bluuebunny/crossref_metadata_2025_split huggingface dataset:
HRD1 Elicitation of an Anti-Warburg Effect by Targeting PFKP to Inhibit Breast Cancer Growth and Progression
Authors: Fan Ya , Wang Jia , Xu Yuemei , Wang Yipin , Song Tao , Liang Xiubin , Jin Feng , Su Dongming 
Published: September 2020

Abstract
Background: Our previous studies have shown that the E3 ubiquitin ligase of HMG-CoA reductase degradation 1 (HRD1) functions as a tumor suppressor, as overexpression of HRD1 suppressed breast cancer proliferation and invasion. However, its role in breast cancer cell glucose metabolism was unclear. Here, our aim was to uncover the role and molecular mechanisms of HRD1 in regulating aerobic glycolysis in breast cancer. Methods: The effect of HRD1 on robic glycolysis in breast cancer cells were assessed. Then the proliferation, colony formation ability, invasion and migration of breast cancer cells were evaluated. The relationship between HRD1 and PFKP was validated by Mass spectrometry analysis, immunofluorescence and co-immunoprecipitation. The level of PFKP ubiquitination was measured using ubiquitylation assay. Furthermore, the tumor growth and metastasis in mice xenografts were observed. Results: We found that upregulation of HRD1 clearly decreased aerobic glycolysis, and subsequently inhibited breast cancer proliferation and invasion. Mass spectrometry analysis results revealed a large HRD1 interactome, which included PFKP (platelet isoform of phosphofructokinase), a critical enzyme involved in the Warburg Effect in breast cancer. Mechanistically, HRD1 interacted and colocalized with PFKP in the cytoplasm, targeted PFKP for ubiquitination and degradation, and ultimately reduced PFKP expression and activity in breast cancer cells. HRD1 inhibited breast cancer growth and metastasis in vivo through a PFKP-dependent way.Conclusions: Our findings reveal a new regulatory role of HRD1 in Warburg effect and provide a key contributor in breast cancer metabolism.
CXCR7: A β-arrestin-biased receptor that potentiates cell migration and recruits β-arrestin2 exclusively through Gβγ subunits and GRK2
Authors: Nguyen Huong Thi , Alcaraz Arfaxad Reyes , Yong Hyo Jeong , Nguyen Lan Phuong , Park Hee kyung , Inoue Asuka , Lee Cheol Soon , Seong Jae Young , Hwang Jong-Ik 
Published: September 2020

Abstract
Background
Some chemokine receptors referred to as atypical chemokine receptors (ACKRs) are thought to non-signaling decoys because of their inability to activate typical G-protein signaling pathways. It is generally accepted that their main role focuses on scavenging several chemokines to limit their spatial availability in biological processes. CXCR7, also known as ACKR3, unlike other ACKRs, binds to only two chemokines, SDF-1α and I-TAC, and recruits β-arrestins to plasma membrane. Other than CXCR7, SDF-1α binds to its own conventional receptor, CXCR4, involving in homeostatic modulation such as development and immune surveillance as well as pathological condition such as inflammation, ischemia, and cancers. Recently, CXCR7 is suggested as a key therapeutic target together with CXCR4 in such conditions. However, the molecular mechanisms underlying cellular responses and functional relation with CXCR7 and CXCR4 have not been elucidated, despite massive studies. Therefore, we aimed to reveal the molecular networks of CXCR7 and CXCR4 and compare their effects on cell migration.
Methods
Base on structural complementation assay using NanoBiT technology, we characterized the distinct mechanisms underlying β-arrestin2 recruitment by both CXCR4 and CXCR7 through molecular-interaction of the signaling molecules. Crosslinking and immunoprecipitation were conducted to analyze complex formation of the receptors. Gene deletion using CRISPR and reconstitution of the receptors in cells were applied to analysis of ligand dependent ERK phosphorylation and cell migration. All experiments were performed in triplicate and repeated more than three times. Unpaired Student’s t-tests or ANOVA using PRISM5 software were employed for statistical analyses.
Results
We found that ligand binding to CXCR7 does not result in activation of typical signaling pathways via Gα subunits but activation of GRK2 via βγ subunits and receptor phosphorylation with subsequent β-arrestin2 recruitment. In contrast, CXCR4 induced Gαi activation and recruited β-arrestin2 through C-terminal phosphorylation by both GRK2 and GRK5. SDF-1α-stimulated ERK phosphorylation was facilitated by CXCR4, but not CXCR7. Heterodimerization of CXCR4 and CXCR7 was not confirmed in this study, while homodimerization of them was verified by crosslinking experiment and NanoBiT assay. Regarding to chemotaxis, a deletion and reconstitution of the receptors revealed that SDF-1α-stimulated cell migration was mediated by both CXCR4 and CXCR7.
Conclusion
This study demonstrates that SDF-1α-stimulated CXCR7 mediates β-arrestin2 recruitment via different molecular networking from that of CXCR4. CXCR7 may be neither a simple scavenger nor auxiliary receptor but plays an essential role in cell migration through cooperation with CXCR4.
The TNFA -308G&gt;A and IL10 -1082A&gt;G Polymorphisms as Predictive Biomarkers of Chronic HCV Infection
Authors: Santiago Angélica Menezes , Amoras Ednelza da Silva Graça , Queiroz Maria Alice Freitas , Conde Simone Regina Souza da Silva , Cayres-Vallinoto Izaura Maria Vieira , Ishak Ricardo , Vallinoto Antonio C. R. 
Published: September 2020

Abstract
Background: Genetic changes may induce dysregulated cytokine production and affect the progression of the chronic disease caused by the hepacivirus C (HCV) because the balance of pro- and anti-inflammatory cytokines determines the outcome of infection. This study evaluated the TNFA -308G>A and IL10 -1082A>G polymorphisms in the susceptibility and progress of chronic hepatitis CMethods: The study included 101 samples from patients with chronic hepatitis C and 300 samples from healthy donors. Polymorphisms were typed by real-time PCR and were analyzed for associations with histopathological parameters (according to METAVIR classification) and HCV viral load. Results: The polymorphic genotype for the TNFA -308G>A variant was not present in the group of patients with chronic hepatitis C and was associated with protection against HCV infection (p = 0.0477). Patients with the polymorphic genotype of the IL10 -1082A>G polymorphism had higher HCV viral load than wild-type patients (p = 0.0428). Neither polymorphism was associated with different levels of necroinflammatory activity or fibrosis scores. Conclusion: The polymorphic genotype at TNFA -308G>A protected against chronic HCV infection, and the polymorphic genotype at the IL10 -1082A>G variant was associated with viral persistence.
Manufacturing and Banking Canine Adipose-Derived Mesenchymal Stem Cells for Veterinary Clinical Application
Authors: Luo Huina , Li Dongsheng , Chen Zhisheng , Wang Bingyun , Chen Shengfeng 
Published: September 2020

Abstract
BACKGROUND: Mesenchymal stem cells (MSCs) have generated a great amount of interest in recent years as a novel therapeutic application for improving the quality of pet life and helping them free from painful conditions and diseases. It has now become critical to address the challenges related to the safety and efficacy of MSCs expanded in vitro. In this study, we establish a standardized process for manufacture of canine adipose-derived MSCs (AD-MSCs), including tissue sourcing, cell isolation and culture, cryopreservation, thawing and expansion, quality control and testing, and evaluate the safety and efficacy of those cells for clinical applications. RESULTS: After expansion, the viability of AD-MSCs manufactured under our standardized process was above 90 %. Expression of surface markers and differentiation potential was consistent with ISCT standards. Sterility, mycoplasma, and endotoxin tests were consistently negative. No adverse events were noted in two cases treated with intravenously AD-MSCs. CONCLUSION: Herein we demonstrated the establishment of a feasible bioprocess for manufacturing and banking canine AD-MSCs for veterinary clinical use.
Effects of Hyaluronidase on Structural Cells and the Extracellular Matrix of the Skin
Authors: Buhren Bettina Alexandra , Schrumpf Holger , Gorges Katharina , Reiners Oliver , Boelke Edwin , Fischer Jens W , Homey Bernhard , Gerber Peter Arne 
Published: September 2020

Abstract
Hyaluronic acid (hyaluronan; HA) is an essential component of the extracellular matrix (ECM) of the skin. The HA-degrading enzyme hyaluronidase (HYAL) is critically involved in the HA-metabolism. Yet, only little information is available regarding the skin´s HA-HYAL interactions on the molecular and cellular levels.OBJECTIVETo analyze the dose- and time-dependent molecular and cellular effects of HYAL on structural cells and the HA-metabolism in the skin.MATERIALS AND METHODSChip-based, genome-wide expression analyses (Affymetrix® GeneChip PrimeView™ Human Gene Expression Array), quantitative real-time PCR analyses, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (DAB), and in vitro wound healing assays were performed to assess dose-dependent and time-kinetic effects of HA and HYAL (bovine hyaluronidase, Hylase “Dessau”) on normal human dermal fibroblasts (NHDF), primary human keratinocytes in vitro and human skin samples ex vivo.RESULTSGenome-wide expression analyses revealed an upregulation of HA synthases (HAS) up to 1.8-fold change in HA- and HYAL-treated NHDF. HA and HYAL significantly accelerated wound closure in an in vitro model for cutaneous wound healing. HYAL induced HAS1 and HAS2 mRNA gene expression in NHDF. Interestingly, low concentrations of HYAL (0.015 U/ml) resulted in a significantly higher induction of HAS compared to moderate (0.15 and 1.5 U/ml) and high concentrations (15 U/ml) of HYAL. This observation corresponded to increased concentrations of HA measured by ELISA in conditioned supernatants of HYAL-treated NHDF with the highest concentrations observed for 0.015 U/ml of HYAL. Finally, immunohistochemical analysis of human skin samples incubated with HYAL for up to 48 h ex vivo demonstrated that low concentrations of HYAL (0.015 U/ml) led to a pronounced accumulation of HA, whereas high concentrations of HYAL (15 U/ml) reduced dermal HA-levels.CONCLUSIONHYAL is a bioactive enzyme that exerts multiple effects on the HA-metabolism as well as on the structural cells of the skin. Our results indicate that HYAL promotes wound healing and exerts a dose-dependent induction of HA-synthesis in structural cells of the skin. Herein, interestingly the most significant induction of HAS and HA were observed for the lowest concentration of HYAL.
Brucine Inhibits Proliferation of U87 Glioblastoma Cells by Targeting the G-quadruplexes in the c-Myb Promoter
Authors: Liu Qiaochu , Huo Di , Wang Qunhui , Lv Chuanqi , Liu Ziqiang , Gao Haijun , Chen Yong , Zhao Gang 
Published: September 2020

Abstract
Background: The proto-oncogene c-Myb plays an important role in the proliferation of cells and its upregulation affects the development of glioblastomas. G-quadruplexes are secondary structures of DNA or RNA that usually form in the promoter region of oncogenes, including c-Myb, and regulate the expression of these genes. The traditional Chinese medicine brucine is a ligand of G-quadruplexes located in the promoter region of c-Myb. In this study, the U87 cell line was used both in vitro and in vivo to investigate the therapeutic effect and mechanism of action of brucine. Methods: MTT assay and flow cytometry were used to determine the effect of brucine on the cell cycle, viability, and apoptosis of U87 cells. The effects of brucine on transcription and expression of c-Myb were determined through RT-PCR and western blotting. Dual-luciferase reporter assay and electrospray ionization-mass spectrometry were used to investigate whether brucine acts directly and binds G-quadruplexes in the promoter region of c-Myb, respectively. Results: The results showed that brucine suppressed the growth of U87 cells in vitro by arresting the cell cycle and reducing the expression of c-Myb. Through the dual luciferase reporter assay, brucine was found to inhibit the expression of c-Myb by targeting the guanine-rich sequence that forms G-quadruplexes in the c-Myb promoter. Moreover, U87 tumors were suppressed by brucine in a tumor xenograft nude mice model. Conclusion: The findings of the study indicate that brucine is a potentially effective medicine for treatment of glioblastomas.
Intrinsic oxidative phosphorylation limitations underlie cellular bioenergetics in leukemia.
Authors: Nelson Margaret , McLaughlin Kelsey , Hagen James , Coalson Hannah , Schmidt Cameron , Kew Kimberly , McClung Joseph , Neufer P. , Brophy Patricia , Vohra Nasreen , Liles Darla , Cabot Myles , Fisher-Wellman Kelsey 
Published: September 2020

Abstract
Currently there is great interest in developing cytotoxic pharmacotherapies that disrupt mitochondrial energy transduction in cancer. Given that mitochondria are critical to mammalian energy homeostasis, clinical success of a given therapeutic will undoubtedly hinge upon its cancer cell selectivity. That said, how the mitochondrial network is intrinsically remodeled to drive/enable the cancer phenotype remains a biological black box, largely due to limitations in analytical approaches. Herein, we leveraged an in-house diagnostic biochemical workflow to comprehensively evaluate mitochondrial bioenergetic efficiency and capacity in human leukemia. Using this platform, we provide direct evidence that despite minimal changes in absolute respiratory kinetics, leukemic mitochondria are hallmarked by intrinsic limitations in oxidative phosphorylation (OXPHOS) that constrain the network’s ability to contribute to cellular ATP free energy (i.e, ΔGATP) charge. Together, these findings link accelerated oxidative metabolism in leukemia to intrinsic OXPHOS deficiency and provide proof-of-concept that restoring, rather than disrupting, OXPHOS across the leukemic mitochondrial network may represent an untapped, but highly feasible, therapeutic avenue.
Ligand based 3D-QSAR pharmacophore, molecular docking and ADME to identify potential fibroblast growth factor receptor 1 inhibitors
Authors: Tang Zizhong , Huang Lu , Fu Xiaoli , Wang Haoxiang , Tang Biao , Xiao Yirong , Zhou Caixia , Zhao Zhiqiao , Wan Yujun , Chen Hui , Yao Huipeng , Shan Zhi , Bu Tongliang , Wu Xulong 
Published: September 2020

Abstract
Background The FGF/FGFR system may affect tumor cells and stromal microenvironment through autocrine and paracrine stimulation, thereby significantly promoting oncogene transformation and tumor growth. Abnormal expression of FGFR1 in cells is considered to be the main cause of tumorigenesis and a potential target for the treatment of cancer.Methods The known inhibitors were collected to construct 3D-QSAR pharmacophore model, which was verified by cost analysis, test set validation and Fischer test. Virtual screening of zinc database based on pharmacophore was carried out. FGFR1 crystal complex was downloaded from the protein database to dock with the compound. Finally, the absorption, distribution, metabolism and excretion (ADME) characteristics and toxicity of a series of potential inhibitors were studied.Results It was found that the constructed pharmacophore had a good ability to predict the activity. 2763 compounds in the database could hit well and the predicted activity value was less than 1 µM. Through molecular docking, we found that six compounds can bind to protein stably and inhibit the activity of FGFR1 through hydrogen bond interaction. In ADME and toxicity studies, we have successfully screened out a compound with a new structure scaffold, and found that it has good oral bioavailability and non-toxic.Conclusions This study screened out a new potential drug for cancer treatment, which can be further studied to explore its better therapeutic effect.
The Folding Propensity of α/Sulfono-γ-AA Peptidic Foldamers with Both Left- and Right-Handedness
Authors: Teng Peng , Zheng Mengmeng , Cerrato Darrell , Shi Yan , Zhou Mi , Xue Songyi , Jiang Wei , Wojtas Lukasz , Ming Li-June , Hu Yong , Cai Jianfeng 
Published: September 2020

Abstract
The discovery and application of new types of helical peptidic foldamers have been an attractive endeavor to enable the development of new materials, catalysts and biological molecules. To maximize their application potential through structure-based design, it is imperative to control their helical handedness based on their molecular scaffold. Herein we first demonstrate the generalizability of the solid-state right-handed helical propensity of the 413-helix of L-α/L-sulfono-γ-AA peptides that as short as 11-mer, using the high-resolution X-ray single crystallography. The atomic level folding conformation of the foldamers was also elucidated by 2D NMR and circular dichroism under various conditions. Subsequently, we show that the helical handedness of this class of foldamer is controlled by the chirality of their chiral side chains, as demonstrated by the left-handed 413-helix comprising 1:1 D-α/D-sulfono-γ-AA peptide. In addition, a heterochiral coiled-coil-like structure was also revealed for the first time, unambiguously supporting the impact of chirality on their helical handedness. Our findings enable the structure-based design of unique folding biopolymers and materials with the exclusive handedness or the racemic form of the foldamers in the future.
Effects of a ‘Baby-Friendly Hospital Initiative’ on exclusive breastfeeding rates at a private hospital in Lebanon: an interrupted time series analysis
Authors: Clermont Adrienne , Gemayel Josianne El , Hammoud Rola , Wang Jiangxia , Beciu Hortenzia , Sinno Mona , Berends Wilma , Rosenblum Nadine , Bienstock Jessica , Byrnes Kristen , Samuels Roger 
Published: September 2020

Abstract
Background: Exclusive breastfeeding (EBF) through six months of age has been scientifically validated as having a wide range of benefits, but remains infrequent in many countries. The WHO/UNICEF Baby-Friendly Hospital Initiative (BFHI) is one approach to improve EBF rates. Methods: This study documents the implementation of BFHI at Clemenceau Medical Center (CMC), a private hospital in Lebanon, and analyzes data on EBF practices among CMC’s patients before, during, and after the implementation period. The process of launching the BFHI at CMC is discussed from the perspective of key stakeholders using the SQUIRE guidelines for reporting on quality improvement initiatives. As an objective measure of the program’s impact, 2,002 live births from July 2015 to February 2018 were included in an interrupted time series analysis measuring the rates of EBF at discharge prior to, during, and following the bundle of BFHI interventions.Results: The steps necessary to bring CMC in line with the BFHI standards were implemented during the period between November 2015 and February 2016. These steps can be grouped into three phases: updates to hospital policies and infrastructure (Phase 1); changes to healthcare staff practices (Phase 2); and improvements in patient education (Phase 3). The baseline percentage of EBF was 2.4% of all live births. Following the BFHI intervention, the observed monthly change in EBF in the “Follow-Up” period (i.e., the 24 months following Phases 1-3) was significantly increased relative to the baseline period (+2.0 percentage points per month, p = 0.006). Overall, the observed rate of EBF at hospital discharge increased from 2.4% to 49.0% of all live births from the first to the final month of recorded data. Conclusions: Meeting the BFHI standards is a complex process for a health facility, requiring changes to policies, practices, and infrastructure. Despite many challenges, the results of the interrupted time series analysis indicate that the BFHI reforms were successful in increasing the EBF rate among CMC’s patients and sustaining that rate over time. These results further support the importance of the hospital environment and health provider practices in breastfeeding promotion, ultimately improving the health, growth, and development of newborns.​TRIAL REGISTRATION: Data collection procedures and protocols were reviewed bythe Johns Hopkins Medicine Office of Human Subjects Research Institutional Review Board (application#IRB00155989), and determined to not constitute human subjects research under DHHS or FDAregulations.
Evaluation of Antibacterial and Acute Oral Toxicity of Impatiens Tinctoria A. Rich Root
Authors: Degu Sileshi , Abebe Abiy , Gemeda Negero , Bitew Adane 
Published: September 2020

Abstract
Background: Infections due to a variety of bacterial etiologic agents become common and are taking the big share of morbidity and mortality. On the other way, development of antibacterial drug resistance has been commonly reported from all over the world. As a solution of stated problems scientific studies have to be conducted on the traditional medicinal plants to develop new, effective and safe antimicrobial drugs since plants are important sources. Traditionally, the study plant (I. tinctoria A. Rich) used to treat fungal infections like ring worms that cause tinea pedis and it has also different medicinal values .These were some of the provoking information to undertake the evaluation of antibacterial activities with its oral acute toxicity study. Objectives: To evaluate the antibacterial activities and acute oral toxicity of aqueous, ethanol and ethyl acetate root extracts of Impatiens tinctoria A. Rich.Methods: The roots of Impatiens tinctoria A. Rich were extracted using solvents of water, ethanol and ethyl acetate. Agar well diffusion for preliminary antibacterial screening and agar dilution methods for determination of minimal inhibitory concentration were used. The minimum bactericidal concentration of the extracts was determined. by taking inoculums from all concentrations of the plant extract plates exhibiting invisible growth (from inhibition zone of minimal inhibitory concentration plates) and subcultures onto appropriate media plate. Finally, the plant extracts were subjected to oral acute toxicity study according to the organization of economic co-operation and development test Guidelines 420. Result: Gram positive bacteria were more susceptible to the extracts compared to gram negative bacteria especially against S. aureus and S. epidermis which are commonly found in the skin even though the traditional application is to control fungal infections and to toughen the skin. Ethyl acetate extract was more potent than ethanol and aqueous extracts. The LD50 was above 9600 mg/kg.Conclusion: This study provides scientific basis as the root of I.tinctoria A.Rich had a promising antibacterial activity in extract dependent manner in which ethyl acetate extract showed better potency. Therefore, the antibacterial potential and practically non toxicness of the study plant could take the attention of scientific communities for the development of new, effective and safe antimicrobial drugs by further studying the plant in different directions.