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The New England Journal of Medicine Dec 2016The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain.
METHODS
Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated.
RESULTS
A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19).
CONCLUSIONS
At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216 .).
Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Cardiovascular Diseases; Celecoxib; Cyclooxygenase 2 Inhibitors; Female; Gastrointestinal Diseases; Humans; Ibuprofen; Intention to Treat Analysis; Kidney Diseases; Male; Middle Aged; Naproxen; Risk
PubMed: 27959716
DOI: 10.1056/NEJMoa1611593 -
The Protein Journal Apr 2020Cancers are a great threat to humans. In cancer therapy, surgical removal of the tumor combined with radiotherapy and chemotherapy is the most routine treatment... (Review)
Review
Cancers are a great threat to humans. In cancer therapy, surgical removal of the tumor combined with radiotherapy and chemotherapy is the most routine treatment procedure and usually the most effective. However, radiotherapy and chemotherapy drugs that kill cancer cells efficiently also kill normal cells, thus exhibiting large side effects. Cancer-targeted drugs, which aim to specifically recognize proteins or signaling pathways associated with tumor proliferation and migration, have achieved marked progress in recent years. Azurin is a copper-containing redox protein secreted by Pseudomonas aeruginosa. Azurin and its derived peptide p28 preferentially enter a variety of cancer cells and induce apoptosis or cell cycle arrest. Mechanistic studies revealed that azurin and p28 target the p53 and receptor tyrosine kinase signaling pathways as well as other pathways. Two phase I trials of p28 have been carried out, with findings that p28 is safe and exhibits anticancer activity in both adult and pediatric patients. In this review paper, we provide an up-to-date summary of progress on the anticancer mechanisms and therapeutic strategies for azurin and p28.
Topics: Animals; Antineoplastic Agents; Azurin; Cell Line, Tumor; Clinical Trials, Phase I as Topic; Humans; Neoplasms; Peptides
PubMed: 32180097
DOI: 10.1007/s10930-020-09891-3 -
Cellular and Molecular Life Sciences :... Mar 2015Laccases are phenol oxidases that belong to the family of multi-copper oxidases and the superfamily of cupredoxins. A number of potential industrial applications for... (Review)
Review
Laccases are phenol oxidases that belong to the family of multi-copper oxidases and the superfamily of cupredoxins. A number of potential industrial applications for laccases have led to intensive structure-function studies and an increased amount of crystal structures has been solved. The objective of this review is to summarize and analyze available crystal structures of laccases. The experimental crystallographic data are now easily available from the websites and electron density maps can be used for the interpretation of the structural models. The crystal structures can give valuable insights into the functional mechanisms and may serve as the basis for the development of laccases for industrial applications.
Topics: Azurin; Bacteria; Binding Sites; Copper; Databases, Protein; Laccase; Protein Structure, Tertiary
PubMed: 25586561
DOI: 10.1007/s00018-014-1827-5 -
Pharmaceutics Apr 2018Despite much progress in the diagnosis and treatment of cancer, tumour diseases constitute one of the main reasons of deaths worldwide. The side effects of chemotherapy... (Review)
Review
Despite much progress in the diagnosis and treatment of cancer, tumour diseases constitute one of the main reasons of deaths worldwide. The side effects of chemotherapy and drug resistance of some cancer types belong to the significant current therapeutic problems. Hence, searching for new anticancer substances and medicines are very important. Among them, bacterial proteins and peptides are a promising group of bioactive compounds and potential anticancer drugs. Some of them, including anticancer antibiotics (actinomycin D, bleomycin, doxorubicin, mitomycin C) and diphtheria toxin, are already used in the cancer treatment, while other substances are in clinical trials (e.g., p28, arginine deiminase ADI) or tested in in vitro research. This review shows the current literature data regarding the anticancer activity of proteins and peptides originated from bacteria: antibiotics, bacteriocins, enzymes, nonribosomal peptides (NRPs), toxins and others such as azurin, p28, Entap and Pep27anal2. The special attention was paid to the still poorly understood active substances obtained from the marine sediment bacteria. In total, 37 chemical compounds or groups of compounds with antitumor properties have been described in the present article.
PubMed: 29710857
DOI: 10.3390/pharmaceutics10020054 -
Journal of the American Chemical Society Jul 2016Cupredoxins are electron-transfer proteins that have active sites containing a mononuclear Cu center with an unusual trigonal monopyramidal structure (Type 1 Cu). A...
Cupredoxins are electron-transfer proteins that have active sites containing a mononuclear Cu center with an unusual trigonal monopyramidal structure (Type 1 Cu). A single Cu-Scys bond is present within the trigonal plane that is responsible for its unique physical properties. We demonstrate that a cysteine-containing variant of streptavidin (Sav) can serve as a protein host to model the structure and properties of Type 1 Cu sites. A series of artificial Cu proteins are described that rely on Sav and a series of biotinylated synthetic Cu complexes. Optical and EPR measurements highlight the presence of a Cu-Scys bond, and XRD analysis provides structural evidence. We further provide evidence that changes in the linker between the biotin and Cu complex within the synthetic constructs allows for small changes in the placement of Cu centers within Sav that have dramatic effects on the structural and physical properties of the resulting artificial metalloproteins. These findings highlight the utility of the biotin-Sav technology as an approach for simulating active sites of metalloproteins.
Topics: Azurin; Biotinylation; Catalytic Domain; Copper; Cysteine; Ligands; Streptavidin
PubMed: 27385206
DOI: 10.1021/jacs.6b05428 -
Protein Science : a Publication of the... Dec 2017Azurin secreted by Pseudomonas aeruginosa is an anticancer bacteriocin, which preferentially enters human cancer cells and induces apoptosis or growth inhibition. It... (Review)
Review
Azurin secreted by Pseudomonas aeruginosa is an anticancer bacteriocin, which preferentially enters human cancer cells and induces apoptosis or growth inhibition. It turns out that azurin is a multi-target anticancer agent interfering in the p53 signaling pathway and the non-receptor tyrosine kinases signaling pathway. This suggests that azurin exerts its anticancer activity by interacting with multiple targets and interfering in multiple steps in disease progression. Therefore, azurin could overcome resistance to therapy. Besides azurin, putative bacteriocins that possess functional properties similar to those of azurin have been identified in more bacteria species. A systematic investigation on the anticancer mechanisms of azurin and the azurin-like bacteriocins will provide more and better options in cancer therapy. In this review, we summarize how azurin and the derived peptides hijack key cellular regulators or cell surface receptors to remodel the cellular signaling networks. In particular, we highlight the necessity of determining the structure of azurin/p53 complex and investigating the influence of post-translational modifications on interactions between azurin and p53. Therapeutic applications of azurin and derived peptides are also discussed.
Topics: Animals; Antineoplastic Agents; Azurin; Bacterial Proteins; Cell Line, Tumor; Humans; MCF-7 Cells; Mice; Protein Processing, Post-Translational; Pseudomonas aeruginosa; Signal Transduction; Tumor Suppressor Protein p53
PubMed: 28960574
DOI: 10.1002/pro.3310 -
Frontiers in Oncology 2020Cancer remains a major cause of morbidity and mortality irrespective of the type of conventional chemotherapy. Therefore, there is an urgent need for new and effective... (Review)
Review
Cancer remains a major cause of morbidity and mortality irrespective of the type of conventional chemotherapy. Therefore, there is an urgent need for new and effective anticancer therapeutic agents. Bacterial proteins and their derivative peptides appear as a promising approach for cancer treatment. Several, including an amphipathic, α-helical, 28-amino acid peptide derived from azurin, a 128-amino acid copper-containing redox protein secreted from , show clinical promise in the treatment of adult and pediatric solid tumors. The peptide, p28, is a post-translational, multi-target anticancer agent that preferentially enters a wide variety of solid tumor cells. Mechanistically, after entry, p28 has two major avenues of action. It binds to both wild-type and mutant p53 protein, inhibiting constitutional morphogenic protein 1 (Cop1)-mediated ubiquitination and proteasomal degradation of p53. This results in increased levels of p53, which induce cell-cycle arrest at G2/M and an eventual apoptosis that results in tumor cell shrinkage and death. In addition, p28 also preferentially enters nascent endothelial cells and decreases the phosphorylation of FAK and Akt inhibiting endothelial cell motility and migration. Here, we review the current basic and clinical evidence suggesting the potential of p28 as a cancer therapeutic peptide.
PubMed: 32850408
DOI: 10.3389/fonc.2020.01303 -
Microorganisms Dec 2021Azurin is a bacterial-derived cupredoxin, which is mainly involved in electron transport reactions. Interest in azurin protein has risen in recent years due to its...
Azurin is a bacterial-derived cupredoxin, which is mainly involved in electron transport reactions. Interest in azurin protein has risen in recent years due to its anticancer activity and its possible applications in anticancer therapies. Nevertheless, the attention of the scientific community only focused on the azurin protein found in (, ). In this work, we performed the first comprehensive screening of all the bacterial genomes available in online repositories to assess azurin distribution in the three domains of life. The Azurin coding gene was not detected in the domains Archaea and Eucarya, whereas it was detected in phyla other than , such as , and and a phylogenetic analysis of the retrieved sequences was performed. Observed patchy distribution and phylogenetic data suggest that once it appeared in the bacterial domain, the azurin coding gene was lost in several bacterial phyla and/or anciently horizontally transferred between different phyla, even though a vertical inheritance appeared to be the major force driving the transmission of this gene. Interestingly, a shared conserved domain has been found among azurin members of all the investigated phyla. This domain is already known in as p28 domain and its importance for azurin anticancer activity has been widely explored. These findings may open a new and intriguing perspective in deciphering the azurin anticancer mechanisms and to develop new tools for treating cancer diseases.
PubMed: 35056457
DOI: 10.3390/microorganisms10010009 -
World Journal of Microbiology &... Mar 2019Acidithiobacillus ferrooxidans is a gram-negative, autotrophic and rod-shaped bacterium. It can gain energy through the oxidation of Fe(II) and reduced inorganic sulfur... (Review)
Review
Acidithiobacillus ferrooxidans is a gram-negative, autotrophic and rod-shaped bacterium. It can gain energy through the oxidation of Fe(II) and reduced inorganic sulfur compounds for bacterial growth when oxygen is sufficient. It can be used for bio-leaching and bio-oxidation and contributes to the geobiochemical circulation of metal elements and nutrients in acid mine drainage environments. The iron and sulfur oxidation pathways of A. ferrooxidans play key roles in bacterial growth and survival under extreme circumstances. Here, the electrons transported through the thermodynamically favourable pathway for the reduction to HO (downhill pathway) and against the redox potential gradient reduce to NAD(P)(H) (uphill pathway) during the oxidation of Fe(II) were reviewed, mainly including the electron transport carrier, relevant operon and regulation of its expression. Similar to the electron transfer pathway, the sulfur oxidation pathway of A. ferrooxidans, related genes and operons, sulfur oxidation mechanism and sulfur oxidase system are systematically discussed.
Topics: Acidithiobacillus; Azurin; Biological Transport, Active; Cytochromes c; Dioxygenases; Electron Transport; Electron Transport Complex IV; Gene Expression Regulation, Bacterial; Genes, Bacterial; Hydrolases; Iron; Metabolic Networks and Pathways; Operon; Oxidation-Reduction; Oxidoreductases; Oxidoreductases Acting on Sulfur Group Donors; Oxygen; Sulfur; Sulfur Compounds
PubMed: 30919119
DOI: 10.1007/s11274-019-2632-y -
Journal of Biological Inorganic... Dec 2023Circular permutation (CP) is a technique by which the primary sequence of a protein is rearranged to create new termini. The connectivity of the protein is altered but...
Circular permutation (CP) is a technique by which the primary sequence of a protein is rearranged to create new termini. The connectivity of the protein is altered but the overall protein structure generally remains unperturbed. Understanding the effect of CP can help design robust proteins for numerous applications such as in genetic engineering, optoelectronics, and improving catalytic activity. Studies on different protein topologies showed that CP usually affects protein stability as well as unfolding rates. Though a significant number of proteins contain metals or other cofactors, reports of metalloprotein CPs are rare. Thus, we chose a bacterial metalloprotein, azurin, and its CP within the metal-binding site (cpF114). We studied the stabilities, folding, and unfolding rates of apo- and Zn-bound CP azurin using fluorescence and circular dichroism. The introduced CP had destabilizing effects on the protein. Also, the folding of the Zn-CP protein was much slower than that of the Zn-WT or apo-protein. We compared this study to our previously reported azurin-cpN42, where we had observed an equilibrium and kinetic intermediate. cpF114 exhibits an apparent two-state equilibrium unfolding but has an off-pathway kinetic intermediate. Our study hinted at CP as a method to modify the energy landscape of proteins to alter their folding pathways. WT azurin, being a faster folder, may have evolved to optimize the folding rate of metal-bound protein compared to its CPs, albeit all of them have the same structure and function. Our study underscores that protein sequence and protein termini positions are crucial for metalloproteins. TOC Figure. (Top) Zn-azurin WT structure (PDB code: 1E67) and 2-D topology diagram of Zn-cpF114 azurin. (Bottom) Cartoon diagram representing folding (red arrows) and unfolding (blue arrows) of apo- and Zn- WT and cpF114 azurins. The width of the arrows represents the rate of the corresponding processes.
Topics: Azurin; Protein Folding; Catalytic Domain; Apoproteins; Metals; Circular Dichroism; Kinetics
PubMed: 37957357
DOI: 10.1007/s00775-023-02023-z