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1.
Further characterization of the binding of human recombinant interleukin 2 to heparin and identification of putative binding sites 总被引:1,自引:1,他引:1
We have previously provided compelling evidence that human recombinant
interleukin 2 (IL-2) binds to the sulfated polysaccharides heparin, highly
sulfated heparan sulfate and fucoidan. Here we show that IL-2 binding is
dependent on heparin chain length, but with fragments as small as 15-mers
retaining binding activity. The addition of exogenous heparin has no effect
on the in vitro biological activity of IL-2. In addition soluble IL-2
receptor alpha and beta polypeptides do not compete with heparin for the
binding of IL-2. IL-2 bound by heparin is still recognized by two IL-2
specific monoclonal antibodies, 3H9 and H2- 8, whose epitopes lie in the
amino terminal region. Murine IL-2 unlike its human counterpart fails to
bind to heparin. Human IL-2 analogs with single amino acid substitutions at
positions Lys43, Thr51, and Gln126 analogs no longer bind to heparin. By
contrast the Arg38Ala analog retains heparin full heparin binding activity.
These experimental findings together with molecular modeling studies
suggest two putative heparin binding sites on human IL-2, one involving
four basic residues, Lys48, Lys49, Lys54, and His55, and the other being a
discontinuous site comprising Lys43, Lys64, Arg81, and Arg83. Neither of
these two clusters is completely conserved in murine IL-2. Overall our data
suggest that the binding of human IL-2 to heparin and heparan sulfate does
not interfere with IL-2/IL-2 receptor interactions. Therefore, binding to
glycosaminoglycan may be a mechanism for retaining the cytokine in an
active form close to its site of secretion in the tissue, thus favoring a
paracrine role for IL-2.
相似文献
2.
Uxmal and Tulum are two important Mayan sites in the Yucatan peninsula. The buildings are mainly composed of limestone and grey/black discoloration is seen on exposed walls and copious greenish biofilms on inner walls. The principal microorganisms detected on interior walls at both Uxmal and Tulum were cyanobacteria; heterotrophic bacteria and filamentous fungi were also present. A dark‐pigmented mitosporic fungus and Bacillus cereus, both isolated from Uxmal, were shown to be acidogenic in laboratory cultures. Cyanobacteria belonging to rock‐degrading genera Synechocystis and Gloeocapsa were identified at both sites. Surface analysis previously showed that calcium ions were present in the biofilms on buildings at Uxmal and Tulum, suggesting the deposition of biosolubilized stone. Apart from their potential to degrade the substrate, the coccoid cyanobacteria supply organic nutrients for bacteria and fungi, which can produce organic acids, further increasing stone degradation. 相似文献
3.
Novak V Yang AC Lepicovsky L Goldberger AL Lipsitz LA Peng CK 《Biomedical engineering online》2004,3(1):39
Background
This study evaluated the effects of stroke on regulation of cerebral blood flow in response to fluctuations in systemic blood pressure (BP). The autoregulatory dynamics are difficult to assess because of the nonstationarity and nonlinearity of the component signals.Methods
We studied 15 normotensive, 20 hypertensive and 15 minor stroke subjects (48.0 ± 1.3 years). BP and blood flow velocities (BFV) from middle cerebral arteries (MCA) were measured during the Valsalva maneuver (VM) using transcranial Doppler ultrasound.Results
A new technique, multimodal pressure-flow analysis (MMPF), was implemented to analyze these short, nonstationary signals. MMPF analysis decomposes complex BP and BFV signals into multiple empirical modes, representing their instantaneous frequency-amplitude modulation. The empirical mode corresponding to the VM BP profile was used to construct the continuous phase diagram and to identify the minimum and maximum values from the residual BP (BPR) and BFV (BFVR) signals. The BP-BFV phase shift was calculated as the difference between the phase corresponding to the BPR and BFVR minimum (maximum) values. BP-BFV phase shifts were significantly different between groups. In the normotensive group, the BFVR minimum and maximum preceded the BPR minimum and maximum, respectively, leading to large positive values of BP-BFV shifts.Conclusion
In the stroke and hypertensive groups, the resulting BP-BFV phase shift was significantly smaller compared to the normotensive group. A standard autoregulation index did not differentiate the groups. The MMPF method enables evaluation of autoregulatory dynamics based on instantaneous BP-BFV phase analysis. Regulation of BP-BFV dynamics is altered with hypertension and after stroke, rendering blood flow dependent on blood pressure.4.
Danilo E Xavier Renata C Picão Raquel Girardello Lorena CC Fehlberg Ana C Gales 《BMC microbiology》2010,10(1):217
Background
Multi-drug efflux pumps have been increasingly recognized as a major component of resistance in P. aeruginosa. We have investigated the expression level of efflux systems among clinical isolates of P. aeruginosa, regardless of their antimicrobial susceptibility profile. 相似文献5.
Anna CC Aguiar Ananda C Cunha Isabela Penna Ceravolo Regina A Correia Gon?alves Arildo JB Oliveira Antoniana Ursine Krettli 《Memórias do Instituto Oswaldo Cruz》2015,110(7):906-913
Several species of Aspidosperma plants are used to treat diseases in
the tropics, including Aspidosperma ramiflorum, which acts against
leishmaniasis, an activity that is experimentally confirmed. The species, known as
guatambu-yellow, yellow peroba,
coffee-peroba andmatiambu, grows in the Atlantic
Forest of Brazil in the South to the Southeast regions. Through a guided
biofractionation of A. ramiflorum extracts, the plant activity
against Plasmodium falciparum was evaluated in vitro for toxicity
towards human hepatoma G2 cells, normal monkey kidney cells and nonimmortalised human
monocytes isolated from peripheral blood. Six of the seven extracts tested were
active at low doses (half-maximal drug inhibitory concentration < 3.8 µg/mL); the
aqueous extract was inactive. Overall, the plant extracts and the purified compounds
displayed low toxicity in vitro. A nonsoluble extract fraction and one purified
alkaloid isositsirikine (compound 5) displayed high selectivity indexes (SI) (= 56
and 113, respectively), whereas compounds 2 and 3 were toxic (SI < 10). The
structure, activity and low toxicity of isositsirikine in vitro are described here
for the first time in A. ramiflorum, but only the neutral and
precipitate plant fractions were tested for activity, which caused up to 53%
parasitaemia inhibition of Plasmodium berghei in mice with
blood-induced malaria. This plant species is likely to be useful in the further
development of an antimalarial drug, but its pharmacological evaluation is still
required. 相似文献
6.
Rodrigo A. Fuentealba Maria Udan Shaughn Bell Iga Wegorzewska Jieya Shao Marc I. Diamond Conrad C. Weihl Robert H. Baloh 《The Journal of biological chemistry》2010,285(34):26304-26314
The identification of pathologic TDP-43 aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, followed by the discovery of dominantly inherited point mutations in TDP-43 in familial ALS, have been critical insights into the mechanism of these untreatable neurodegenerative diseases. However, the biochemical basis of TDP-43 aggregation and the mechanism of how mutations in TDP-43 lead to disease remain enigmatic. In efforts to understand how TDP-43 alters its cellular localization in response to proteotoxic stress, we found that TDP-43 is sequestered into polyglutamine aggregates. Furthermore, we found that binding to polyglutamine aggregates requires a previously uncharacterized glutamine/asparagine (Q/N)-rich region in the C-terminal domain of TDP-43. Sequestration into polyglutamine aggregates causes TDP-43 to be cleared from the nucleus and become detergent-insoluble. Finally, we observed that sequestration into polyglutamine aggregates led to loss of TDP-43-mediated splicing in the nucleus and that polyglutamine toxicity could be partially rescued by increasing expression of TDP-43. These data indicate pathologic sequestration into polyglutamine aggregates, and loss of nuclear TDP-43 function may play an unexpected role in polyglutamine disease pathogenesis. Furthermore, as Q/N domains have a strong tendency to self-aggregate and in some cases can function as prions, the identification of a Q/N domain in TDP-43 has important implications for the mechanism of pathologic aggregation of TDP-43 in ALS and other neurodegenerative diseases. 相似文献
7.
8.
Stephan P. Frankenfeld Leonardo P. Oliveira Victor H. Ortenzi Igor CC. Rego-Monteiro Elen A. Chaves Andrea C. Ferreira Alvaro C. Leit?o Denise P. Carvalho Rodrigo S. Fortunato 《PloS one》2014,9(9)
The abuse of anabolic androgenic steroids (AAS) may cause side effects in several tissues. Oxidative stress is linked to the pathophysiology of most of these alterations, being involved in fibrosis, cellular proliferation, tumorigenesis, amongst others. Thus, the aim of this study was to determine the impact of supraphysiological doses of nandrolone decanoate (DECA) on the redox balance of liver, heart and kidney. Wistar male rats were treated with intramuscular injections of vehicle or DECA (1 mg.100 g−1 body weight) once a week for 8 weeks. The activity and mRNA levels of NADPH Oxidase (NOX), and the activity of catalase, glutathione peroxidase (GPx) and total superoxide dismutase (SOD), as well as the reduced thiol and carbonyl residue proteins, were measured in liver, heart and kidney. DECA treatment increased NOX activity in heart and liver, but NOX2 mRNA levels were only increased in heart. Liver catalase and SOD activities were decreased in the DECA-treated group, but only catalase activity was decreased in the kidney. No differences were detected in GPx activity. Thiol residues were decreased in the liver and kidney of treated animals in comparison to the control group, while carbonyl residues were increased in the kidney after the treatment. Taken together, our results show that chronically administered DECA is able to disrupt the cellular redox balance, leading to an oxidative stress state. 相似文献
9.
DA strain and other members of the TO subgroup of Theiler's murine encephalomyelitis virus (TMEV) produce a chronic demyelinating disease in which the virus persists but has a restricted expression. We previously reported that TO subgroup strains, in addition to synthesizing the picornaviral polyprotein, use an alternative initiation codon just downstream from the polyprotein's AUG to translate an 18-kDa protein called L* that is out of frame with the polyprotein (H. H. Chen et al., Nat. Med. 1:927-931, 1995; W. P. Kong and R. P. Roos, J. Virol. 65:3395-3399, 1991). L* is critically important for virus persistence and the induction of the demyelinating disease (Chen et al., 1995; G. D. Ghadge et al. J. Virol. 72:8605-8612, 1998). We have proposed that variations in the amount of translation initiation from the L* AUG versus the polyprotein AUG may occur in different cell types and therefore affect the degree of expression of viral capsid proteins. We now demonstrate that ribosomal translation initiation at the polyprotein's initiation codon affects initiation at the L* AUG, suggesting that ribosomes land at the polyprotein's initiation codon before scanning downstream and initiating at the L* AUG. We also find that the viral 5' untranslated region affects utilization of the L* AUG. Surprisingly, mutant DA cDNAs were found to be infectious despite the presence of mutations of the polyprotein initiation codon or placement of a stop codon upstream of the L* AUG in the polyprotein's reading frame. Sequencing studies showed that these viruses had a second site mutation, converting the reading frame of L* into the polyprotein's reading frame; the results suggest that translation of the polyprotein during infection of these mutant viruses can be initiated at the L* AUG. These data are important in our understanding of translation initiation of TMEV and other RNAs that contain an internal ribosome entry site. 相似文献
10.
VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy
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Chrisovalantis Papadopoulos Philipp Kirchner Monika Bug Daniel Grum Lisa Koerver Nina Schulze Robert Poehler Alina Dressler Sven Fengler Khalid Arhzaouy Vanda Lux Michael Ehrmann Conrad C Weihl Hemmo Meyer 《The EMBO journal》2017,36(2):135-150
Rupture of endosomes and lysosomes is a major cellular stress condition leading to cell death and degeneration. Here, we identified an essential role for the ubiquitin‐directed AAA‐ATPase, p97, in the clearance of damaged lysosomes by autophagy. Upon damage, p97 translocates to lysosomes and there cooperates with a distinct set of cofactors including UBXD1, PLAA, and the deubiquitinating enzyme YOD1, which we term ELDR components for Endo‐Lysosomal Damage Response. Together, they act downstream of K63‐linked ubiquitination and p62 recruitment, and selectively remove K48‐linked ubiquitin conjugates from a subpopulation of damaged lysosomes to promote autophagosome formation. Lysosomal clearance is also compromised in MEFs harboring a p97 mutation that causes inclusion body myopathy and neurodegeneration, and damaged lysosomes accumulate in affected patient tissue carrying the mutation. Moreover, we show that p97 helps clear late endosomes/lysosomes ruptured by endocytosed tau fibrils. Thus, our data reveal an important mechanism of how p97 maintains lysosomal homeostasis, and implicate the pathway as a modulator of degenerative diseases. 相似文献