101 results match your criteria 8701 nucleotides


Essential requirement for JPT2 in NAADP-evoked Ca signaling.

Sci Signal 2021 03 23;14(675). Epub 2021 Mar 23.

Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger that releases Ca from acidic organelles through the activation of two-pore channels (TPCs) to regulate endolysosomal trafficking events. NAADP action is mediated by NAADP-binding protein(s) of unknown identity that confer NAADP sensitivity to TPCs. Here, we used a "clickable" NAADP-based photoprobe to isolate human NAADP-binding proteins and identified Jupiter microtubule-associated homolog 2 (JPT2) as a TPC accessory protein required for endogenous NAADP-evoked Ca signaling. Read More

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Chemo-enzymatic synthesis of adenine substituted nicotinic acid adenine dinucleotide phosphate (NAADP) analogs.

Bioorg Med Chem 2021 01 1;30:115901. Epub 2020 Dec 1.

Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, 3000 Arlington Avenue, Toledo, OH 43614, United States. Electronic address:

Nicotinamide adenine dinucleotide phosphate (NADP) is an indispensable metabolic co-substrate and nicotinic acid adenine dinucleotide phosphate (NAADP) is an important Ca releasing intracellular second messenger. Exploration of the NADP and NAADP interactome often requires the synthesis of NADP derivatives substituted on the adenosine nucleoside. The introduction of the 2'-phosphate of NADP makes the synthesis of substituted NADP derivatives difficult. Read More

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January 2021

The synthesis and characterization of a clickable-photoactive NAADP analog active in human cells.

Cell Calcium 2019 11 1;83:102060. Epub 2019 Aug 1.

Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, 3000 Arlington Avenue, Toledo, OH, 43614, United States. Electronic address:

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca mobilizing second messenger which triggers Ca release in both sea urchin egg homogenates and in mammalian cells. The NAADP binding protein has not been identified and the regulation of NAADP mediated Ca release remains controversial. To address this issue, we have synthesized an NAADP analog in which 3-azido-5-azidomethylbenzoic acid is attached to the amino group of 5-(3-aminopropyl)-NAADP to produce an NAADP analog which is both a photoaffinity label and clickable. Read More

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November 2019

5-Azido-8-ethynyl-NAADP: A bifunctional, clickable photoaffinity probe for the identification of NAADP receptors.

Biochim Biophys Acta Mol Cell Res 2019 07 4;1866(7):1180-1188. Epub 2018 Dec 4.

Department of Pharmacology, University of Minnesota Medical School, 312 Church St., Minneapolis, MN 55455-0217, United States of America. Electronic address:

Nicotinic acid adenine dinucleotide phosphate is an evolutionarily conserved second messenger, which mobilizes Ca from acidic stores. The molecular identity of the NAADP receptor has yet to be defined. In pursuit of isolating and identifying NAADP-binding proteins, we synthesized and characterized a bifunctional probe that incorporates both a photoactivatable crosslinking azido moiety at the 5-position of the nicotinic ring and a 'clickable' ethynyl moiety to the 8-adenosyl position in NAADP. Read More

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A Screen Using iPSC-Derived Hepatocytes Reveals NAD as a Potential Treatment for mtDNA Depletion Syndrome.

Cell Rep 2018 11;25(6):1469-1484.e5

Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA. Electronic address:

Patients with mtDNA depletion syndrome 3 (MTDPS3) often die as children from liver failure caused by severe reduction in mtDNA content. The identification of treatments has been impeded by an inability to culture and manipulate MTDPS3 primary hepatocytes. Here we generated DGUOK-deficient hepatocyte-like cells using induced pluripotent stem cells (iPSCs) and used them to identify drugs that could improve mitochondrial ATP production and mitochondrial function. Read More

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November 2018

Current status and strategies of long noncoding RNA research for diabetic cardiomyopathy.

BMC Cardiovasc Disord 2018 10 20;18(1):197. Epub 2018 Oct 20.

Department of Ophthalmology, Stanford School of Medicine, 1651 Page Mill Road, Stanford, CA, 94304, USA.

Long noncoding RNAs (lncRNAs) are endogenous RNA transcripts longer than 200 nucleotides which regulate epigenetically the expression of genes but do not have protein-coding potential. They are emerging as potential key regulators of diabetes mellitus and a variety of cardiovascular diseases. Diabetic cardiomyopathy (DCM) refers to diabetes mellitus-elicited structural and functional abnormalities of the myocardium, beyond that caused by ischemia or hypertension. Read More

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October 2018

Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors.

Int J Cancer 2018 08 30;143(4):886-896. Epub 2018 Mar 30.

Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, RM C4930, 8701 Watertown Plank Rd, Milwaukee, WI, 53226.

Free fatty acid receptor 2 (FFAR2, also named GPR43), is activated by short-chain fatty acids (SCFAs), such as butyrate, that are produced when gut bacteria ferment dietary fiber. FFAR2 has been suggested to regulate colonic inflammation, which is a major risk factor for the development of colon cancer and is also linked to epigenetic dysregulation in colon carcinogenesis. The current study assessed whether FFAR2, acting as an epigenetic regulator, protects against colon carcinogenesis. Read More

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Resveratrol modulates cocaine-induced inhibitory synaptic plasticity in VTA dopamine neurons by inhibiting phosphodiesterases (PDEs).

Sci Rep 2017 Nov 15;7(1):15657. Epub 2017 Nov 15.

Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.

Resveratrol is a natural phytoalexin synthesized by plants, including grapes. It displays a wide range of neuroprotective benefits associated with anti-aging. Recent studies have shown that resveratrol regulates dopaminergic transmission and behavioral effects of drugs of abuse. Read More

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November 2017

Genome Sequence of Grapevine Virus T, a Novel Foveavirus Infecting Grapevine.

Genome Announc 2017 Sep 14;5(37). Epub 2017 Sep 14.

Department of Agricultural Biotechnology, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea

Here, we report the genome sequence of grapevine virus T (GVT), a novel single-stranded RNA virus identified from a transcriptome of grapevine. The genome of GVT is 8,701 nucleotides in length and encodes five open reading frames. GVT is a putative member of the genus in the family . Read More

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September 2017

Teaching the basics of cancer metabolism: Developing antitumor strategies by exploiting the differences between normal and cancer cell metabolism.

Redox Biol 2017 08 13;12:833-842. Epub 2017 Apr 13.

Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, USA. Electronic address:

This review of the basics of cancer metabolism focuses on exploiting the metabolic differences between normal and cancer cells. The first part of the review covers the different metabolic pathways utilized in normal cells to generate cellular energy, or ATP, and the glycolytic intermediates required to build the cellular machinery. The second part of the review discusses aerobic glycolysis, or the Warburg effect, and the metabolic reprogramming involving glycolysis, tricarboxylic acid cycle, and glutaminolysis in the context of developing targeted inhibitors in cancer cells. Read More

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Renal Delivery of Anti-microRNA Oligonucleotides in Rats.

Methods Mol Biol 2017 ;1527:409-419

Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, 8701 Watertown PlankRoad, Milwaukee, WI, 53226, USA.

MicroRNAs are endogenous small, non-protein-coding RNA molecules that play an important role in the regulation of a wide variety of cellular functions and disease processes. A novel role for microRNAs in the development of hypertension and hypertensive tissue injury is emerging in recent studies. Development of hypertension involves multiple organ systems and cannot be modeled in vitro. Read More

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January 2018

Hypothermia in mouse is caused by adenosine A and A receptor agonists and AMP via three distinct mechanisms.

Neuropharmacology 2017 03 30;114:101-113. Epub 2016 Nov 30.

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA. Electronic address:

Small mammals have the ability to enter torpor, a hypothermic, hypometabolic state, allowing impressive energy conservation. Administration of adenosine or adenosine 5'-monophosphate (AMP) can trigger a hypothermic, torpor-like state. We investigated the mechanisms for hypothermia using telemetric monitoring of body temperature in wild type and receptor knock out (Adora1, Adora3) mice. Read More

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Evidence that a threshold of serine/arginine-rich (SR) proteins recruits CFIm to promote rous sarcoma virus mRNA 3' end formation.

Virology 2016 11 4;498:181-191. Epub 2016 Sep 4.

Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Electronic address:

The weak polyadenylation site (PAS) of Rous sarcoma virus (RSV) is activated by the juxtaposition of SR protein binding sites within the spatially separate negative regulator of splicing (NRS) element and the env RNA splicing enhancer (Env enhancer), which are far upstream of the PAS. Juxtaposition occurs by formation of the NRS - 3' ss splicing regulatory complex and is thought to provide a threshold of SR proteins that facilitate long-range stimulation of the PAS. We provide evidence for the threshold model by showing that greater than three synthetic SR protein binding sites are needed to substitute for the Env enhancer, that either the NRS or Env enhancer alone promotes polyadenylation when the distance to the PAS is decreased, and that SR protein binding sites promote binding of the polyadenylation factor cleavage factor I (CFIm) to the weak PAS. Read More

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November 2016

Influence of metabolic dysfunction on cardiac mechanics in decompensated hypertrophy and heart failure.

J Mol Cell Cardiol 2016 05 13;94:162-175. Epub 2016 Apr 13.

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address:

Alterations in energetic state of the myocardium are associated with decompensated heart failure in humans and in animal models. However, the functional consequences of the observed changes in energetic state on mechanical function are not known. The primary aim of the study was to quantify mechanical/energetic coupling in the heart and to determine if energetic dysfunction can contribute to mechanical failure. Read More

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Characterization of Dahl salt-sensitive rats with genetic disruption of the A2B adenosine receptor gene: implications for A2B adenosine receptor signaling during hypertension.

Purinergic Signal 2015 Dec 18;11(4):519-31. Epub 2015 Sep 18.

Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.

The A(2B) adenosine receptor (AR) has emerged as a unique member of the AR family with contrasting roles during acute and chronic disease states. We utilized zinc-finger nuclease technology to create A(2B)AR gene (Adora2b)-disrupted rats on the Dahl salt-sensitive (SS) genetic background. This strategy yielded a rat strain (SS-Adora2b mutant rats) with a 162-base pair in-frame deletion of Adora2b that included the start codon. Read More

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December 2015

Antiproliferative effects of mitochondria-targeted cationic antioxidants and analogs: Role of mitochondrial bioenergetics and energy-sensing mechanism.

Cancer Lett 2015 Aug 21;365(1):96-106. Epub 2015 May 21.

Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Electronic address:

One of the proposed mechanisms for tumor proliferation involves redox signaling mediated by reactive oxygen species such as superoxide and hydrogen peroxide generated at moderate levels. Thus, the antiproliferative and anti-tumor effects of certain antioxidants were attributed to their ability to mitigate intracellular reactive oxygen species (ROS). Recent reports support a role for mitochondrial ROS in stimulating tumor cell proliferation. Read More

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The conserved Trp114 residue of thioredoxin reductase 1 has a redox sensor-like function triggering oligomerization and crosslinking upon oxidative stress related to cell death.

Cell Death Dis 2015 Jan 22;6:e1616. Epub 2015 Jan 22.

Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.

The selenoprotein thioredoxin reductase 1 (TrxR1) has several key roles in cellular redox systems and reductive pathways. Here we discovered that an evolutionarily conserved and surface-exposed tryptophan residue of the enzyme (Trp114) is excessively reactive to oxidation and exerts regulatory functions. The results indicate that it serves as an electron relay communicating with the FAD moiety of the enzyme, and, when oxidized, it facilitates oligomerization of TrxR1 into tetramers and higher multimers of dimers. Read More

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January 2015

Mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide.

Free Radic Biol Med 2015 Jan 29;78:42-55. Epub 2014 Oct 29.

Biotechnology and Bioengineering Center and Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Electronic address:

The thioredoxin system, which consists of a family of proteins, including thioredoxin (Trx), peroxiredoxin (Prx), and thioredoxin reductase (TrxR), plays a critical role in the defense against oxidative stress by removing harmful hydrogen peroxide (H2O2). Specifically, Trx donates electrons to Prx to remove H2O2 and then TrxR maintains the reduced Trx concentration with NADPH as the cofactor. Despite a great deal of kinetic information gathered on the removal of H2O2 by the Trx system from various sources/species, a mechanistic understanding of the associated enzymes is still not available. Read More

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January 2015

Transcriptional inhibition of etv2 expression is essential for embryonic cardiac development.

Dev Biol 2014 Sep 28;393(1):71-83. Epub 2014 Jun 28.

Medical College of Wisconsin, Department of Pediatrics, CRI Developmental Vascular Biology Program, Translational and Biomedical Research Center, CRI C3420, 8701 Watertown Plank Road, P.O. Box 26509, Milwaukee, WI 53226, USA. Electronic address:

E-twenty six variant 2 (Etv2) transcription factor participates in cardiac, vascular-endothelial and blood cell lineage specification decisions during embryonic development. Previous studies have identified genomic elements in the etv2 locus responsible for vascular endothelial cell specification. Using transgenic analysis in zebrafish, we report here an etv2 proximal promoter fragment that prevents transgene misexpression in myocardial progenitor cells. Read More

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September 2014

ExoY from Pseudomonas aeruginosa is a nucleotidyl cyclase with preference for cGMP and cUMP formation.

Biochem Biophys Res Commun 2014 Jul 24;450(1):870-4. Epub 2014 Jun 24.

Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address:

In addition to the well known second messengers cAMP and cGMP, mammalian cells contain the cyclic pyrimidine nucleotides cCMP and cUMP. Soluble guanylyl cyclase and soluble adenylyl cyclase produce all four cNMPs. Several bacterial toxins exploit mammalian cyclic nucleotide signaling. Read More

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Cyclic AMP regulates the migration and invasion potential of human pancreatic cancer cells.

Mol Carcinog 2015 Mar 24;54(3):203-15. Epub 2013 Sep 24.

Department of Microbiology and Molecular Genetics, The Medical College of Wisconsin Cancer Center, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226.

Aggressive dissemination and metastasis of pancreatic ductal adenocarcinoma (PDAC) results in poor prognosis and marked lethality. Rho monomeric G protein levels are increased in pancreatic cancer tissue. As the mechanisms underlying PDAC malignancy are little understood, we investigated the role for cAMP in regulating monomeric G protein regulated invasion and migration of pancreatic cancer cells. Read More

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Spinal muscular atrophy astrocytes exhibit abnormal calcium regulation and reduced growth factor production.

Glia 2013 Sep 10;61(9):1418-1428. Epub 2013 Jul 10.

Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin. 8701 Watertown Plank Rd, Milwaukee, WI 53226.

Spinal muscular atrophy (SMA) is a genetic disorder caused by the deletion of the survival motor neuron 1 (SMN1) gene that leads to loss of motor neurons in the spinal cord. Although motor neurons are selectively lost during SMA pathology, selective replacement of SMN in motor neurons does not lead to full rescue in mouse models. Due to the ubiquitous expression of SMN, it is likely that other cell types besides motor neurons are affected by its disruption and therefore may contribute to disease pathology. Read More

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September 2013

Characterization of the second ion-binding site in the G domain of H-Ras.

Biochemistry 2012 Dec 20;51(48):9638-46. Epub 2012 Nov 20.

Biochemistry Department, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

Ras is a small monomeric GTPase acting as molecular switch in multiple cellular processes. The N-terminal G domain of Ras binds GTP or GDP accompanied by a magnesium ion, which is strictly required for GTPase activity and performs a structural role. Another ion-binding site on the opposite face of the G domain has been recently observed to specifically associate with calcium acetate in the crystal [Buhrman, G. Read More

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December 2012

Type V collagen and protein kinase C η down-regulation in 8701-BC breast cancer cells.

Mol Carcinog 2013 May 27;52(5):348-58. Epub 2011 Dec 27.

Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari, STEMBIO, Università di Palermo, Palermo, Italy.

We previously reported that ductal infiltrating carcinomas (d.i.c. Read More

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Polyamidoamine (PAMAM) dendrimer conjugate specifically activates the A3 adenosine receptor to improve post-ischemic/reperfusion function in isolated mouse hearts.

BMC Pharmacol 2011 Oct 31;11:11. Epub 2011 Oct 31.

Department of Pharmacology/Toxicology and the Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

Background: When stimulated by small molecular agonists, the A3 adenosine receptor (AR) mediates cardioprotective effects without inducing detrimental hemodynamic side effects. We have examined pharmacologically the protective properties of a multivalent dendrimeric conjugate of a nucleoside as a selective multivalent agonist for the mouse A3AR.

Results: A PAMAM dendrimer fully substituted by click chemistry on its peripheral groups with 64 moieties of a nucleoside agonist was shown to be potent and selective in binding to the mouse A3AR and effective in cardioprotection in an isolated mouse heart model of ischemia/reperfusion (I/R) injury. Read More

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October 2011

Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways.

Proc Natl Acad Sci U S A 2011 Oct 11;108(43):17655-60. Epub 2011 Oct 11.

Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 West Watertown Plank Road, Milwaukee, WI 53214, USA.

Chemokines and chemokine receptors are extensively and broadly involved in cancer metastasis. Previously, we demonstrated that epigenetic silencing of the chemokine CXCL12 sensitizes breast and colon cancer cells to endocrine signaling and metastasis to distant tissues. Yet, the precise mechanism whereby CXCL12 production by tumor cells regulates dissemination remains unclear. Read More

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October 2011

Assignments of backbone ¹H, ¹³C and ¹⁵N resonances in H-Ras (1-166) complexed with GppNHp at physiological pH.

Biomol NMR Assign 2012 Apr 4;6(1):91-3. Epub 2011 Aug 4.

Biochemistry Department, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA.

The small GTPase Ras is an important signaling molecule acting as a molecular switch in eukaryotic cells. Recent findings of global conformational exchange and a putative allosteric binding site in the G domain of Ras opened an avenue to understanding novel aspects of Ras function. To facilitate detailed NMR studies of Ras in physiological solution conditions, we performed backbone resonance assignments of Ras bound to slowly hydrolysable GTP mimic, guanosine 5'-[ß, γ-imido]triphosphate at pH 7. Read More

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Characterization of the E506Q and H537A dysfunctional mutants in the E. coli ABC transporter MsbA.

Biochemistry 2011 May 13;50(18):3599-608. Epub 2011 Apr 13.

Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA.

MsbA is a member of the ABC transporter superfamily that is specifically found in Gram-negative bacteria and is homologous to proteins involved in both bacterial and human drug resistance. The E506Q and H537A mutations have been introduced and used for crystallization of other members of the ABC transporter protein family, including BmrA and the ATPase domains MalK, HlyB-NBD, and MJ0796, but have not been previously studied in detail or investigated in the MsbA lipid A exporter. We utilized an array of biochemical and EPR spectroscopy approaches to characterize the local and global effects of these nucleotide binding domain mutations on the E. Read More

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Effects of the L511P and D512G mutations on the Escherichia coli ABC transporter MsbA.

Biochemistry 2011 Apr 8;50(13):2594-602. Epub 2011 Mar 8.

Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.

MsbA is a member of the ABC transporter superfamily and is homologous to ABC transporters linked to multidrug resistance. The nucleotide binding domains (NBDs) of these proteins include conserved motifs that are involved in ATP binding, including conserved SALD residues (D-loop) that are diagnostic in identifying ABC transporters but whose roles have not been identified. Within the D-loop, single point mutations L511P and D512G were discovered by random mutational analysis of MsbA to disrupt protein function in the cell [Polissi, A. Read More

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MnTMPyP, a superoxide dismutase/catalase mimetic, decreases inflammatory indices in ischemic acute kidney injury.

Inflamm Res 2011 Mar 12;60(3):299-307. Epub 2010 Dec 12.

Division of Transplant Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA.

Objective: This study investigates the effect of a superoxide dismutase mimetic, MnTMPyP, on pro- and anti-inflammatory cytokines in acute renal ischemia-reperfusion (IR).

Materials And Treatment: Male Sprague-Dawley rats underwent bilateral clamping of the renal arteries for 45 min followed by 1, 4, or 24 h of reperfusion. A subset of animals was treated with MnTMPyP (5 mg/kg, i. Read More

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