ABSTRACT
In cholinergic urticaria (CholU), small, itchy wheals are induced by exercise or passive warming and reduced sweating has been reported. Despite the described reduced muscarinic receptor expression, sweat duct obstruction, or sweat allergy, the underlying pathomechanisms are not well understood. To gain further insights, we collected skin biopsies before and after pulse-controlled ergometry and sweat after sauna provocation from CholU patients as well as healthy controls. CholU patients displayed partially severely reduced local sweating, yet total sweat volume was unaltered. However, sweat electrolyte composition was altered, with increased K+ concentration in CholU patients. Formalin-fixed, paraffin-embedded biopsies were stained to explore sweat leakage and tight junction protein expression. Dermcidin staining was not found outside the sweat glands. In the secretory coils of sweat glands, the distribution of claudin-3 and -10b as well as occludin was altered, but the zonula occludens-1 location was unchanged. In all, dermcidin and tight junction protein staining suggests an intact barrier with reduced sweat production capability in CholU patients. For future studies, an ex vivo skin model for quantification of sweat secretion was established, in which sweat secretion could be pharmacologically stimulated or blocked. This ex vivo model will be used to further investigate sweat gland function in CholU patients and decipher the underlying pathomechanism(s).
Subject(s)
Chronic Inducible Urticaria , Sweat Glands , Sweat , Tight Junctions , Sweat/chemistry , Tight Junctions/metabolism , Sweat Glands/metabolism , Ergometry , Tight Junction Proteins/metabolism , Chronic Inducible Urticaria/metabolism , Chronic Inducible Urticaria/pathology , Humans , Male , Female , Adult , Receptor, Muscarinic M3/metabolism , Biopsy, NeedleABSTRACT
α-Methylene-γ-lactones are present in â¼3% of known natural products, and compounds comprising this motif display a range of biological activities. However, this reactive lactone limits informed structure-activity relationships for these bioactive molecules. Herein, we describe chemically tuning the electrophilicity of the α-methylene-γ-lactone by replacement with an α-methylene-γ-lactam. Guaianolide analogues having α-methylene-γ-lactams are synthesized using the allenic Pauson-Khand reaction. Substitution of the lactam nitrogen with electronically different groups affords diverse thiol reactivity. Cellular NF-κB inhibition assays for these lactams were benchmarked against parthenolide and a synthetic α-methylene-γ-lactone showing a positive correlation between thiol reactivity and bioactivity. Cytotoxicity assays show good correlation at the outer limits of thiol reactivity but less so for compounds with intermediate reactivity. A La assay to detect reactive molecules by nuclear magnetic resonance and mass spectrometry peptide sequencing assays with the La antigen protein demonstrate that lactam analogues with muted nonspecific thiol reactivities constitute a better electrophile for rational chemical probe and therapeutic molecule design.
Subject(s)
Cysteamine/chemistry , Lactams/pharmacology , Sesquiterpenes, Guaiane/pharmacology , A549 Cells , Animals , Chlorocebus aethiops , HEK293 Cells , Humans , Lactams/chemical synthesis , Lactams/toxicity , NF-kappa B/metabolism , Proof of Concept Study , Sesquiterpenes, Guaiane/chemical synthesis , Sesquiterpenes, Guaiane/toxicity , Signal Transduction/drug effects , Vero CellsABSTRACT
PURPOSE: Retethering after transection of a tight filum terminale (TFT) deemed to be a rare and usually only years after initial surgery occurring complication. Possible perioperative factors that might influence the retethering rate or help to allow a prognostic risk assessment are still poorly investigated. The aim of this study was to analyze our patient cohort who underwent a TFT transection by assessing clinical outcome, retethering rate, and pre- and postoperative MRI studies. METHODS: All consecutive patients undergoing transection of a TFT from January 2011 to December 2018 were evaluated. Inclusion criteria were defined as exclusive TFT intervention and a minimum follow up period of 1 year. Epidemiological data, treatment modalities, complication characteristics, and MRI studies were recorded and analyzed. RESULTS: A total of 58 patients met our inclusion criteria. The retethering rate in our patient cohort was 5.2% (3/58); one of the three patients developed two episodes of a retethering. Patients with an unchanged conus level, no improvement in the syringomyelia, and an unchanged thickness of the spinal cord postoperatively seem to have a significant higher risk to develop a retethering episode in the follow-up. CONCLUSION: Retethering after transection of the filum terminale did occur more often than expected. Certain existing factors on the routine postoperative MR images may help to identify patients with an increased likelihood to develop a retethering episode. These results may contribute to improve the follow-up for patients after transection of a TFT and may facilitate adequate treatment.
Subject(s)
Cauda Equina , Neural Tube Defects , Cauda Equina/diagnostic imaging , Cauda Equina/surgery , Humans , Magnetic Resonance Imaging , Neural Tube Defects/diagnostic imaging , Neural Tube Defects/surgery , Reoperation , Retrospective StudiesABSTRACT
A transfer of chirality in an intramolecular Rh(I)-catalyzed allenic Pauson-Khand reaction (APKR) to access tetrahydroazulenones, tetrahydrocyclopenta[c]azepinones and dihydrocyclopenta[c]oxepinones enantioselectively (22-99% ee) is described. The substitution pattern of the allene affected the transfer of chiral information. Complete transfer of chirality was obtained for all trisubstituted allenes, but loss of chiral information was observed for disubstituted allenes. This work constitutes the first demonstration of a transfer of chiral information from an allene to the 5-position of a cyclopentenone using a cyclocarbonylation reaction. The absolute configuration of the corresponding cyclocarbonylation product was also established, something that is rarely done.
Subject(s)
Alkadienes/chemistry , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/chemical synthesis , Cyclopentanes/chemistry , Rhodium/chemistry , Catalysis , Cyclization , Molecular Structure , StereoisomerismABSTRACT
Cyclocarbonylation of α-methylene butyrolactone-containing allene-ynes affords 6,12-guaianolide ring systems. Incorporation of the α-methylene butyrolactone early in a synthetic sequence is rare for reactivity reasons; however, this moiety proves to be beneficial to the allenic Pauson-Khand reaction. The three double bonds and the ketone in the resulting 5-7-5 ring system bear significant differences in their reactivity and are ideally positioned for synthetic application to 6,12-guaianolides and analogs.
Subject(s)
4-Butyrolactone/chemistry , Alkadienes/chemistry , Alkynes/chemistry , Sesquiterpenes, Guaiane/chemical synthesis , 4-Butyrolactone/analogs & derivatives , Catalysis , Combinatorial Chemistry Techniques , Molecular Structure , Sesquiterpenes, Guaiane/chemistryABSTRACT
A series of 22-hydroxyacuminatine analogs was prepared by using different Friedländer condensations. Several of the new compounds were tested for antiproliferative activity on cancer cell lines and for topoisomerase I inhibitory activity.
