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Dive into the research topics where Jacek Hawiger is active.

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Featured researches published by Jacek Hawiger.


Journal of Clinical Investigation | 1983

Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man.

Garret A. FitzGerald; John A. Oates; Jacek Hawiger; R L Maas; L J Roberts nd; John A. Lawson; Alan R. Brash

To assess the pharmacologic effects of aspirin on endogenous prostacyclin and thromboxane biosynthesis, 2,3-dinor-6-keto PGF1 alpha (PGI-M) and 2,3-dinor-thromboxane B2 (Tx-M) were measured in urine by mass spectrometry during continuing administration of aspirin. To define the relationship of aspirin intake to endogenous prostacyclin biosynthesis, sequential urines were initially collected in individuals prior to, during, and subsequent to administration of aspirin. Despite inter- and intra-individual variations, PGI-M excretion was significantly reduced by aspirin. However, full mass spectral identification confirmed continuing prostacyclin biosynthesis during aspirin therapy. Recovery of prostacyclin biosynthesis was incomplete 5 d after drug administration was discontinued. To relate aspirin intake to indices of thromboxane biosynthesis and platelet function, volunteers received 20 mg aspirin daily followed by 2,600 mg aspirin daily, each dose for 7 d in sequential weeks. Increasing aspirin dosage inhibited Tx-M excretion from 70 to 98% of pretreatment control values; platelet TxB2 formation from 4.9 to 0.5% and further inhibited platelet function. An extended study was performed to relate aspirin intake to both thromboxane and prostacyclin generation over a wide range of doses. Aspirin, in the range of 20 to 325 mg/d, resulted in a dose-dependent decline in both Tx-M and PGI-M excretion. At doses of 325-2,600 mg/d Tx-M excretion ranged from 5 to 3% of control values while PGI-M remained at 37-23% of control. 3 d after the last dose of aspirin (2,600 mg/d) mean Tx-M excretion had returned to 85% of control, whereas mean PGI-M remained at 40% of predosing values. Although the platelet aggregation response (Tmax) to ADP ex vivo was inhibited during administration of the lower doses of aspirin the aggregation response returned to control values during the final two weeks of aspirin administration (1,300 and 2,600 mg aspirin/d) despite continued inhibition of thromboxane biosynthesis. These results suggest that although chronic administration of aspirin results in inhibition of endogenous thromboxane and prostacyclin biosynthesis over a wide dose range, inhibition of thromboxane biosynthesis is more selective at 20 than at 2,600 mg aspirin/d. However, despite this, inhibition of platelet function is not maximal at the lower aspirin dosage. Doses of aspirin in excess of 80 mg/d resulted in substantial inhibition of endogenous prostacyclin biosynthesis. Thus, it is unlikely that any dose of aspirin can maximally inhibit thromboxane generation without also reducing endogenous prostacyclin biosynthesis. These results also indicate that recovery of endogenous prostacyclin biosynthesis is delayed following aspirin administration and that the usual effects of aspirin on platelet function ex vivo may be obscured during chronic aspirin administration in man.


Nature Medicine | 2005

Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis

Daewoong Jo; Danya Liu; Shan Yao; Robert D. Collins; Jacek Hawiger

Suppressor of cytokine signaling (SOCS) 3 attenuates proinflammatory signaling mediated by the signal transducer and activator of transcription (STAT) family of proteins. But acute inflammation can occur after exposure to pathogen-derived inducers staphylococcal enterotoxin B (SEB) and lipopolysaccharide (LPS), or the lectin concanavalin A (ConA), suggesting that physiologic levels of SOCS3 are insufficient to stem proinflammatory signaling under pathogenic circumstances. To test this hypothesis, we developed recombinant cell-penetrating forms of SOCS3 (CP-SOCS3) for intracellular delivery to counteract SEB-, LPS- and ConA-induced inflammation. We found that CP-SOCS3 was distributed in multiple organs within 2 h and persisted for at least 8 h in leukocytes and lymphocytes. CP-SOCS3 protected animals from lethal effects of SEB and LPS by reducing production of inflammatory cytokines and attenuating liver apoptosis and hemorrhagic necrosis. It also reduced ConA-induced liver apoptosis. Thus, replenishing the intracellular stores of SOCS3 with CP-SOCS3 effectively suppresses the devastating effects of acute inflammation.


Immunologic Research | 2001

Innate immunity and inflammation: A transcriptional paradigm

Jacek Hawiger

The innate immune response and the process of inflammation are interwoven. Excessive and continuing cytokine production in response to bacterial lipopolysacharides (LPS) or super antigens is a hallmark of the systemic inflammatory response (IR), which can be life-threatening. Dissemination of these bacterial products induces waves of proin flammatory cytokines that cause vascular injury and multiple organ dysfunction. Both LPS and super antigens induce signaling to the nucleus in mononuclear phagocytes and T cells, respectively. These signaling pathways are mediated by NF-κB and other stress-responsive transcription factors (SRTFs), which play a critical role in reprogramming gene expression. The nuclear import of NF-κB allow stranscriptional activation of over 100 genes that encode mediators of inflammatory and immune responses. We have developed a novel method to block nuclear import of NF-κB through cell-permeable peptide transduction in monocytes, macrophages, T lymphocytes, and endothelial cells. Strikingly, a cell-permeable peptide that antagonizes nuclear import of NF-κB and other SRTFs, suppressed the systemic production of proinflammatory cytokines (TNFα and interferon γ) in mice challenged with a lethal dose of LPS, and increased their survival by at least 90%. Thus, systemic inflammatory responses are critically dependent on the transcriptional activation of cytokine genes that are controlled by NF-κB and other SRTFs.


Current Opinion in Chemical Biology | 1999

Noninvasive intracellular delivery of functional peptides and proteins.

Jacek Hawiger

In order to probe intracellular signaling based on interactions of thousands of proteins expressed in the living cell, new methods of noninvasive delivery of functional peptides and proteins to cells have been developed. These include cellular import of peptides and proteins based on the cell-membrane-permeable properties of the hydrophobic region of a signal peptide sequence. The prototypical cell-permeable SN50 peptide, which contains the nuclear localization signal sequence of NK-kappaB p50, has been applied in multiple cell types to block nuclear import of this and other transcription factors. Further developments, including site-specific ligation of bipartite import peptides and production of import-competent recombinant proteins, provide the means for easy and rapid delivery of peptides and proteins to a wide spectrum of cells in order to regulate intracellular pathways involved in adhesion, signaling and trafficking to the nucleus.


Journal of Clinical Investigation | 1982

Thrombin-induced exposure and prostacyclin inhibition of the receptor for factor VIII/von Willebrand factor on human platelets.

T Fujimoto; S Ohara; Jacek Hawiger

The receptor for Factor VIII/von Willebrand factor (F. VIIIVWF) is readily available on circulating platelets. We have found that the stimulation of platelets with traces of thrombin at concentrations that are generated physiologically (0.008 U-0.05 U/ml) induced concentration-dependent binding of 125I-labeled F. VIIIVWF in a steady-state system. The binding induced by thrombin was specific because it was inhibited by a 100-fold molar excess of unlabeled F. VIIIVWF factor, by rabbit monospecific antibody against Factor VIII, and was not inhibited by an excess of fibrinogen or fibronectin. Binding induced by thrombin required metabolically active platelets, in contrast to a system with ristocetin that also prompted binding to glutaraldehyde-treated platelets. The thrombin effects on binding of 125I-F. VIIIVWF was not observed when platelets were washed with EDTA-containing buffers; EDTA and EGTA both inhibited thrombin-induced binding. Platelet membrane glycoproteins were required because enzymatic stripping od them from the platelet surface with chymotrypsin reduced binding 2.5-5.0-fold. Prostacyclin, in the concentration range of 1 to 50 nM, had two distinct effects on the receptor for F. VIIIWVF: (a) it prevented exposure of this receptor when added 10 min before thrombin, and (b) it reversed the binding of 125I-F. VIIIVWF to the platelet receptor when added 30 min after thrombin and the ligand, ie., when binding was at equilibrium. The dual effect of prostacyclin on the receptor for F. VIIIVWF was reproduced by dibutyryl cyclic AMP.


Journal of Biological Chemistry | 1998

The Tax Oncoprotein of Human T-cell Leukemia Virus Type 1 Associates with and Persistently Activates IκB Kinases Containing IKKα and IKKβ

Zhi Liang Chu; Joseph A. DiDonato; Jacek Hawiger; Dean W. Ballard

The Tax oncoprotein of human T-cell leukemia virus type 1 (HTLV1) chronically activates transcription factor NF-κB by a mechanism involving degradation of IκBα, an NF-κB-associated cytoplasmic inhibitor. Tax-induced breakdown of IκBα requires phosphorylation of the inhibitor at Ser-32 and Ser-36, which is also a prerequisite for the transient activation of NF-κB in cytokine-treated T lymphocytes. However, it remained unclear how Tax interfaces with the cellular NF-κB/IκB signaling machinery to generate a chronic rather than a transient NF-κB response. We now demonstrate that Tax associates with cytokine-inducible IκB kinase (IKK) complexes containing catalytic subunits IKKα and IKKβ, which mediate phosphorylation of IκBα at Ser-32 and Ser-36. Unlike their transiently activated counterparts in cytokine-treated cells, Tax-associated forms of IKK are constitutively active in either Tax transfectants or HTLV1-infected T lymphocytes. Moreover, point mutations in Tax that ablate its IKK-binding function also prevent Tax-mediated activation of IKK and NF-κB. Together, these findings suggest that the persistent activation of NF-κB in HTLV1-infected T-cells is mediated by a direct Tax/IKK coupling mechanism.


Biochemical and Biophysical Research Communications | 1982

Localization of a site interacting with human platelet receptor on carboxy-terminal segment of human fibrinogen γ chain

Marek Kloczewiak; Sheila Timmons; Jacek Hawiger

Abstract We report that the 27-residue carboxy-terminal cyanogen bromide fragment of human fibrinogen γ chain inhibits binding of [ 125 I]fibrinogen to human platelet receptors and blocks fibrinogen-mediated aggregation of ADP-treated human platelets. The blocking activity of the peptide was preserved after proteolysis of the isolated peptide with staphylococcal protease to generate a mixture of a dodecapeptide and a pentadecapeptide. Trypsin treatment destroyed blocking activity of the isolated peptide. These results indicate that the site responsible for the interaction of human fibrinogen with the platelet receptor resides in the 27-residue carboxy-terminal region of the γ chain.


Thrombosis Research | 1983

Recognition site for the platelet receptor is present on the 15-residue carboxy-terminal fragment of the γ chain of human fibrinogen and is not involved in the fibrin polymerization reaction

Marek Kloczewiak; Sheila Timmons; Jacek Hawiger

A pentadecapeptide, derived from a staphylococcal protease digest of the 27-residue carboxy-terminal cyanogen bromide fragment of human fibrinogen gamma chain, inhibits binding of 125I-fibrinogen to human platelet receptors and aggregation of platelets induced by ADP and fibrinogen. Amino acid composition and NH2 terminal analysis indicate that the isolated pentadecapeptide corresponds to residues 397 to 411 of the gamma chain. A synthetic peptide also inhibited binding of 125I-fibrinogen and aggregation of platelets. In contrast, the isolated pentadecapeptide and its parent 27-residue fragment lack inhibitory activity toward the polymerization reaction of fibrin monomer. Thus, the site recognizing the platelet receptor encompasses residues 397-411 of the gamma chain of fibrinogen and is distinct from the site(s) involved in polymerization of fibrin monomers.


Journal of Biological Chemistry | 1996

Role of the Nuclear Localization Sequence in Fibroblast Growth Factor-1-stimulated Mitogenic Pathways

Yao-Zhong Lin; SongYi Yao; Jacek Hawiger

Fibroblast growth factor-1 (FGF-1) is a potent mitogen for mesoderm- and neuroectoderm-derived cell types in vitro. However, a mutant FGF-1 with deletion in its nuclear localization sequence (NLS, residues 21-27) is not mitogenic in vitro. We demonstrated that synthetic peptides containing this NLS were able to stimulate DNA synthesis in a FGF receptor-independent manner after they were delivered into living NIH 3T3 cells by a cell-permeable peptide import technique. The stimulation of maximal DNA synthesis by these peptides required the presence of peptides during the entire G phase of the cell cycle. The mitogenic effect was specific for the NLS of FGF-1 because a peptide with double point mutations at lysine residues was inactive in stimulating DNA synthesis. Our results suggest that the NLS plays an important role in the mitogenic pathway initiated by exogenous FGF-1 by its direct involvement in the nuclear transport and signaling of internalized FGF-1.


Current Opinion in Immunology | 1997

Cellular import of functional peptides to block intracellular signaling.

Jacek Hawiger

During the past few years, new approaches to the delivery of functional peptides to cells have been developed to probe intracellular protein-protein interactions. These approaches include a method based on the cell membrane permeability properties of the hydrophobic region of the signal sequence. This method provides easy and rapid delivery of functional peptides to a wide spectrum of cells involved in inflammatory and immune reactions (monocytes, endothelial cells, and T lymphocytes) as well as to NIH 3T3 cells and erythroleukemia HEL cells. The method has been applied to block signaling to the nucleus by transcription factors unclear factor-kappa B, AP-1, and nuclear factor of activated T cells, and to inhibit cell adhesion regulated by the cytoplasmic tails of integrins beta 3 and beta 1. New methods of peptide delivery provide direct access to intracellular proteins involved in adhesion, signaling, and trafficking to the nucleus.

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