Matthias Majetschak

Loyola University Chicago, Chicago, Illinois, United States

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Publications (106)320.2 Total impact

  • Matthias Majetschak
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    ABSTRACT: Ubiquitin is a post-translational protein modifier and plays essential roles in all aspects of biology. Although the discovery of ubiquitin introduced this highly conserved protein as a molecule with extracellular actions, the identification of ubiquitin as the ATP-dependent proteolysis factor 1 has focused subsequent research on its important intracellular functions. Little attention has since been paid to its role outside of the cell. During recent years, multiple observations suggest that extracellular ubiquitin can modulate immune responses and that exogenous ubiquitin has therapeutic potential to attenuate exuberant inflammation and organ injury. These observations have not been integrated into a comprehensive assessment of its possible role as an endogenous immune modulator. This review recapitulates the current knowledge about extracellular ubiquitin and discusses an emerging facet of its role in biology during infectious and noninfectious inflammation. The synopsis of these data along with the recent identification of ubiquitin as a CXCR4 agonist suggest that extracellular ubiquitin may have pleiotropic roles in the immune system and functions as an endogenous opponent of DAMPs. Functions of extracellular ubiquitin could constitute an evolutionary conserved control mechanism aimed to balance the immune response and prevent exuberant inflammation. Further characterization of its mechanism of action and cellular signaling pathways is expected to provide novel insights into the regulation of the innate immune response and opportunities for therapeutic interventions.
    Journal of leukocyte biology 02/2011; 89(2):205-19. DOI:10.1189/jlb.0510316 · 4.29 Impact Factor
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    Vikas Saini · Jacqueline Romero · Adriano Marchese · Matthias Majetschak
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    ABSTRACT: Utilizing the human monocyte/macrophage cell line THP1, we recently identified extracellular ubiquitin as an endogenous agonist of the G protein-coupled receptor CXC chemokine receptor (CXCR) 4. Because receptor binding and signaling properties of extracellular ubiquitin have not been evaluated in primary human leukocytes, we analyzed its binding characteristics and subsequent Ca(2+) signaling in freshly isolated human B cells, T cells and monocytes. Ubiquitin binding shows typical receptor binding characteristics and promotes intracellular Ca(2+) flux within seconds in all three cell populations. The K(d) for the ubiquitin receptor interaction in freshly isolated human monocytes is consistent with the affinity of the ubiquitin CXCR4 interaction that we reported for THP1 cells. As detected in THP1 cells previously, the ubiquitin induced Ca(2+) flux can be attenuated with a phospholipase C inhibitor in all primary leukocyte cultures. Our observations further support the finding that ubiquitin is a CXCR4 agonist and demonstrate that extracellular ubiquitin induces physiological relevant signaling events in primary human leukocytes. Although the exact mechanism of the ubiquitin CXCR4 interaction, its receptor selectivity and subsequent signaling events remain to be determined, our findings identify a novel and unexpected biological role of extracellular ubiquitin as an endogenous immune modulator.
    Communicative & integrative biology 11/2010; 3(6):608-10. DOI:10.4161/cib.3.6.13375
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    ABSTRACT: Recently, we provided evidence for a possible role of the cardiac proteasome during ischemia, suggesting that a subset of 26S proteasomes is a cell-destructive protease, which is activated as the cellular energy supply declines. Although proteasome inhibition during cold ischemia (CI) reduced injury of ischemic hearts, it remains unknown whether these beneficial effects are maintained throughout reperfusion, and thus, may have pathophysiological relevance. Therefore, we evaluated the effects of epoxomicin (specific proteasome inhibitor) in a rat heterotopic heart transplantation model. Donor hearts were arrested with University of Wisconsin solution (UW) and stored for 12 h/24 h in 4 °C UW±epoxomicin, followed by transplantation. Efficacy of epoxomicin was confirmed by proteasome peptidase activity measurements and analyses of myocardial ubiquitin pools. After 12hCI, troponin I content of UW was lower with epoxomicin. Although all hearts after 12hCI started beating spontaneously, addition of epoxomicin to UW during CI reduced cardiac edema and preserved the ultrastructural integrity of the post-ischemic cardiomyocyte. After 24hCI in UW±epoxomicin, hearts did not regain contractility. When hearts were perfused with epoxomicin during cardioplegia, the cardiac proteasome was inhibited immediately, all of these hearts started beating after 24hCI in UW plus epoxomicin and cardiac edema and myocardial ultrastructure were comparable to hearts after 12hCI. Epoxomicin did not affect markers of lipid peroxidation or neutrophil infiltration in post-ischemic hearts. These data further support the concept that proteasome activation during ischemia is of pathophysiological relevance and suggest proteasome inhibition as a promising approach to improve organ preservation strategies.
    Biochemical and Biophysical Research Communications 09/2010; 401(4):548-53. DOI:10.1016/j.bbrc.2010.09.093 · 2.30 Impact Factor
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    Vikas Saini · Adriano Marchese · Matthias Majetschak
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    ABSTRACT: Ubiquitin is one of the most highly conserved proteins in eukaryotes and plays major biological roles as a post-translational protein modifier. Ubiquitin is also a natural constituent of plasma, and several lines of evidence suggest that extracellular ubiquitin is an immune modulator with anti-inflammatory properties. In addition, ubiquitin treatment has been shown to limit inflammation and reduce organ injury in various disease models and species in vivo. However, its mechanism of action is unknown. Here we show that extracellular ubiquitin is a natural CXC chemokine receptor 4 (CXCR4 and CD184) agonist. Extracellular ubiquitin promotes intracellular Ca2+ flux and reduces cAMP levels through a G protein-coupled receptor that signals via a Gαi/o protein in THP1 cells. Toll-like receptor 4 stimulation reduces ubiquitin-binding sites, which enabled identification of four Gαi/o PCRs as ubiquitin receptor candidates. Overexpression of candidate genes in HEK293 cells, gene silencing in THP1 cells, competition binding, and signaling studies with the CXCR4 agonist stromal cell-derived factor-1α (chemokine (CXC motif) ligand 12) and inhibitor AMD3100 identify CXCR4 as a functional ubiquitin receptor. Our finding uncovers a fundamentally new aspect of the role of ubiquitin in biology, has implications for the understanding of CXCR4-mediated events, and is expected to facilitate development of new therapeutic avenues for a variety of diseases.
    Journal of Biological Chemistry 03/2010; 285(20):15566-76. DOI:10.1074/jbc.M110.103408 · 4.57 Impact Factor
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    ABSTRACT: The objective of the study is to test whether circulating proteasomes are increased in burn patients and to assess whether possible alterations are associated with severity of injury, organ failure, and/or clinically relevant outcomes. In this study, plasma was obtained from burn patients on days 0 (admission, n = 50), 1 (n = 36), 3 (n = 35), 5 (n = 28), 7 (n=34), and 30 (n = 10) (controls: 40 volunteers). The 20S/26S proteasome levels were measured by enzyme-linked immunosorbent assay. Proteasome peptidase activity was assessed using a chymotryptic-like peptide substrate in combination with epoxomicin (specific proteasome inhibitor). Percentage of TBSA burned, presence of inhalation injury, development of sepsis/multiple organ failure, and sequential organ failure assessment scores were documented. On admission, plasma proteasome activity was higher in patients than in controls (P = .011). 26S proteasomes were not detectable. The 20S proteasome concentrations (median [25th/75th percentile]) peaked on day 0 (673 [399/1566] ng/mL; control: 195 [149/249] ng/mL, P < .001), gradually declined within 7 days, and fully returned to baseline at day 30 (116.5 [78/196] ng/mL). Elevated 20S proteasomes were associated with the presence of inhalation injury and correlated linearly with %TBSA in patients without inhalation injury. Initial 20S proteasome concentrations discriminated the presence of inhalation injury in patients with (sensitivity 0.88 and specificity 0.71) and without (sensitivity 0.83 and specificity 0.97) cutaneous burns but did not discriminate sepsis/multiple organ failure development or survival. Circulating 20S proteasome is a biomarker of tissue damage. The 20S proteasome plasma concentrations in patients with burns and/or inhalation injury are unlikely to predict outcomes but may be useful for the diagnosis of inhalation injury.
    Journal of burn care & research: official publication of the American Burn Association 02/2010; 31(2):243-50. DOI:10.1097/BCR.0b013e3181d0f55d · 1.43 Impact Factor
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    ABSTRACT: Molecular mechanisms leading to myocardial injury during warm or cold ischemia are insufficiently understood. Although proteasomes are thought to contribute to myocardial ischemia-reperfusion injury, their roles during the ischemic period remain elusive. Because donor hearts are commonly exposed to prolonged global cold ischemia prior to cardiac transplantation, we evaluated the role and regulation of the proteasome during cold ischemic storage of rat hearts in context of the myocardial ATP content. When measured at the actual tissue ATP concentration, cardiac proteasome peptidase activity increased by 225% as ATP declined during cold ischemic storage of hearts in University of Wisconsin (UW) solution for up to 48h. Addition of the specific proteasome inhibitor epoxomicin to the UW solution inhibited proteasome activity in the cardiac extracts, significantly reduced edema formation and preserved the ultrastructural integrity of the cardiomyocyte. Utilizing purified 20S/26S proteasome enzyme preparations, we demonstrate that this activation can be attributed to a subset of 26S proteasomes which are stable at ATP concentrations far below physiological levels, that ATP negatively regulates its activity and that maximal activation occurs at ATP concentrations in the low mumol/L range. These data suggest that proteasome activation is a pathophysiologically relevant mechanism of cold ischemic myocardial injury. A subset of 26S proteasomes appears to be a cell-destructive protease that is activated as ATP levels decline. Proteasome inhibition during cold ischemia preserves the ultrastructural integrity of the cardiomyocyte.
    Biochemical and Biophysical Research Communications 12/2009; 390(4):1136-41. DOI:10.1016/j.bbrc.2009.10.067 · 2.30 Impact Factor
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    ABSTRACT: The purpose of this study was to determine whether 26S proteasome is detectable in human bronchoalveolar lavage fluid (BALF) and whether burn and inhalation injury is accompanied by changes in BALF proteasome content or activity. BALF was obtained on hospital admission from 28 patients with burn and inhalation injury (controls: 10 healthy volunteers). Proteasome concentrations were quantified by enzyme-linked immunosorbent assay, and their native molecular mass was assessed by gel filtration. Proteasome peptidase activity was measured using a chymotryptic-like peptide substrate in combination with epoxomicin (specific proteasome inhibitor). BALF protein was increased in patients (P<.001) and correlated positively with the degree of inhalation injury. The 20S/26S proteasomes were detectable in all BALF by enzyme-linked immunosorbent assay. Gel filtration confirmed the presence of intact 20S and 26S proteasome that was stable without soluble ATP/Mg. In all BALF chymotryptic-like activity was detectable and could be inhibited with epoxomicin by 60 to 70% (P<.01). Absolute amounts of 20S/26S proteasomes and proteasome activity were increased in patients (P<.001 for all). The relative BALF composition after injury was characterized by increased concentrations of 20S proteasome/mg protein (P=.0034 vs volunteers), decreased concentrations of 26S proteasome/mg protein (P=.041 vs volunteers), and reduced specific proteasome activity (P=.044 vs volunteers). The 26S proteasome per milligram and specific proteasome activity were even further reduced in patients who developed ventilator-associated pneumonia (P=.045 and P=.03 vs patients without ventilator-associated pneumonia). This study supports the novel concept that extracellular proteasomes could play a pathophysiological role in the injured lung and suggests that insufficient proteasome function may increase susceptibility for pulmonary complications.
    Journal of burn care & research: official publication of the American Burn Association 10/2009; 30(6):948-56. DOI:10.1097/BCR.0b013e3181c07f37 · 1.43 Impact Factor
  • Q Geng · J Romero · V Saini · M B Patel · M Majetschak
    Vox Sanguinis 10/2009; 97(3):273-4. DOI:10.1111/j.1423-0410.2009.001210.x · 2.80 Impact Factor
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    ABSTRACT: Several lines of evidence suggest that the proteasome contributes to ischemia-reperfusion injury (I-RI) of organs. Although I-RI contributes to multiple disease processes in the lung, the regulation of proteasome activities during pulmonary I-RI is unknown. Thus, the authors performed a pilot study to define time-related changes of lung proteasome peptidase activities and to evaluate if possible alterations correspond to morphological and functional consequences of I-RI using a rat model. Animals underwent 120 minutes of unilateral lung ischemia. Ischemic and contralateral lungs were harvested at multiple time points for up to 168 hours of reperfusion (I-R30 min-168 h). Chymotryptic-like (CT-L) and tryptic-like (T-L) proteasome peptidase activities were measured in lung extracts. An early I-R-associated inactivation of proteasome activities paralleled impairment of oxygenation, edema formation, and degree of histopathology, and resolved with restoration of function within 24 to 72 hours. Although functional and histomorphological baseline conditions were still not fully achieved at I-R168h, proteasome activities increased continuously 1.4-fold (CT-L) and 5.7-fold (T-L) until I-R168h. Apparent K(M) values for the CT-L/T-L substrates were not influenced by I-R. This pilot study establishes an initial link between proteasome activities and physiological relevant consequences of lung I-RI, and further points towards a possible role of the proteasome during the postischemic tissue repair process.
    Experimental Lung Research 06/2009; 35(4):284-95. DOI:10.1080/01902140802668823 · 1.41 Impact Factor
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    ABSTRACT: Recent observations suggest the presence of 20S proteasomes (20S) in the lung epithelial lining fluid. However, the physiological relevance of 20S in the alveolar space and possible contribution to disease processes are unknown. Thus, we evaluated whether extracellular proteasomes could have a pathophysiological role in the injured lung using a rat model of lung contusion (LC). Bronchoalveolar lavage fluids (BALF) were obtained at various time points for up to 168 h after LC or sham procedure. Enzyme activities, ELISA and Western blots indicated enzymatically active 20S, the 19S subunit Rpt5 and ubiquitin in BALF. 20S and ubiquitin increased significantly after LC, peaked at 24 h and normalized within 168 h. Mg(2+)/ATP-dependent peptidase activities were detectable 6-24 h after LC. BALF after LC also contained ubiquitin-protein-ligase activity. Addition of Mg(2+)/ATP to BALF after LC led to significant proteolysis and could be prevented with epoxomicin and EDTA. These data suggest for the first time that the Mg(2+)/ATP-dependent 26S proteasome complex exists outside the cell, is released into the lung epithelial lining fluid after LC and contributes to the proteolysis of the bulk of protein in the alveolar space of the injured lung. We infer that proteasome complexes may have a pathophysiological role during lung edema clearance.
    Physiological research / Academia Scientiarum Bohemoslovaca 01/2009; 58(3):363-72. · 1.29 Impact Factor
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    ABSTRACT: The associations of circulating 20S proteasomes (c20S) with clinical and serologic disease indices in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) are unknown. We present the initial report that c20S levels are elevated in MCTD and correlate with clinically relevant changes in disease activity in SLE and MCTD.
    Clinical and vaccine Immunology: CVI 10/2008; 15(9):1489-93. DOI:10.1128/CVI.00187-08 · 2.47 Impact Factor
  • Matthias Majetschak · Luis T Sorell
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    ABSTRACT: The ubiquitin-proteasome pathway plays major roles in all aspects of biology and contributes to various disease processes. Due to the lack of assays that permit proteasome quantification in crude cell extracts, its concentrations in health and disease states as well as the relationship between free 20S core particles (20S) and 26S proteasomes (26S) that consist of 20S singly or doubly capped with 19S regulator complexes (19S) are still largely unknown. Thus, we established a 20S ELISA for the detection of total 20S, and developed a specific 26S ELISA. The latter utilizes the ATP/Mg2+ requirement for 26S stability and shows no cross-reactivity with 20S. Both ELISAs demonstrate intra- and inter-assay variations between 4.9% and 9.4% and recoveries of 105%-109%. Initial application showed that maintenance of the physiological ATP concentration is essential for accurate 26S assessment. Measurements in erythrocyte and peripheral blood mononuclear cell (PBMNC) extracts revealed that the concentrations of 20S were 15-fold and of 26S 130-fold higher in PBMNCs, and suggested that the 26S is the physiological relevant form in PBMNCs (molar ratio 20S/26S 1.1+/-0.4), whereas free 20S is predominant in erythrocytes (molar ratio 20S/26S: 11.5+/-4.0). During storage of packed red blood cell units spontaneous 26S assembly was detectable while specific 26S enzyme activities decreased, indicating that these assays are useful to assess the dynamic interplay between the 20S and 19S. During 26S assay development we further observed that solid phase affinity immobilization (SPAI) of 26S enables quantification of its dissociation into 20S and 19S. Utilizing the SPAI-26S method in combination with the non-hydrolyzable analogue ATP[beta,gamma-NH] and Mg2+ depletion, we provided evidence that ATP binding without hydrolysis via a high affinity binding site (Kd 4-6 microM) as well as ATP binding with hydrolysis via a low affinity binding site that is virtually not saturable under physiological conditions is required to fully stabilize the 26S. Application of these immunological techniques is expected to facilitate proteasome analyses, and may help to better understand its roles in health and disease processes.
    Journal of Immunological Methods 06/2008; 334(1-2):91-103. DOI:10.1016/j.jim.2008.02.004 · 1.82 Impact Factor
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    ABSTRACT: To determine whether ubiquitin treatment modulates the lung cytokine response and attenuates lung ischemia-reperfusion injury. Randomized and blinded treatment of unilateral lung ischemia-reperfusion injury in a research laboratory. Twenty anesthetized and mechanically ventilated Brown Norway rats. Unilateral clamping of the left lung for 90 mins followed by 60 mins of reperfusion. Intravenous administration of 1.5 mg/kg of ubiquitin (n = 10) or albumin (n = 10) 5 mins before reperfusion. Blood pressure was measured by the tail-cuff method. Oxygenation via the ischemic lung was assessed by PaO2 measurements after right lung exclusion. Wet-to-dry weight ratios of the ischemic lungs were determined gravimetrically. Tissue homogenates (n = 5/group) were prepared from ischemic lungs at the end of reperfusion and assayed for malondialdehyde in combination with 4-hydroxyalkenals to assess lipid peroxidation, and for a panel of 22 cytokines/chemokines using a multiplex assay. Ubiquitin serum levels were determined by enzyme-linked immunosorbent assay.All animals were hemodynamically stable during the experimental procedure. Ubiquitin serum levels (mean +/- SD) were 650 +/- 40 ng/mL in controls and 1206 +/- 181 ng/mL in the ubiquitin treatment group at the end of the experiment. PaO2 after right lung exclusion was 45 (32-72) mm Hg with albumin and 61 (range, 36-132) mm Hg with ubiquitin (p = .0185). Wet-to-dry weight ratios of the injured lungs were 8.7 (range, 5.5-19.1) and 7.8 (range, 5.7-8.3) in the albumin and ubiquitin groups, respectively (p = .035). Malondialdehyde/4-hydroxyalkenals concentrations (mean +/- SD, nmol/mg protein) were 2.5 +/- 0.4 with ubiquitin and 3.0 +/- 0.3 with albumin (p > .05). Concentrations of the interleukins 4, 10, and 13 were significantly increased in lung homogenates after ubiquitin treatment (p < .05). Ubiquitin treatment enhances the Th2 cytokine response in postischemic lungs during reperfusion, reduces lung edema formation, and improves pulmonary function during lung ischemia-reperfusion injury. This study further defines ubiquitin's anti-inflammatory properties, and suggests that it could be used therapeutically to improve function of postischemic lungs.
    Critical care medicine 04/2008; 36(3):979-82. DOI:10.1097/CCM.0B013E318164E417 · 6.31 Impact Factor
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    ABSTRACT: Recent data suggest that ubiquitin (Ub) is systemically released after trauma, has pleiotropic effects on host defense mechanisms, and that Ub administration reduces fluid shifts into tissues during inflammation. Ub release after burns (B) has not been studied and its association with injury severity and outcome after blunt trauma (T) is unknown. Thus, we evaluated Ubs association with injury severity and outcomes after B and T. Injury severity was assessed with the Injury Severity Score (ISS) in T and burn size (% total body surface area, %TBSA) in B. A total of 129 T (ISS: 26 +/- 13) and 55 B (46% +/- 18% TBSA) were observed for sepsis/multiple organ failure (MOF) and survival. In B, sequential organ failure assessment scores were documented daily. Fifty volunteers served as controls (C) Ub serum levels were measured on day 0 (admission), 1, 3, 5, and 7 by enzyme-linked immunosorbent assay. Data were analyzed using bivariate or partial correlation analyses, t test, and analysis of variance with Tukey post-hoc test for multiple comparisons (two-tailed p < 0.05). Ub was significantly elevated in patients. Peak levels (ng/mL) were detectable on day 0 (C: 118 +/- 76; T: 359 +/- 205; B: 573 +/- 331) and increased with increased ISS, %TBSA, and presence of inhalation injury. In T, Ub normalized by day 3, but remained elevated in B. In B, Ub correlated significantly negative with sequential organ failure assessment scores (r: -0.143; p = 0.0147), sepsis/MOF development (r: -0.363; p = 0.001), and survival (r: -0.231; p = 0.009). Compared with B who recovered uneventfully, Ub levels were significantly lower on days 1 to 7 and on days 5/7 in B who developed sepsis/MOF or died, respectively. Ub concentrations reflect the extent of tissue damage. Along with Ubs previously described anti- inflammatory properties, this study suggests that its systemic release is protective, that burn patients who develop sepsis/MOF have a relative Ub deficiency and that Ub could play an important role during the physiologic response to burn injury.
    The Journal of trauma 04/2008; 64(3):586-96; discussion 596-8. DOI:10.1097/TA.0b013e3181641bc5 · 2.96 Impact Factor
  • Matthias Majetschak · Mayur B Patel · Luis T Sorell · Carlos Liotta · Sen Li · Si M Pham
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    ABSTRACT: Recent observations suggest that the ubiquitin-proteasome system (UPS) contributes to the pathophysiology of myocardial ischemia-reperfusion injury. Since its regulation during cold ischemia-reperfusion is unknown, we evaluated the cardiac UPS in a model of heart transplantation in mice. Cardiac ubiquitylation rates and ubiquitin-protein conjugates increased after 3h of cold ischemia (CI) and normalized post-transplant. 20S proteasome content and proteasome peptidase activities were unchanged after CI. 4h/24h post-transplant 20S proteasome concentrations decreased and chymotryptic-like but not tryptic-like proteasome peptidase activity was inactivated. Epoxomicin sensitivity of the proteasome increased 5.7-fold during CI and normalized 4h/24h post-transplant. This was accompanied by the disappearance of a 13.5 kDa-ubiquitin-conjugate during CI that could be attenuated by addition of epoxomicin to the preservation fluid. We conclude that substrate specificity of the proteasome changes during cold ischemia and that proteasome inhibition preserves the physiological ubiquitin-protein conjugate pool during organ preservation. Reduced proteasome activity during reperfusion is caused by a decrease in proteasome content and enzyme inhibition.
    Biochemical and Biophysical Research Communications 02/2008; 365(4):882-8. DOI:10.1016/j.bbrc.2007.11.092 · 2.30 Impact Factor
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    ABSTRACT: Recent data suggest that ubiquitin has anti-inflammatory properties and therapeutic potential after severe trauma and brain injuries. However, direct evidence for its neuroprotective effects has not yet been provided. We hypothesized that ubiquitin treatment is neuroprotective, and thus reduces brain edema formation and cortical contusion volume after closed traumatic brain injuries. To test this hypothesis, a focal cortical contusion was induced using a controlled cortical impact (CCI) model in Sprague-Dawley rats. Animals (n = 27) were randomized to either 1.5 mg/kg ubiquitin or vehicle (placebo) intravenously within 5 min after CCI. Blood pressure, arterial blood gases (ABG) and intracranial pressure (ICP) were monitored. Ubiquitin serum and cerebrospinal fluid levels were measured by ELISA. Brain water content was quantified gravimetrically after 24 h and cerebral contusion volume was determined in triphenyltetrazolium-chloride stained brains after 7 days. All animals recovered to normal activity. ICP and cerebral perfusion pressures were normal at the end of the observation period. Ubiquitin serum and CSF levels at 24 h and 7 days after CCI were similar in both groups. With ubiquitin brain water content of the injured hemisphere was slightly lower (n = 6/group; 79.97 +/- 0.29% vs. 81.11 +/- 0.52%; p = 0.08). Cortical contusion volume was significantly lower with ubiquitin (n = 7-8/group; 32.88 +/- 2.1 mm(3) vs. 43.96 +/- 4.56 mm(3); p = 0.025). This study shows that ubiquitin treatment after brain injury has direct neuroprotective effects, as demonstrated by improved brain morphology 7 days after brain injury. In connection with its beneficial effects in our previous studies, these data suggest ubiquitin as a promising candidate protein therapeutic for the treatment of brain injuries.
    Journal of Neurotrauma 10/2007; 24(9):1529-35. DOI:10.1089/neu.2007.0306 · 3.71 Impact Factor
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    M B Patel · M Majetschak
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    ABSTRACT: The ubiquitin-proteasome pathway fulfills major biological functions, but its physiologic tissue distribution and the interrelationship between pathway component activities and ubiquitin pools are unknown. Therefore, we analyzed free and conjugated ubiquitin, ubiquitin-protein ligation rates (UbPL) and chymotryptic- and tryptic-like proteasome peptidase activities in porcine skeletal muscle, heart, lung, liver, spleen and kidney (n=5 each). There were considerable differences between tissues (p<0.05 for all parameters). Lung and spleen showed high levels of free and conjugated ubiquitin and high UbPL. Proteasome activities were highest in kidney and heart. There were linear relationships between tryptic-like and chymotryptic-like proteasome peptidase activities (r(2) = 0.624, p<0.001) and between free and conjugated ubiquitin tissue levels (r(2) = 0.623, p<0.001). Tissue levels of free and conjugated ubiquitin correlated linear with UbPL (p<0.005), but they were not correlated with proteasome peptidase activities. The results suggest that tissue ubiquitin pools are tightly regulated and indicate a constant proportion of conjugated ubiquitin. They further support the hypothesis that ubiquitin-protein ligase systems, and probably deubiquitylating enzymes, are key regulators of ubiquitin homeostasis. The detected differences are suggestive of tissue-specific roles of ubiquitin-proteasome pathway components. Besides the known importance of the ubiquitin proteasome pathway in heart, kidney and the immune system, the results suggest the lung as another organ in which ubiquitin proteasome pathway components may also significantly contribute to disease processes.
    Physiological research / Academia Scientiarum Bohemoslovaca 02/2007; 56(3):341-50. · 1.29 Impact Factor
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    M Seiffert · D Gosenca · N Ponelies · N Ising · M B Patel · U Obertacke · M Majetschak
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    ABSTRACT: Metabolic consequences of direct muscle trauma are insufficiently defined. Their effects on the ubiquitin-proteasome pathway (UPP) of protein degradation in human skeletal muscles are as yet unknown. Thus, we investigated whether the UPP is involved in the metabolic response evoked in directly traumatized human skeletal muscles. Biopsies were obtained from contused muscles after fractures and from normal muscles during elective implant removal (control). As estimated by western blot analyses, concentrations of free ubiquitin and ubiquitin protein conjugates were similar in extracts from injured and uninjured muscles. Ubiquitin protein ligation rates were reduced after injury (1.5+/-0.2 vs. 1.0+/-0.15 fkat/microg; p=0.04). Chymotryptic-, tryptic- and caspase-like proteasome peptidase activities (total activity minus activity in the presence of proteasome inhibitors) increased significantly after trauma (p=0.04 - 0.001). Significant increases in total chymotryptic- and caspase-like activities were attributable to proteasome activation. Our results extend the possible role of the UPP in muscle wasting to direct muscle trauma. They further suggest that the effects of direct mechanical trauma are not limited to the proteasome and imply that ubiquitin protein ligase systems are also involved. Based on the potential role of the UPP in systemic diseases, it might also be a therapeutic target to influence muscle loss in critically ill blunt trauma patients, in which large proportions of muscle are exposed to direct trauma.
    Physiological research / Academia Scientiarum Bohemoslovaca 02/2007; 56(2):227-33. · 1.29 Impact Factor
  • M. Majetschak · M. B. Patel · C. Liotta · S. Li · L. T. Busby · S. M. Pham
    The Journal of Heart and Lung Transplantation 02/2007; 26(2). DOI:10.1016/j.healun.2006.11.074 · 6.65 Impact Factor
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    M B Patel · S A Earle · M Majetschak
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    ABSTRACT: Based on the biological significance of the ubiquitin-proteasome pathway (UPP) and its potential role during sepsis, burns and ischemia-reperfusion injury, we hypothesized that the systemic response to traumatic shock (TS) is accompanied by tissue-specific UPP alterations. Therefore, we studied tissue ubiquitin pools, chymotryptic- and tryptic-like proteasome peptidase activities and ubiquitin-protein ligation (UbPL) rates in skeletal muscle, heart, lung, liver, spleen and kidney using a clinically relevant porcine model (bilateral femur fracture/hemorrhage followed by fluid resuscitation). TS induced a systemic reduction of tissue-specific high molecular mass ubiquitin-protein conjugates (>50 kDa). Free ubiquitin was unaffected. The dynamic organ patterns of ubiquitin pools paralleled the typical physiological response to TS and resuscitation. Reduction of ubiquitin-protein conjugates was most pronounced in heart and lung (p<0.05 vs. control) and accompanied by significant increases in proteasome peptidase and UbPL activities in these organs. Unlike all other tissues, spleen proteasome peptidase and UbPL activities were significantly reduced 10 h after TS. These findings support the concept that the UPP could play an important role in regulation of cell functions during the early whole-body response to TS. The UPP might be a therapeutic target to improve the metabolic care after TS, particularly in the heart, lung, and spleen.
    Physiological research / Academia Scientiarum Bohemoslovaca 01/2007; 56(5):547-57. · 1.29 Impact Factor

Publication Stats

2k Citations
320.20 Total Impact Points


  • 2009–2014
    • Loyola University Chicago
      • • Department of Surgery
      • • Department of Molecular Pharmacology and Therapeutics
      Chicago, Illinois, United States
  • 1996–2012
    • University Hospital Essen
      • Klinik für Unfallchirurgie
      Essen, North Rhine-Westphalia, Germany
  • 2009–2011
    • Loyola University
      New Orleans, Louisiana, United States
  • 2010
    • Ludwig-Maximilians-University of Munich
      • Department of Anatomy III - Cell Biology
      München, Bavaria, Germany
    • Loyola University Medical Center
      • Burn and Shock Trauma Institute
      Maywood, Illinois, United States
  • 2005–2008
    • University of Miami
      كورال غيبلز، فلوريدا, Florida, United States
  • 2004–2008
    • University of Miami Miller School of Medicine
      • • Division of Trauma and Surgical Critical Care
      • • Ryder Trauma Center
      Miami, Florida, United States
  • 2002–2005
    • Universität Mannheim
      Mannheim, Baden-Württemberg, Germany
  • 2000–2005
    • Universität Heidelberg
      • Department of Orthopedics and Traumatology
      Heidelburg, Baden-Württemberg, Germany