitro studies, we predict that the change of proline to leucine may change the rigidity of the protein, causing conformational changes in POR, leading to altered electron transfer to redox partners. A single amino acid change can affect protein stability and cause a severe reduction in POR activity. Molecular characterisation of individual POR mutations is crucial for a better understanding of the impact on different redox partners of POR.
Dapagliflozin Mitigates Doxorubicin-Caused Myocardium Damage by Regulating AKT-Mediated Oxidative Stress, Cardiac Remodeling, and Inflammation
Authors: Hsieh Pei-Ling , Chu Pei-Ming , Cheng Hui-Ching , Huang Yu-Ting , Chou Wan-Ching , Tsai Kun-Ling , Chan Shih-Hung
Published: September 2022

Doxorubicin (Dox) is a commonly used anthracycline chemotherapy with a side effect of cardiotoxicity, which may increase the risk of heart failure for cancer patients. Although various studies have demonstrated the cardioprotective property of dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor, the detailed mechanism underlying its effect on Dox-induced cardiomyopathy is still limited. In this study, we showed that DAPA induced the activation of AKT/PI3K signaling in cardiac myoblast H9c2 cells following Dox treatment, leading to the upregulation of antioxidant HO-1, NQO1, and SOD, as well as an improved mitochondrial dysfunction via Nrf2. In addition, the reduced oxidative stress resulted in the downregulation of hypertrophy (ANP and BNP) and fibrosis (phospho-Smad3, collagen I, fibronectin, and α-SMA) markers. Furthermore, the inflammatory IL-8 concentration was inhibited after DAPA, possibly through PI3K/AKT/Nrf2/p38/NF-κB signaling. Moreover, our results were validated in vivo, and echocardiography results suggested an improved cardiac function in DAPA-receiving rats. In summary, we demonstrated that the administration of DAPA could mitigate the Dox-elicited cardiotoxicity by reducing oxidative stress, mitochondrial dysfunction, fibrosis, hypertrophy, and inflammation via PI3K/AKT/Nrf2 signaling.
Plastomes of Bletilla (Orchidaceae) and Phylogenetic Implications
Authors: Han Shiyun , Wang Rongbin , Hong Xin , Wu Cuilian , Zhang Sijia , Kan Xianzhao
Published: September 2022

The genus Bletilla is a small genus of only five species distributed across Asia, including B. chartacea, B. foliosa, B. formosana, B. ochracea and B. striata, which is of great medicinal importance. Furthermore, this genus is a member of the key tribe Arethuseae (Orchidaceae), harboring an extremely complicated taxonomic history. Recently, the monophyletic status of Bletilla has been challenged, and the phylogenetic relationships within this genus are still unclear. The plastome, which is rich in both sequence and structural variation, has emerged as a powerful tool for understanding plant evolution. Along with four new plastomes, this work is committed to exploring plastomic markers to elucidate the phylogeny of Bletilla. Our results reveal considerable plastomic differences between B. sinensis and the other three taxa in many aspects. Most importantly, the specific features of the IR junction patterns, novel pttRNA structures and codon aversion motifs can serve as useful molecular markers for Bletilla phylogeny. Moreover, based on maximum likelihood and Bayesian inference methods, our phylogenetic analyses based on two datasets of Arethuseae strongly imply that Bletilla is non-monophyletic. Accordingly, our findings from this study provide novel potential markers for species identification, and shed light on the evolution of Bletilla and Arethuseae.
Serum Proteome Signatures of Anti-SARS-CoV-2 Vaccinated Healthcare Workers in Greece Associated with Their Prior Infection Status
Authors: Stamoula Eleni , Sarantidi Eleana , Dimakopoulos Vasilis , Ainatzoglou Alexandra , Dardalas Ioannis , Papazisis Georgios , Kontopoulou Konstantina , Anagnostopoulos Athanasios K.
Published: September 2022

Over the course of the pandemic, proteomics, being in the frontline of anti-COVID-19 research, has massively contributed to the investigation of molecular pathogenic properties of the virus. However, data on the proteome on anti-SARS-CoV-2 vaccinated individuals remain scarce. This study aimed to identify the serum proteome characteristics of anti-SARS-CoV-2 vaccinated individuals who had previously contracted the virus and comparatively assess them against those of virus-naïve vaccine recipients. Blood samples of n = 252 individuals, out of whom n = 35 had been previously infected, were collected in the “G. Gennimatas” General Hospital of Thessaloniki, from 4 January 2021 to 31 August 2021. All participants received the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). A label-free quantitative proteomics LC-MS/MS approach was undertaken, and the identified proteins were analyzed using the GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes) databases as well as processed by bioinformatics tools. Titers of total RBD-specific IgGs against SARS-CoV-2 were also determined using the SARS-CoV-2 IgG II Quant assay. A total of 47 proteins were significantly differentially expressed, the majority of which were down-regulated in sera of previously infected patients compared to virus-naïve controls. Several pathways were affected supporting the crucial role of the humoral immune response in the protection against SARS-CoV-2 infection provided by COVID-19 vaccination. Overall, our comprehensive proteome profiling analysis contributes novel knowledge of the mechanisms of immune response induced by anti-SARS-CoV-2 vaccination and identified protein signatures reflecting the immune status of vaccine recipients.
Sunscreen Ingredient Octocrylene’s Potency to Disrupt Vitamin D Synthesis
Authors: Abdi Sayed Aliul Hasan , Ali Amena , Sayed Shabihul Fatma , Nagarajan Sumathi , Abutahir  , Alam Prawez , Ali Abuzer
Published: September 2022

Octocrylene is a widely used ingredient in sunscreen products, and it has been observed that the use of sunscreen has been increasing over the last few decades. In this paper, we investigated the way in which sunscreen’s ingredient octocrylene may disrupt normal vitamin D synthesis pathway, resulting in an imbalance in vitamin D levels in the body. The key techniques used for this insilico investigation were molecular docking, molecular dynamic (MD) simulation, and MMPBSA-based assessment. Vitamin D abnormalities have become very common in human health. Unknown exposure to chemicals may be one of the important risk factors. In molecular docking analysis, octocrylene exhibited a binding energy of −11.52 kcal/mol with vitamin D binding protein (1KXP) and −11.71 for the calcitriol native ligand. Octocrylene had a binding potency of −11.152 kcal/mol with the vitamin D receptor (1DB1), and calcitriol had a binding potency of −8.73 kcal/mol. In addition, octocrylene has shown binding energy of −8.96 kcal/mol with CYP2R1, and the calcitriol binding energy was −10.36 kcal/mol. Regarding stability, the root-mean-square deviation (RMSD), the root-mean-square fluctuation (RMSF), the radius of gyration, hydrogen bonding, and the solvent-accessible surface area (SASA) exhibited that octocrylene has a stable binding pattern similar to calcitriol. These findings revealed that incessant exposure to octocrylene may disrupt normal vitamin D synthesis.
Identification of Potential Biomarkers and Metabolic Pathways of Different Levels of Heat Stress in Beef Calves
Authors: Kim Won-Seob , Kim Jongkyoo , Lee Hong-Gu
Published: September 2022

Heat stress (HS) damages the global beef industry by reducing growth performance causing high economic losses each year. However, understanding the physiological mechanisms of HS in Hanwoo calves remains elusive. The objective of this study was to identify the potential biomarkers and metabolic pathways involving different levels of heat stress in Hanwoo calves. Data were collected from sixteen Hanwoo bull calves (169.6 ± 4.6 days old, BW of 136.9 ± 6.2 kg), which were maintained at four designated ranges of HS according to the temperature–humidity index (THI) including: threshold (22 to 24 °C, 60%; THI = 70 to 73), mild (26 to 28 °C, 60%; THI = 74 to 76), moderate (29 to 31 °C, 80%; THI = 81 to 83), and severe (32 to 34 °C, 80%; THI = 89 to 91) using climate-controlled chambers. Blood was collected once every three days to analyze metabolomics. Metabolic changes in the serum of calves were measured using GC-TOF-MS, and the obtained data were calculated by multivariate statistical analysis. Five metabolic parameters were upregulated and seven metabolic parameters were downregulated in the high THI level compared with the threshold (p < 0.05). Among the parameters, carbohydrates (ribose, myo-inositol, galactose, and lactose), organic compounds (acetic acid, urea, and butenedioic acid), fatty acid (oleic acid), and amino acids (asparagine and lysine) were remarkably influenced by HS. These novel findings support further in-depth research to elucidate the blood-based changes in metabolic pathways in heat-stressed Hanwoo beef calves at different levels of THI. In conclusion, these results indicate that metabolic parameters may act as biomarkers to explain the HS effects in Hanwoo calves.
Impact of LTR-Retrotransposons on Genome Structure, Evolution, and Function in Curcurbitaceae Species
Authors: Li Shu-Fen , She Hong-Bing , Yang Long-Long , Lan Li-Na , Zhang Xin-Yu , Wang Li-Ying , Zhang Yu-Lan , Li Ning , Deng Chuan-Liang , Qian Wei , Gao Wu-Jun
Published: September 2022

Long terminal repeat (LTR)-retrotransposons (LTR-RTs) comprise a major portion of many plant genomes and may exert a profound impact on genome structure, function, and evolution. Although many studies have focused on these elements in an individual species, their dynamics on a family level remains elusive. Here, we investigated the abundance, evolutionary dynamics, and impact on associated genes of LTR-RTs in 16 species in an economically important plant family, Cucurbitaceae. Results showed that full-length LTR-RT numbers and LTR-RT content varied greatly among different species, and they were highly correlated with genome size. Most of the full-length LTR-RTs were amplified after the speciation event, reflecting the ongoing rapid evolution of these genomes. LTR-RTs highly contributed to genome size variation via species-specific distinct proliferations. The Angela and Tekay lineages with a greater evolutionary age were amplified in Trichosanthes anguina, whereas a recent activity burst of Reina and another ancient round of Tekay activity burst were examined in Sechium edule. In addition, Tekay and Retand lineages belonging to the Gypsy superfamily underwent a recent burst in Gynostemma pentaphyllum. Detailed investigation of genes with intronic and promoter LTR-RT insertion showed diverse functions, but the term of metabolism was enriched in most species. Further gene expression analysis in G.pentaphyllum revealed that the LTR-RTs within introns suppress the corresponding gene expression, whereas the LTR-RTs within promoters exert a complex influence on the downstream gene expression, with the main function of promoting gene expression. This study provides novel insights into the organization, evolution, and function of LTR-RTs in Cucurbitaceae genomes.
Functional Interplay between Arginyl-tRNA Synthetases and Arginyltransferase
Authors: Avcilar-Kucukgoze Irem , MacTaggart Brittany , Kashina Anna
Published: September 2022

Protein arginylation, mediated by arginyltransferase ATE1, is a post-translational modification of emerging biological importance that consists of transfer of the amino acid Arg to protein and peptide substrates. ATE1 utilizes charged tRNAArg as the donor of the arginyl group, which depends on the activity of Arg-tRNA synthetases (RARS) and is also utilized in translation. The mechanisms that regulate the functional balance among ATE1, RARS and translation are unknown. Here, we addressed the question of how these two enzymes can partition Arg-tRNAArg to functionally distinct pathways using an intracellular arginylation sensor in cell lines with overexpression or deletion of ATE1 and RARS isoforms. We found that arginylation levels depend on the physiological state of the cells but are not directly affected by translation activity or the availability of RARS isoforms. However, displacement of RARS from the multi-synthetase complex leads to an increase in intracellular arginylation independently of RARS enzymatic activity. This effect is accompanied by ATE1′s redistribution into the cytosol. Our results provide the first comprehensive analysis of the interdependence among translation, arginyl-tRNA synthesis and arginylation.
TRAF4 Promotes the Proliferation of Glioblastoma by Stabilizing SETDB1 to Activate the AKT Pathway
Authors: Gu Hongyu , Zhu Shunqin , Peng Cheng , Wei Zekun , Shen Yang , Yuan Chaoyu , Yang He , Cui Hongjuan , Yang Liqun
Published: September 2022

The process of ubiquitination regulates the degradation, transport, interaction, and stabilization of substrate proteins, and is crucial for cell signal transduction and function. TNF receptor-associated factor 4, TRAF4, is a member of the TRAF family and is involved in the process of ubiquitination as an E3 ubiquitin protein ligase. Here, we found that TRAF4 expression correlates with glioma subtype and grade, and that TRAF4 is significantly overexpressed in glioblastoma and predicts poor prognosis. Knockdown of TRAF4 significantly inhibited the growth, proliferation, migration, and invasion of glioblastoma cells. Mechanistically, we found that TRAF4 only interacts with the Tudor domain of the AKT pathway activator SETDB1. TRAF4 mediates the atypical ubiquitination of SETDB1 to maintain its stability and function, thereby promoting the activation of the AKT pathway. Restoring SETDB1 expression in TRAF4 knockdown glioblastoma cells partially restored cell growth and proliferation. Collectively, our findings reveal a novel mechanism by which TRAF4 mediates AKT pathway activation, suggesting that TRAF4 may serve as a biomarker and promising therapeutic target for glioblastoma.
Trifuhalol A Suppresses Allergic Inflammation through Dual Inhibition of TAK1 and MK2 Mediated by IgE and IL-33
Authors: Bong Sim-Kyu , Park No-June , Lee Sang Heon , Lee Jin Woo , Kim Aaron Taehwan , Liu Xiaoyong , Kim Sang Moo , Yang Min Hye , Kim Yong Kee , Kim Su-Nam
Published: September 2022

The activation and degranulation of immune cells play a pivotal role in allergic inflammation, a pathological condition that includes anaphylaxis, pruritus, and allergic march-related diseases. In this study, trifuhalol A, a phlorotannin isolated from Agarum cribrosum, inhibited the degranulation of immune cells and the biosynthesis of IL-33 and IgE in differentiated B cells and keratinocytes, respectively. Additionally, trifuhalol A suppressed the IL-33 and IgE-mediated activation of RBL-2H3 cells through the regulation of the TAK1 and MK2 pathways. Hence, the effect of trifuhalol A on allergic inflammation was evaluated using a Compound 48/80-induced systemic anaphylaxis mouse model and a house dust mite (HDM)-induced atopic dermatitis (AD) mouse model. Trifuhalol A alleviated anaphylactic death and pruritus, which appeared as an early-phase reaction to allergic inflammation in the Compound 48/80-induced systemic anaphylaxis model. In addition, trifuhalol A improved symptoms such as itching, edema, erythema, and hyperkeratinization in HDM-induced AD mice as a late-phase reaction. Moreover, the expression of IL-33 and thymic stromal lymphopoietin, inflammatory cytokines secreted from activated keratinocytes, was significantly reduced by trifuhalol A administration, resulting in the reduced infiltration of immune cells into the skin and a reduction in the blood levels of IgE and IL-4. In summarizing the above results, these results confirm that trifuhalol A is a potential therapeutic candidate for the regulation of allergic inflammation.
Increased Lipids in Chlamydomonas reinhardtii by Multiple Regulations of DOF, LACS2, and CIS1
Authors: Jia Bin , Yin Jianbo , Li Xiaolian , Li Yingling , Yang Xingcai , Lan Chengxiang , Huang Ying
Published: September 2022

Microalgal lipids are essential for biofuel and dietary supplement production. Lipid engineering for higher production has been studied for years. However, due to the complexity of lipid metabolism, single-gene engineering gradually encounters bottlenecks. Multiple gene regulation is more beneficial to boosting lipid accumulation and further clarifying the complex regulatory mechanism of lipid biosynthesis in the homeostasis of lipids, carbohydrates, and protein metabolism. Here, three lipid-related genes, DOF, LACS2, and CIS, were co-regulated in Chlamydomonas reinhartii by two circles of transformation to overexpress DOF and knock down LACS2 and CIS simultaneously. With the multiple regulations of these genes, the intracellular lipids and FA content increased by 142% and 52%, respectively, compared with CC849, whereas the starch and protein contents decreased by 45% and 24%. Transcriptomic analysis showed that genes in TAG and FA biosynthesis were up-regulated, and genes in starch and protein metabolism were down-regulated. This revealed that more carbon precursor fluxes from starch and protein metabolism were redirected towards lipid synthesis pathways. These results showed that regulating genes in various metabolisms contributed to carbon flux redirection and significantly improved intracellular lipids, demonstrating the potential of multiple gene regulation strategies and providing possible candidates for lipid overproduction in microalgae.
Ectopic Expression of AeNAC83, a NAC Transcription Factor from Abelmoschus esculentus, Inhibits Growth and Confers Tolerance to Salt Stress in Arabidopsis
Authors: Zhao Xuan , Wu Tingting , Guo Shixian , Hu Junling , Zhan Yihua
Published: September 2022

NAC transcription factors play crucial roles in plant growth, development and stress responses. Previously, we preliminarily identified that the transcription factor AeNAC83 gene was significantly up-regulated under salt stress in okra (Abelmoschus esculentus). Herein, we cloned the nuclear-localized AeNAC83 from okra and identified its possible role in salt stress response and plant growth. The down-regulation of AeNAC83 caused by virus-induced gene silencing enhanced plant sensitivity to salt stress and increased the biomass accumulation of okra seedlings. Meanwhile, AeNAC83-overexpression Arabidopsis lines improved salt tolerance and exhibited many altered phenotypes, including small rosette, short primary roots, and promoted crown roots and root hairs. RNA-seq showed numerous genes at the transcriptional level that changed significantly in the AeNAC83-overexpression transgenic and the wild Arabidopsis with or without NaCl treatment, respectively. The expression of most phenylpropanoid and flavonoid biosynthesis-related genes was largely induced by salt stress. While genes encoding key proteins involved in photosynthesis were almost declined dramatically in AeNAC83-overexpression transgenic plants, and NaCl treatment further resulted in the down-regulation of these genes. Furthermore, DEGs encoding various plant hormone signal pathways were also identified. These results indicate that AeNAC83 is involved in resistance to salt stress and plant growth.
Leonurine Reduces Oxidative Stress and Provides Neuroprotection against Ischemic Injury via Modulating Oxidative and NO/NOS Pathway
Authors: Deng Ziteng , Li Jiao , Tang Xiaoquan , Li Dan , Wang Yazhou , Wu Shengxi , Fan Kai , Ma Yunfei
Published: September 2022

Leonurine (Leo) has been found to have neuroprotective effects against cerebral ischemic injury. However, the exact molecular mechanism underlying its neuroprotective ability remains unclear. The aim of the present study was to investigate whether Leo could provide protection through the nitric oxide (NO)/nitric oxide synthase (NOS) pathway. We firstly explored the effects of NO/NOS signaling on oxidative stress and apoptosis in in vivo and in vitro models of cerebral ischemia. Further, we evaluated the protective effects of Leo against oxygen and glucose deprivation (OGD)-induced oxidative stress and apoptosis in PC12 cells. We found that the rats showed anxiety-like behavior, and the morphology and number of neurons were changed in a model of photochemically induced cerebral ischemia. Both in vivo and in vitro results show that the activity of superoxide dismutase (SOD) and glutathione (GSH) contents were decreased after ischemia, and reactive oxygen species (ROS) and malondialdehyde (MDA) levels were increased, indicating that cerebral ischemia induced oxidative stress and neuronal damage. Moreover, the contents of NO, total NOS, constitutive NOS (cNOS) and inducible NOS (iNOS) were increased after ischemia in rat and PC12 cells. Treatment with L-nitroarginine methyl ester (L-NAME), a nonselective NOS inhibitor, could reverse the change in NO/NOS expression and abolish these detrimental effects of ischemia. Leo treatment decreased ROS and MDA levels and increased the activity of SOD and GSH contents in PC12 cells exposed to OGD. Furthermore, Leo reduced NO/NOS production and cell apoptosis, decreased Bax expression and increased Bcl-2 levels in OGD-treated PC12 cells. All the data suggest that Leo protected against oxidative stress and neuronal apoptosis in cerebral ischemia by inhibiting the NO/NOS system. Our findings indicate that Leo could be a potential agent for the intervention of ischemic stroke and highlighted the NO/NOS-mediated oxidative stress signaling.