bluuebunny/crossref_metadata_2025_split huggingface dataset:
β‐Catenin and GSK‐3β are targets for regenerative therapies for acetaminophen‐induced acute liver failure (398.4)
Authors: Bhushan Bharat , Walesky Chad , Borude Prachi , Manley Michael , Apte Udayan 
Published: June 2021

Acetaminophen (APAP) overdose is the major cause of acute liver failure (ALF) with limited treatment options. Liver regeneration is a critical determinant of survival after APAP overdose and regenerative therapies hold a great potential to treat APAP‐induced ALF. However, mechanisms of regeneration following APAP overdose are not known. We did a comprehensive analysis of pathways involved in liver regeneration using a novel incremental dose model of a “regenerative” dose (300 mg/kg, APAP300) and a “non‐regenerative” dose (600 mg/kg, APAP600) of APAP in mice. Stimulation of regeneration at APAP300 resulted in complete recovery, while inhibited regeneration at APAP600 resulted in delayed recovery and decreased survival. The inhibition of regeneration in APAP600 was due to inhibited cyclinD1 expression leading to delayed cell cycle. Further biochemical and genomic analysis revealed that many known regenerative pathways (e.g. EGFR/c‐Met, STAT3, MAPKs) remain activated even at non‐regenerative dose. However, Wnt/β‐catenin was specifically activated only at the regenerative dose. ChIP analysis revealed increased binding of β‐catenin to cyclinD1 promoter only at APAP300 correlating with higher cyclinD1 induction and liver regeneration. Further, mice overexpressing stable form of β‐catenin exhibited significantly higher regeneration and faster recovery after APAP overdose. Finally, pharmacological inhibition of GSK3β, the upstream regulator of β‐catenin, as late as 4 hr after APAP600 dose resulted in cyclinD1 induction and improved regeneration. These data demonstrate that canonical Wnt signaling pathway is a target for regenerative therapies for APAP‐induced ALF.Grant Funding Source: NIH ‐ R01 DK098414, P20 RR021940‐07 and AASLD‐ALF Liver Scholar Award (Udayan Apte)
Death‐associated protein kinase mediates myofibril degeneration and myocyte apoptosis induced by beta‐adrenergic receptors (404.3)
Authors: Guo Xinji , Hooshdaran Bahman , Rafiq Khadija , Xi Hang , Kolpakov Mikhail , Houser Steven , Koch Walter , Liggett Stephen , Sabri Abdelkarim 
Published: June 2021

Background: In cardiac muscle, persistent stimulation of β‐adrenergic receptors (β‐ARs) and calcium (Ca)2+ signaling plays a central role in regulating contractility, hypertrophy, and apoptosis. The Ca2+/calmodulin‐regulated Serine/Threonine kinase, death‐associated protein kinase (DAPK), regulates cytoskeletal dynamics and cell death. However, the role and activation mechanisms of DAPK in cardiac myocytes and heart failure (HF) are unknown. This study examines the role of DAPK in myocyte death induced by β‐AR stimulation.Methods and Results: We found increased DAPK expression and activation in human failing hearts and in hearts of cardiac‐specific β1‐ARs transgenic mice. This activation of DAPK correlated with myofibril degeneration, myocyte death and cardiac contractile dysfunction, pointing to a possible role of DAPK in the development of HF. We therefore assessed whether DAPK activation was involved in myocyte apoptosis secondary to excess exposure of catecholamine. Chronic treatment with β1‐AR agonist or adenoviral expression of β1‐ARs induced DAPK activation, which was dependent on intracellular Ca(2+) elevation and calcineurin activation. Adenoviral expression of wild‐type DAPK or a constitutively active DAPK mutant significantly enhanced myofibril degeneration and myocyte apoptosis induced in response to β1‐AR stimulation. In contrast, expression of a dominant negative DAPK mutant blocked β1‐AR‐induced myocyte apoptosis and promoted myocyte hypertrophy and myofibril organization.Conclusions: These findings reveal an unprecedented role of DAPK as a regulator of myofibril organization and myocyte apoptosis induced by persistent stimulation of β1‐AR. Thus, modulating DAPK activation to attenuate myofibril degeneration and myocyte death could be considered as a therapy target to treat patients with HF.Grant Funding Source: NIH R01 360998
microRNA‐26b modulates NF‐κB pathway by regulating PTEN in alveolar macrophages (406.2)
Authors: Zhang Li , Huang Chaoqun , Guo Yujie , Liu Lin 
Published: June 2021

NF‐κB is one of the best‐characterized transcription factors providing the link between early membrane‐proximal signaling events and changes in gene expression. It regulates the expression of many genes that play a role in inflammation. MicroRNAs are small non‐coding RNAs that can either cleave specific mRNAs or inhibit mRNA translation and subsequently silence target genes to modulate signaling pathways. Here, we report that miR‐26b, a lipopolysaccharide (LPS) ‐ responsive microRNA, repressed the phosphatase and tensin homolog (PTEN) involved in the activation of NF‐κB signaling pathway in macrophages. miR‐26b was down‐regulated in bovine alveolar macrophages after 6 and 36 h stimulation of LPS. Furthermore, we demonstrated that miR‐26b enhanced the LPS‐induced expression of tumor necrosis factor‐α (TNF‐ α), Interleukin‐1 β (IL‐1β) and Interleukin‐10 (IL‐10), but inhibited Interleukin‐6 (IL‐6). In addition, we found that miR‐26b directly bind to the 3’ untranslated region of PTEN and affected NF‐κB activity. Taken together, we conclude that miR‐26b modulates NF‐κB pathway by targeting PTEN in LPS‐stimulated bovine alveolar macrophages. These studies may provide a potential therapeutic target for bovine respiratory disease.Grant Funding Source: supported by the Agriculture and Food Research Initiative Competitive Grant no. 09PRE2300211
Assembly and interrogation of regulatory networks elucidates synergistic dependencies in human malignancies (475.3)
Authors: Califano Andrea 
Published: June 2021

The recent onslaught of molecular data, across multiple human malignancies, is producing an unprecedented repertoire of genetic and epigenetic alterations contributing to tumorigenesis and progression. Yet, the direct impact of this knowledge on tumor treatment and prevention is still largely unproven. Loss of tumor suppressor function is difficult to target pharmacologically and, with a handful of exceptions, alterations providing potential drug targets are relatively infrequent in cancer patients and are thus unlikely to support clinical development.By reconstructing and interrogating the in vivo regulatory logic of distinct cancer cells, which integrates multiple aberrant signals resulting from genetic and epigenetic alterations, systems biology is starting to elucidate and mechanistically validate both oncogene and non‐oncogene addiction mechanisms. These mechanisms are exquisitely dependent on the molecular landscape of cancer subtypes, can be targeted pharmacologically, and are frequently synergistic, thus providing uniquely specific entry points for combination therapy.In this presentation, we will discuss recent result in the discovery of synergistic, non‐oncogene addiction mechanisms and their application to the stratification and treatment of prostate cancer, high‐grade glioma, and non‐small cell lung cancer. This approach is highly extensible and has been applied to a variety of additional tumor subtypes, to the study of stem cell differentiation, reprogramming, and pluripotency control, as well as to the study of neurodegenerative diseases, such as ALS.
Oncostatin M induces epithelial to mesenchymal transition and increased invasiveness in hepatic cancer cells through redox mechanisms (488.6)
Authors: Paternostro Claudia , Cannito Stefania , Colombatto Sebastiano , Novo Erica , Parola Maurizio 
Published: June 2021

Oncostatin M (OSM), a member of IL‐6 family of cytokines, can affect hypoxia‐modulated liver processes contributing to chronic liver disease progression and hepatocellular carcinoma (HCC) development. In this study we investigated whether OSM may induce epithelial‐to‐mesenchymal transition (EMT) in human hepatic cancer cells and increased invasiveness by employing a) morphological, molecular and cell biology techniques in HepG2, HuH7 and Madin‐Darby canine kidney (MDCK) cells exposed to human recombinant OSM or b) immunohistochemistry on liver specimens from HCV cirrhotic patients carrying G1 and G2 HCC.OSM induced EMT‐related changes (SNAI1/2 and β‐catenin nuclear translocation, E‐cadherin down‐regulation, up‐regulation of fibronectin, α‐smooth muscle actin and matrix metalloprotease‐2) and increased invasiveness in all cells. This involved early intracellular generation of reactive oxygen species (ROS), phosphorylation/inactivation of GSK‐3β and activation of PI‐3K, ERK1/2, JNK1/2, p38MAPK and STAT3. Cancer cell invasiveness was prevented by inhibiting ERK1/2, PI3K or JNK1/2 or by preventing ROS generation. Finally, OSM was expressed in HCC tumor cells in areas also positive for hypoxia‐related antigens. OSM can induce EMT in human hepatic cancer cells and stimulate invasiveness through redox‐dependent activation of EMT‐related critical kinases and transcription factors.
Molecular basis of histone acetyllysine recognition by the BRPF1 bromodomain (537.1)
Authors: Lubula Mulu 
Published: June 2021

Covalent modifications on histone tails play a key role in determining the outcome of many nuclear processes including transcription, DNA repair, recombination, and replication. In humans, translocation of the monocytic leukemia zinc finger (MOZ) histone acetyltransferase (HAT) complex has been linked to a subtype of acute myeloid leukemia (AML). MOZ forms tetrameric complexes with ING5 (inhibitor of growth 5), EAF6 (Esa1‐associated factor 6 ortholog), and the bromodomain‐PHD finger protein. BRPF proteins have been shown to bridge the association of MOZ with ING5 and EAF6. Deletion mapping studies have also revealed that the acetyltransferase domain of MOZ is sufficient for the interaction with BRPF1. BRPF proteins therefore play a key role in assembling and activating MOZ acetyltransferase complexes. BRPF1 contains a unique combination of domains typically found in chromatin‐associated factors, including PHD (plant homeodomain) fingers, a bromodomain and a PWWP (Pro‐Trp‐Trp‐Pro) domain. The bromodomain and PWWP domain of BRPF1 help recruit MOZ to distinct sites of active chromatin. Bromodomains are highly conserved motifs generally known to acetylated lysines on the histone tail, but the ligands recognized by BRPF1 bromodomain are currently unknown. In this study we identified the N‐terminal histone tail ligands for the BRPF1 bromodomain, characterized the protein‐ligand binding affinities and determined the functional importance of these interactions. We also used extensive molecular dynamics simulations to generate structural models of bromodomain‐histone ligand complexes, to analyze H‐bonding and other interactions, and to calculate the binding free energies. Our results outline the molecular mechanism driving binding specificity of the BRPF1 bromodomain for discrete acetyllysine residues on the N‐terminal histone tails. A better understanding of this process will be important for the development of drugs to treat acute myeloid leukemia and other cancers.Grant Funding Source: NIH
Cardiac fibroblasts network organization and activation in the junctional region of the giant danio heart (543.8)
Authors: Manalo Trina , Roell Julia , Johnson Adedoyin , Lafontant Pascal 
Published: June 2021

The Giant danio (GD) and zebrafish (ZF) are small fish belonging to the diverse family of cyprinids; they both display the remarkable ability for heart regeneration. Our lab has recently described the complex junctional region (JR) at the interface of the compact and spongy myocardial layers of the ZF. However, how these two distinct layers are integrated in the GD has not been studied. Using light, scanning, and transmission electron microscopy (TEM), our study reveals that the GD possesses a complex JR with transitional cardiac myocytes (CM) linking compact heart CM and CM of the spongy heart, and that luminal and abluminal contacts are mediated through discrete membrane appositions and adherens junctions. More importantly we also found a complex network of fibroblasts (FB) with extensive cytoplasmic processes occupying the JR and investing the GD compact heart. To ascertain (FB) function, we treated GD with low dose of the antineoplastic agent Doxorubicin (DOX). Using Masson’s trichrome staining, we observed the accumulation of collagen in the compact heart. In addition, TEM shows increased level of collagen in the JR of treated hearts, as well as increase in FB endoplasmic reticulum and cytoplasmic polyribosomes suggesting a state of activation. We conclude that cardiac FB are resident in the complex JR and compact heart of the GD. Moreover our data suggest they are key to the accumulation of collagen that accompany the DOX‐induced injury response.Grant Funding Source: Supported by FDC‐DePauw University
Ischemic disease of the heart and professional adaptability of motor transport drivers (547.6)
Authors: Tursynbetov E.A. , Shaidarov M. Z. , Dubitsky A.A. , Karp L.L. 
Published: June 2021

Purpose: to determine the frequency of ischemic disease of the heart at drivers of motor transport and to reveal the changes of professional functions.Materials and methods. Cards of ambulance calls for the last 5 years are analyzed and psychophysiological testing (PPhT) of 248 drivers with a syndrome of coronary insufficiency is carried out. Starting PPhT is performed during 1‐2 days after a call of emergency doctor, final ‐ for the 6‐7 day after applying medical aid.Results. The number of drivers’ referrals concerning to cardiovascular diseases is increased in 1,5 times. The percentage of hospitalization is increased in 12%. The particular interest is represented by results of PPhT with cardiovascular urgent conditions in dynamics. Initial testing revealed changes of latent and motor reaction, tracking speed for the moving object, testifying about the system deterioration of operative response. Final testing found positive dynamics (from 0,785±0,078 till 0,704±0,765), motor (from 1,609±1,065 till 1,509±1,120) and the tracking speed for the moving object (from 23,5±2,1 till 22,3±1,9). At all drivers system parameters of operative response authentically differed from psychophysiological indicators of healthy drivers (р<0,001).Conclusions. PPhT authentically showed deterioration of professional qualities of drivers that increased the emergence risk of the road conflicts.
STAT3 regulation by S‐nitrosylation: implication for inflammatory disease (555.8)
Authors: Won Jeseong , Kim Jinsu , Singh Avtar , Sharma Anand , Singh Inderjit 
Published: June 2021

S‐nitrosylation and S‐glutathionylation, redox based modifications of protein thiols, are recently emerging as an important signaling mechanisms. Here, we assessed S‐nitrosylation based regulation of JAK2/STAT3 pathway that plays critical roles in immune/inflammatory responses and tumorigenesis. Our studies show that STAT3 in stimulated microglia underwent two distinct redox‐dependent modifications, S‐nitrosylation and S‐glutathionylation. STAT3 S‐nitrosylation was associated with iNOS‐produced nitric oxide (NO) and S‐nitrosoglutathione (GSNO), while S‐glutathionylation of STAT3 was associated with cellular oxidative stress. NO produced by iNOS or treatment of microglia with exogenous GSNO inhibited STAT3 activation via inhibiting STAT3 phosphorylation (Tyr705). Consequently, the IL‐6 induced microglial proliferation and associated gene expressions were also reduced. In cell free kinase assay using purified JAK2 and STAT3, STAT3 phosphorylation was inhibited by its selective preincubation with GSNO, but not by preincubation of JAK2 with GSNO, indicating that GSNO‐mediated mechanisms inhibit STAT3 phosphorylation through S‐nitrosylation of STAT3 rather than JAK2. In this study, we identified that Cys259 was the target Cys residue of GSNO‐mediated S‐nitrosylation of STAT3. The replacement of Cys259 residue with Ala abolished the inhibitory role of GSNO in IL‐6‐induced STAT3 phosphorylation and transactivation, suggesting the role of Cys259 S‐nitrosylation in STAT3 phosphorylation. Our results indicate the regulation of STAT3 by NO‐based post‐translational modification (S‐nitrosylation). These findings have important implications for development of new therapeutics targeting STAT3 for treating diseases associated with inflammatory/immune responses and abnormal cell proliferation, including cancer.Grant Funding Source: NS072511, BX001062, NS037766 and BX001072
Nucleosome binding and cell‐type specific gene expression (561.4)
Authors: Gjidoda Alison , Tagore Mohita , McAndrew Michael , Floer Monique 
Published: June 2021

How nucleosome occupancy at transcriptional regulatory regions is altered to allow expression of inducible genes in mammals is not clear. We have used a quantitative assay to analyze changes in nucleosome occupancy upon induction of three pro‐inflammatory cytokines in primary mouse macrophages and find that distal and proximal enhancers are rapidly cleared of nucleosomes. We also show that the cleared enhancers become associated with cis‐regulatory transcription factors required for induction of the associated genes. Surprisingly, we find that the promoters of two of these genes are not cleared of nucleosomes under conditions that lead to high levels of gene expression, and we speculate that competing nucleosomes at the promoters may contribute to the high degree of stochasticity found at these and other inducible genes. Our studies further revealed that enhancers of these inducible genes are only lowly occupied in macrophages prior to induction, suggesting that a permissive chromatin architecture may keep enhancers accessible to subsequent binding of cis‐regulatory transcription factors. Using siRNA we have begun to dissect the involvement of lineage‐specific transcription factors (e.g. PU.1, C/EBPβ, Runx) and nucleosome remodelers (e.g. Brg1/Brm) in determining cell‐type specific chromatin architecture at enhancers of inducible genes in macrophages.Grant Funding Source: AHA 13SDG17260004
A microarray analysis of microRNAs profiles in irritable bowel syndrome (595.1)
Authors: Guo Xian‐Wen , Zhang Fa‐Can , Liang Lie‐Xin , Huang Dan , Zhao Yun‐Zhi , Ye Hui‐Lan , Zhang Guo 
Published: June 2021

The aim of this study is to screen and identify microRNAs (miRNAs) candidates and determine their clinical relevance for different irritable bowel syndrome (IBS) subtype. Based on the Rome III criteria, five patients diagnosed with diarrhea‐predominant IBS(IBS‐D), five with constipation‐predominant IBS (IBS‐C) and five healthy volunteers were enrolled for this study. All people in both groups voluntarily joined this study with informed consents. Endoscopic biopsy samples were first collected from the colon sigmoideum of each subject and frozen in the liquid nitrogen. Microarray assay was then commercially performed to obtain their miRNA expression profiles using miRBase 16 screening for 1205 Homo sapiens (hsa)‐miRNA candidates upon an Agilent platform. To validate the microarray data, the expression of selected miRNAs was measured by quantitative real‐time reverse transcription polymerase chain reaction(RT‐qPCR). It was found that, compared with healthy control, twenty‐three miRNAs were significantly upregulated and one downregulated (hsa‐miR‐204‐5p) in IBS‐D patients, whereas four other miRNAs including hsa‐miR‐29b‐1‐5p, hsa‐miR‐18b‐5p, hsa‐miR‐5003‐3p and hsa‐miR‐3121‐3p obviously increased in IBS‐C subjects. Furthermore, bioinformatics analysis have interestingly shown that among those selected miRNAs, fourteen miRNAs were involving regulating calcium ion channels,seven miRNAs including hsa‐miR‐18b‐5p,hsa‐miR‐3121‐3p,hsa‐miR‐5003‐3p,hsa‐miR‐3158‐3p,hsa‐miR‐204‐5p,hsa‐miR‐4768‐3p and hsa‐miR‐490‐5p were related to neurotransmitter release and two miRNAs(hsa‐miR‐5580‐3p,hsa‐miR‐1323)contributed to the sensitivity to pain. Taken together, this study argued that several specific miRNAs might importantly participate in the IBS pathophysiologic process and their differential expressional pattern is mainly responsible for the diverse clinical manifestation of this disease.Grant Funding Source: Supported by NSFC grants 81160053 to FC.Z. and by 2010GXNSFC013020 to G.Z.
Spreading depression, fish oil supplementation and moderate training modulate antioxidant enzymes in brain’s cortex hemispheres? (596.2)
Authors: Ferreira Diorginis , Pedroza Anderson Apolonio , Interaminense Maria Vitoria , Da Silva Aline Isabel , Lopes Andréia , Mendes da Silva Rosangela , Breckenfeld Meneses Thayanne , Gomes Eveline Geórgia Go , Amâncio dos Santos Angela , Batista‐de‐Oliveira Manuella , Lagranha Claudia 
Published: June 2021

Cortical spreading depression (CSD) is a slowly propagating wave of spontaneous cortical electrical activity and it shares underlying mechanisms with neurological diseases such as migraine and epilepsy. It is well known that the neuronal tissue is susceptible to oxidative stress because of its high oxygen consumption and modest antioxidant defenses; alteration of the physiological pattern can enhance the oxidative stress (OS). Furthermore, ω‐3 polyunsaturated fatty acid of fish oil (FO) protects the brain by reducing OS and moderate treadmill also (MT) counteracts OS. We evaluated the effects of FO supplementation and MT on antioxidant enzymes in rat’s cortexes (right and left hemisphere). All rats were submitted to 2%KCl stimulus to elicit CSD in the right hemisphere. In order to study OS, we analyzed BW, MDA, SOD, CAT and GST. In the left hemisphere, FO supplementation increases MDA production. MT + FO also increases MDA; there is no difference in any antioxidant enzyme. In the right hemisphere, FO supplementation, MT and MT + FO supplementation groups showed decrease in MDA production, on the other hand, there was no influence on enzymatic activities. Briefly, data show that CSD, FO or MT don’t induce significant modulation in antioxidant enzymes, which suggest that CSD is a useful phenomenon that contributes to the study of FO and MT on neurological diseases without cumulative effects of oxidative stress.Grant Funding Source: Supported by FACEPE and CNPq
MED28 mediates Wnt/β‐catenin signaling through HMG box‐containing protein (HBP1) in human colon cancer cells (609.6)
Authors: Hsieh Nien‐Tsu , Li Chun‐I , Huang Chun‐Yin , Lee Ming‐Fen 
Published: June 2021

MED28, a Mediator subunit for transcriptional activation, interacts with multiple proteins, including merlin, actin cytoskeleton, and Grb2. MED28 is often highly expressed in colorectal, breast, and prostate cancers. HMG box‐containing protein 1 (HBP1), a transcriptional repressor, inhibits Wnt/β‐catenin signaling by blocking the binding of β‐catenin to the TCF/LEF transcription factors and reducing the expression of cyclin D1 and c‐Myc. Previously our laboratory found that MED28 modulates cell growth through HBP1 in breast cancer; the objective of the current study is to investigate the putative role of MED28/HBP1 in colorectal cancer. Suppression of MED28 increased the expression of HBP1, but reduced the expression of cyclin D1 and c‐Myc in HCT116 and SW480 colon cancer cells. The reporter activity of an HBP1 promoter increased upon MED28 knockdown. Moreover, suppression of MED28 resulted in β‐catenin translocation from nucleus to cytoplasm, corresponding to a lower transcriptional activity of the TOPflash reporter construct. Out data indicate that MED28 hinders the repressive effect of HBP1, and, thereby, activates the Wnt/β‐catenin pathway in colorectal cancer.Grant Funding Source: Supported by NSC101‐2320‐B‐309‐001 and NSC102‐2320‐B‐309‐001‐MY3 to M‐F Lee