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Cell and Developmental Biology

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Full-Text Articles in Medicinal-Pharmaceutical Chemistry

Histone Citrullination Represses Mirna Expression Resulting In Increased Oncogene Mrnas In Somatolactotrope Cells., Stanley B Devore, Coleman H. Young, Guangyuan Li, Anitha Sundararajan, Thiruvarangan Ramaraj, Joann Mudge, Faye Schilkey, Aaron Muth, Paul R. Thompson, Brian D. Cherrington Sep 2018

Histone Citrullination Represses Mirna Expression Resulting In Increased Oncogene Mrnas In Somatolactotrope Cells., Stanley B Devore, Coleman H. Young, Guangyuan Li, Anitha Sundararajan, Thiruvarangan Ramaraj, Joann Mudge, Faye Schilkey, Aaron Muth, Paul R. Thompson, Brian D. Cherrington

University of Massachusetts Medical School Publications

Peptidylarginine deiminase (PAD) enzymes convert histone arginine residues into citrulline to modulate chromatin organization and gene expression. Although PADs are expressed in anterior pituitary gland cells, their functional role and expression in pituitary adenomas is unknown. To begin to address these questions, we first examined normal human pituitaries and pituitary adenomas and found that PAD2, PAD4 and citrullinated histones are highest in prolactinomas and somatoprolactinomas. In the somatoprolactinoma-derived GH3 cell line, PADs citrullinate histone H3, which is attenuated by a pan-PAD inhibitor. RNA-sequencing and ChIP studies show that the expression of microRNAs let-7c-2, miR-23b and miR-29c is suppressed by histone ...


Modulating Viscoelasticity, Stiffness, And Degradation Of Synthetic Cellular Niches Via Stoichiometric Tuning Of Covalent Versus Dynamic Noncovalent Cross-Linking, Yu Tan, Henry Huang, David C. Ayers, Jie Song Aug 2018

Modulating Viscoelasticity, Stiffness, And Degradation Of Synthetic Cellular Niches Via Stoichiometric Tuning Of Covalent Versus Dynamic Noncovalent Cross-Linking, Yu Tan, Henry Huang, David C. Ayers, Jie Song

Open Access Articles

Viscoelasticity, stiffness, and degradation of tissue matrices regulate cell behavior, yet predictive synergistic tuning of these properties in synthetic cellular niches remains elusive. We hypothesize that reversible physical cross-linking can be quantitatively introduced to synthetic hydrogels to accelerate stress relaxation and enhance network stiffness, while strategic placement of isolated labile linkages near cross-linking sites can predict hydrogel degradation, both of which are essential for creating adaptive cellular niches. To test these hypotheses, chondrocytes were encapsulated in hydrogels formed by biorthogonal covalent and noncovalent physical cross-linking of a pair of hydrophilic building blocks. The stiffer and more viscoelastic hydrogels with DBCO-DBCO ...


Ferrocenylchalcone-Uracil Conjugates: Synthesis And Cytotoxic Evaluation, Amandeep Singh, Vishu Mehra, Neda Sadeghiani, Saghar Mozaffari, Keykavous Parang, Vipan Kumar Feb 2018

Ferrocenylchalcone-Uracil Conjugates: Synthesis And Cytotoxic Evaluation, Amandeep Singh, Vishu Mehra, Neda Sadeghiani, Saghar Mozaffari, Keykavous Parang, Vipan Kumar

Pharmacy Faculty Articles and Research

Huisgen’s azide-alkyne cycloaddition reaction was employed to synthesize a series of 1H-1,2,3-triazole-tethered uracil-ferrocenyl chalcone conjugates with the aim of evaluating their in vitro anti-proliferative efficacy on human leukemia (CCRF-CEM) and human breast adenocarcinoma (MDA-MB-468) cell lines. Cytotoxic evaluation studies identified a number of synthesized conjugates that inhibited the proliferation of leukemia cancer cells by ~70% after 72 h. The selected synthesized conjugates were found to be significantly less cytotoxic against normal kidney cell line (LLC-PK1) when compared with CCRF-CEM cancer cells.


Selective Targeting Of Bromodomains Of The Bromodomain-Phd Fingers Family Impairs Osteoclast Differentiation, Julia C. Meier, Hanna Witwicka, Sung-Yong Hwang, Mark J. Birnbaum, Stefan Knapp Oct 2017

Selective Targeting Of Bromodomains Of The Bromodomain-Phd Fingers Family Impairs Osteoclast Differentiation, Julia C. Meier, Hanna Witwicka, Sung-Yong Hwang, Mark J. Birnbaum, Stefan Knapp

Open Access Articles

Histone acetyltransferases of the MYST family are recruited to chromatin by BRPF scaffolding proteins. We explored functional consequences and the therapeutic potential of inhibitors targeting acetyl-lysine dependent protein interaction domains (bromodomains) present in BRPF1-3 in bone maintenance. We report three potent and selective inhibitors: one (PFI-4) with high selectivity for the BRPF1B isoform and two pan-BRPF bromodomain inhibitors (OF-1, NI-57). The developed inhibitors displaced BRPF bromodomains from chromatin and did not inhibit cell growth and proliferation. Intriguingly, the inhibitors impaired RANKL-induced differentiation of primary murine bone marrow cells and human primary monocytes into bone resorbing osteoclasts by specifically repressing transcriptional ...


Diverse Stimuli Engage Different Neutrophil Extracellular Trap Pathways, Elaine F. Kenny, Alf Herzig, Renate Krüger, Aaron Muth, Santanu Mondal, Paul R. Thompson, Volker Brinkmann, Horst Von Bernuth, Arturo Zychlinsky Jun 2017

Diverse Stimuli Engage Different Neutrophil Extracellular Trap Pathways, Elaine F. Kenny, Alf Herzig, Renate Krüger, Aaron Muth, Santanu Mondal, Paul R. Thompson, Volker Brinkmann, Horst Von Bernuth, Arturo Zychlinsky

Thompson Lab Publications

Neutrophils release neutrophil extracellular traps (NETs) which ensnare pathogens and have pathogenic functions in diverse diseases. We examined the NETosis pathways induced by five stimuli; PMA, the calcium ionophore A23187, nigericin, Candida albicans and Group B Streptococcus. We studied NET production in neutrophils from healthy donors with inhibitors of molecules crucial to PMA induced NETs including protein kinase C, calcium, reactive oxygen species, the enzymes myeloperoxidase (MPO) and neutrophil elastase. Additionally, neutrophils from chronic granulomatous disease patients, carrying mutations in the NADPH oxidase complex or a MPO-deficient patient were examined. We show that PMA, C. albicans and GBS use a ...


Role Of Peptidylarginine Deiminase 2 (Pad2) In Mammary Carcinoma Cell Migration, Sachi Horibata, Katherine E. Rogers, David Sadegh, Lynne J. Anguish, John L. Mcelwee, Pragya Shah, Paul R. Thompson, Scott A. Coonrod May 2017

Role Of Peptidylarginine Deiminase 2 (Pad2) In Mammary Carcinoma Cell Migration, Sachi Horibata, Katherine E. Rogers, David Sadegh, Lynne J. Anguish, John L. Mcelwee, Pragya Shah, Paul R. Thompson, Scott A. Coonrod

Thompson Lab Publications

BACKGROUND: Penetration of the mammary gland basement membrane by cancer cells is a crucial first step in tumor invasion. Using a mouse model of ductal carcinoma in situ, we previously found that inhibition of peptidylarginine deiminase 2 (PAD2, aka PADI2) activity appears to maintain basement membrane integrity in xenograft tumors. The goal of this investigation was to gain insight into the mechanisms by which PAD2 mediates this process.

METHODS: For our study, we modulated PAD2 activity in mammary ductal carcinoma cells by lentiviral shRNA-mediated depletion, lentiviral-mediated PAD2 overexpression, or PAD inhibition and explored the effects of these treatments on changes ...


Peptidylarginine Deiminase 1-Catalyzed Histone Citrullination Is Essential For Early Embryo Development, Xiaoqian Zhang, Xiaoqiu Liu, Mei Zhang, Tingting Li, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Xuesen Zhang Dec 2016

Peptidylarginine Deiminase 1-Catalyzed Histone Citrullination Is Essential For Early Embryo Development, Xiaoqian Zhang, Xiaoqiu Liu, Mei Zhang, Tingting Li, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Xuesen Zhang

Thompson Lab Publications

Peptidylarginine deiminase (PADI) enzymes are increasingly being associated with the regulation of chromatin structure and gene activity via histone citrullination. As one of the PADI family members, PADI1 has been mainly reported to be expressed in the epidermis and uterus, where the protein in keratinocytes is thought to promote differentiation by citrullinating filament proteins. However, the roles of PADI1 in preimplantation development have not been addressed. Using a PADI1-specific inhibitor and Padi1-morpholino knockdown, we found that citrullination of histone tails at H4R3 and H3R2/8/17 were markedly reduced in the 2- and 4-cell embryos. Consistent with this observation, early ...


Peroxiredoxin Catalysis At Atomic Resolution, Arden Perkins, Derek Parsonage, Kimberly J. Nelson, O. Maduka Ogba, Paul Ha-Yeon Cheong, Leslie B. Poole, P. Andrew Karplus Sep 2016

Peroxiredoxin Catalysis At Atomic Resolution, Arden Perkins, Derek Parsonage, Kimberly J. Nelson, O. Maduka Ogba, Paul Ha-Yeon Cheong, Leslie B. Poole, P. Andrew Karplus

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Peroxiredoxins (Prxs) are ubiquitous cysteine-based peroxidases that guard cells against oxidative damage, are virulence factors for pathogens, and are involved in eukaryotic redox regulatory pathways. We have analyzed catalytically active crystals to capture atomic resolution snapshots of a PrxQ-subfamily enzyme (from Xanthomonas campestris) proceeding through thiolate, sulfenate, and sulfinate species. These analyses provide structures of unprecedented accuracy for seeding theoretical studies, and show novel conformational intermediates giving insight into the reaction pathway. Based on a highly non-standard geometry seen for the sulfenate intermediate, we infer that the sulfenate formation itself can strongly promote local unfolding of the active site to ...


Peptide Arrays For Detecting Naphthenic Acids In Oil Sands Process Affected Water, Kamaljit Kaur, Subir Bhattacharjee, Rajesh G. Pillai, Sahar Ahmed, Sarfuddin Azmi Nov 2014

Peptide Arrays For Detecting Naphthenic Acids In Oil Sands Process Affected Water, Kamaljit Kaur, Subir Bhattacharjee, Rajesh G. Pillai, Sahar Ahmed, Sarfuddin Azmi

Pharmacy Faculty Articles and Research

Naphthenic acids (NAs) are water-soluble components of petroleum. The characterization and quantification of NAs by analytical methods have proved quite challenging, whilst the toxic effects of these water-soluble compounds on a variety of organisms adversely affecting reproduction and steroid production is becoming apparent. In this study, we report a fluorescence-based competitive binding method for rapid sensing of the presence of NAs using cellulosic peptide array strips as sensors. The peptide array was designed from sequences derived from the estrogen receptor (ER). Several of these peptides were able to detect the presence of NAs at low micromolar (∼5 mg L−1 ...


Small Molecule Tyrosine Kinase Inhibitors Of Erbb2/Her2/Neu In The Treatment Of Aggressive Breast Cancer., Richard L. Schroeder, Cheryl L. Stevens, Jayalakshmi Sridhar Sep 2014

Small Molecule Tyrosine Kinase Inhibitors Of Erbb2/Her2/Neu In The Treatment Of Aggressive Breast Cancer., Richard L. Schroeder, Cheryl L. Stevens, Jayalakshmi Sridhar

Faculty and Staff Publications

he human epidermal growth factor receptor 2 (HER2) is a member of the erbB class of tyrosine kinase receptors. These proteins are normally expressed at the surface of healthy cells and play critical roles in the signal transduction cascade in a myriad of biochemical pathways responsible for cell growth and differentiation. However, it is widely known that amplification and subsequent overexpression of the HER2 encoding oncogene results in unregulated cell proliferation in an aggressive form of breast cancer known as HER2-positive breast cancer. Existing therapies such as trastuzumab (Herceptin®) and lapatinib (Tyverb/Tykerb®), a monoclonal antibody inhibitor and a dual ...


Identification Of Padi2 As A Potential Breast Cancer Biomarker And Therapeutic Target., John L. Mcelwee, Sunish Mohanan, Obi L. Griffith, Heike C. Breuer, Lynne J. Anguish, Brian D. Cherrington, Ashley M. Palmer, Louise R. Howe, Venkataraman Subramanian, Corey P. Causey, Paul R. Thompson, Joe W. Gray, Scott A. Coonrod Oct 2012

Identification Of Padi2 As A Potential Breast Cancer Biomarker And Therapeutic Target., John L. Mcelwee, Sunish Mohanan, Obi L. Griffith, Heike C. Breuer, Lynne J. Anguish, Brian D. Cherrington, Ashley M. Palmer, Louise R. Howe, Venkataraman Subramanian, Corey P. Causey, Paul R. Thompson, Joe W. Gray, Scott A. Coonrod

Thompson Lab Publications

BACKGROUND: We have recently reported that the expression of peptidylarginine deiminase 2 (PADI2) is regulated by EGF in mammary cancer cells and appears to play a role in the proliferation of normal mammary epithelium; however, the role of PADI2 in the pathogenesis of human breast cancer has yet to be investigated. Thus, the goals of this study were to examine whether PADI2 plays a role in mammary tumor progression, and whether the inhibition of PADI activity has anti-tumor effects.

METHODS: RNA-seq data from a collection of 57 breast cancer cell lines was queried for PADI2 levels, and correlations with known ...


Potential Role For Padi-Mediated Histone Citrullination In Preimplantation Development., Rui Kan, Mei Jin, Venkataraman Subramanian, Corey P. Causey, Paul R. Thompson, Scott A. Coonrod Jun 2012

Potential Role For Padi-Mediated Histone Citrullination In Preimplantation Development., Rui Kan, Mei Jin, Venkataraman Subramanian, Corey P. Causey, Paul R. Thompson, Scott A. Coonrod

Thompson Lab Publications

BACKGROUND: The peptidylarginine deiminases (PADIs) convert positively charged arginine residues to neutrally charged citrulline on protein substrates in a process that is known as citrullination or deimination. Previous reports have documented roles for histone citrullination in chromatin remodeling and gene regulation in several tissue types, however, a potential role for histone citrullination in chromatin-based activities during early embryogenesis has not been investigated.

RESULTS: In the present study, we tested by laser scanning confocal indirect immunofluorescence microscopy whether specific arginine residues on the histone H3 and H4 N-terminal tails (H4R3, H3R2 + 8 + 17, and H3R26) were citrullinated in mouse oocytes and ...


Breast Tumour Initiating Cell Fate Is Regulated By Microenvironmental Cues From An Extracellular Matrix, S. Saha, Pang-Kuo Lo, X. Duan, Hexin Chen, Qian Wang Jan 2012

Breast Tumour Initiating Cell Fate Is Regulated By Microenvironmental Cues From An Extracellular Matrix, S. Saha, Pang-Kuo Lo, X. Duan, Hexin Chen, Qian Wang

Faculty Publications

Cancer stem cells, also known as tumour-initiating cells (TICs), are identified as highly tumorigenic population within tumours and hypothesized to be main regulators in tumour growth, metastasis and relapse. Evidence also suggests that a tumour microenvironment plays a critical role in the development and progression of cancer, by constantly modulating cell–matrix interactions. Scientists have tried to characterize and identify the TIC population but the actual combination of extracellular components in deciphering the fate of TICs has not been explored. The basic unanswered question is the phenotypic stability of this TIC population in a tissue extracellular matrix setting. The in ...


The Reaction Of A Water Soluble Platinum Compound With Methionine And Derivatives, Yueh Ying Liao Apr 2010

The Reaction Of A Water Soluble Platinum Compound With Methionine And Derivatives, Yueh Ying Liao

Masters Theses & Specialist Projects

Water soluble platinum complexes are a recent area of emphasis of cisplatin chemistry. The water soluble complexes could have a reduced toxicity compared with cisplatin. Oxaliplatin, which has an oxalate leaving group, has previously been shown to have less nephro-toxicity and higher water solubility than cisplatin. [Pt(en)(oxalate)] (en = ethylenediamine) has been prepared from Pt(en)Cl2 and silver oxalate. This complex has been reacted with methionine and N-acetylmethionine at different molar ratios. At high Pt: methionine ratios, chelates with the sulfur and nitrogen atoms of the methionine are dominant; at lower Pt: methionine ratios, a bis-methionine product is ...


Echinacea In Infection1–4, Diane F. Birt, Mark P. Widrlechner, Carlie A. Lalone, Lankun Wu, Jaehoon Bae, Avery K S Solco, George A. Kraus, Patricia A. Murphy, Eve S. Wurtele, Qiang Leng, Steven C. Hebert, Wendy J. Maury, Jason P. Price Feb 2008

Echinacea In Infection1–4, Diane F. Birt, Mark P. Widrlechner, Carlie A. Lalone, Lankun Wu, Jaehoon Bae, Avery K S Solco, George A. Kraus, Patricia A. Murphy, Eve S. Wurtele, Qiang Leng, Steven C. Hebert, Wendy J. Maury, Jason P. Price

Genetics, Development and Cell Biology Publications

Ongoing studies have developed strategies for identifying key bioactive compounds and chemical profiles in Echinacea with the goal of improving its human health benefits. Antiviral and antiinflammatory–antipain assays have targeted various classes of chemicals responsible for these activities. Analysis of polar fractions of E. purpurea extracts showed the presence of antiviral activity, with evidence suggesting that polyphenolic compounds other than the known HIV inhibitor, cichoric acid, may be involved. Antiinflammatory activity differed by species, with E. sanguinea having the greatest activity and E. angustifolia, E. pallida, and E. simulata having somewhat less. Fractionation and studies with pure compounds indicate ...