En dot he li ns (ET) are a group of en do ge nous pep ti des, whi ch ha ve a stro ng and lo ng-las ti ng va so con stric ti ve eff e ct. Three iso for ms of en dot he li ns co ded by three diff e re nt ge nes ha ve been iden ti fi ed to da te. En dot he li n-1 (ET-1) is the mo st po te nt va so con stric ti ve age nt cur ren tly iden ti fi ed, and it was ori gi nal ly iso la ted and cha rac te ri zed from the cul tu re me dia of aor tic en dot he lial cel ls. Two ot her iso for ms, named en dot he li n-2 (ET-2) and en dot he li n-3 (ET-3), we re sub sequen tly iden ti fi ed, alo ng wi th struc tu ral ho mo lo gues iso la ted from the ve nom of Ac trac ta pis en gad den sis known as the sa ra fo toxi ns. The bio lo gi cal eff ec ts of en dot he lin pro duc tion are de ter mi ned via ac ti va tion of one or two G-pro tein coup led re cep to rs, en dot helin re cep to rs A (ETRA) and B (ET R B1 and ET R B2). Re cen tly en dot he lin re cep tor C (ETRC) was dis co ve red, howe ver, its fun ctio ns and dis tri bu tion sti ll re main un clear. The eff ec ts me dia ted by ET-1 via ETRA are va so con stric tion, bron cho con stric tion and sec re tion of al dos te ro ne. Ago nis ts re la ted to the ET R B1 ac ti va tion cau se va so di la ta tion by sti mu la ti ng NO, PGI2 and en dot he liu m-de ri ved hyper po la ri zi ng fac tor (EDHF). In con tra st, coup li ng to ET R B2 causes va so con stric tion. In vol ve me nt of ET has been de mon stra ted in the pat hop hysio lo gy of cer tain di sor de rs. In this re view, we dis cu ss the physio lo gi cal and pat hop hysio lo gi cal ro le of en dot he liu m-de ri ved ET-1, the phar ma co lo gy of its two re cep to rs, fo cu si ng on the ro le of ET-1 in the deve lop me nt of so me pat hop hysio lo gi cal con di tio ns. Key wor ds: en dot he lin 1; en dot he lin re cep tor; en dot he lin re cep tor an ta go ni st; en dot he lin con ver ti ng en zyme Review In tro duc tionEn dot he li ns we re fi r st iden ti fi ed in a pa per by Yanagisawa et al. as po te nt va soac ti ve pep ti des, regu la ti ng vas cu lar to ne, blood pres su re, ce ll pro li fera tion and hor mo ne pro duc tion (1). Di ver si ty in bio lo gi cal fun ction be ca me ra pid ly ap pa re nt wi th ma ny ot her ro les for the se pep ti des now des cribed (2,3). To date, three iso for ms of en dot he li ns (ET-1, ET-2 and ET-3) co ded by three diff e re nt genes ha ve been iden ti fi ed (2). The hu man ge ne for ET-1 is lo ca ted on chro mo so me 6, the ET-2 ge ne is on the fi r st chro mo so me, and ET-3 ge ne is on chromo so me 20 (2). The pla sma con cen tra tion of ET-1 in adul ts is nor mal ly be tween 0.4-8.1 pg/mL (4). Ea ch iso fo rm, howe ver, shows a tis sue type-depen de nt pat te rn of expres sion. ET-1 is wi de ly expres sed in en dot he lial cel ls, vas cu lar smoo th mus cles, cen tral ner vous system (CNS), and reproduc ti ve tis sues. Le ve ls of ET-2 are hi gh in the in testi ne and kid ney, whe reas ET-3 is main ly expres sed in the brain (5,6).En dot he lin bio synthe sis star ts fr...
Background: Reliable high-throughput microbial pathogen identification in human urine samples is crucial for patients with cystitis symptoms. Currently employed methods are time-consuming and could lead to unnecessary or inadequate antibiotic treatment. Purpose of this study was to assess the potential of mass spectrometry for uropathogen identification from a native urine sample. Methods: In total, 16 urine samples having more than 10 5 CFU/mL were collected from clinical outpatients. These samples were analysed using standard urine culture methods, followed by 16S rRNA gene sequencing serving as control and here described culture-independent MALDI-TOF/TOF MS method being tested. Results: Here we present advantages and disadvantages of bottom-up proteomics, using MALDI-TOF/TOF tandem mass spectrometry, for culture-independent identification of uropathogens (e.g. directly from urine samples). The direct approach provided reliable identification of bacteria at the genus level in monobacterial samples. Taxonomic identifications obtained by proteomics were compared both to standard urine culture test used in clinics and genomic test based on 16S rRNA sequencing. Conclusions: Our findings indicate that mass spectrometry has great potential as a reliable high-throughput tool for microbial pathogen identification in human urine samples. In this case, the MALDI-TOF/TOF, was used as an analytical tool for the determination of bacteria in urine samples, and the results obtained emphasize high importance of storage conditions and sample preparation method impacting reliability of MS2 data analysis. The proposed method is simple enough to be utilized in existing clinical settings and is highly suitable for suspected single organism infectious etiologies. Further research is required in order to identify pathogens in polymicrobial urine samples.
A decade ago, when the Human Microbiome Project was starting, urinary tract (UT) was not included because the bladder and urine were considered to be sterile. Today, we are presented with evidence that healthy UT possesses native microbiota and any major event disrupting its “equilibrium” can impact the host also. This dysbiosis often leads to cystitis symptoms, which is the most frequent lower UT complaint, especially among women. Cystitis is one of the most common causes of antimicrobial drugs prescriptions in primary and secondary care and an important contributor to the problem of antimicrobial resistance. Despite this fact, we still have trouble distinguishing whether the primary cause of majority of cystitis cases is a single pathogen overgrowth, or a systemic disorder affecting entire UT microbiota. There are relatively few studies monitoring changes and dynamics of UT microbiota in cystitis patients, making this field of research still an unknown. In this study variations to the UT microbiota of cystitis patients were identified and microbial dynamics has been modeled. The microbial genetic profile of urine samples from 28 patients was analyzed by 16S rDNA Illumina sequencing and bioinformatics analysis. One patient with bacterial cystitis symptoms was prescribed therapy based on national guideline recommendations on antibacterial treatment of urinary tract infections (UTI) and UT microbiota change was monitored by 16S rDNA sequencing on 24 h basis during the entire therapy duration. The results of sequencing implied that a particular class of bacteria is associated with majority of cystitis cases in this study. The contributing role of this class of bacteria – Gammaproteobacteria, was further predicted by generalized Lotka-Volterra modeling (gLVM). Longitudinal microbiota insight obtained from a single patient under prescribed antimicrobial therapy revealed rapid and extensive changes in microbial composition and emphasized the need for current guidelines revision in regards to therapy duration. Models based on gLVM indicated protective role of two taxonomic classes of bacteria, Actinobacteria and Bacteroidia class, which appear to actively suppress pathogen overgrowth.
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