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Journal of Cellular Biochemistry Feb 2023Arthrofibrosis, which is characterized by excessive scar tissue and limited motion, can complicate the daily functioning of patients after total knee arthroplasty (TKA)....
Arthrofibrosis, which is characterized by excessive scar tissue and limited motion, can complicate the daily functioning of patients after total knee arthroplasty (TKA). Molecular hallmarks of arthrofibrosis include pathologic accumulation of myofibroblasts and disproportionate collagen deposition. Epigenetic mechanisms, including posttranslation modification of histones, control gene expression and may regulate fibrotic events. This study assessed the role of the bromodomain and extra-terminal (BET) proteins on myofibroblast differentiation. This group of epigenetic regulators recognize acetylated lysines and are targeted by a class of drugs known as BET inhibitors. RNA-seq analysis revealed robust mRNA expression of three BET members (BRD2, BRD3, and BRD4) while the fourth member (BRDT) is not expressed in primary TKA knee outgrowth fibroblasts. RT-qPCR and western blot analyses revealed that BET inhibition with the small molecule JQ1 impairs TGFβ1-induced expression of ACTA2, a key myofibroblast marker, in primary outgrowth knee fibroblasts. Similarly, JQ1 administration also reduced COL3A1 mRNA levels and collagen deposition as monitored by picrosirius red staining. Interestingly, the inhibitory effects of JQ1 on ACTA2 mRNA and protein expression, as well as COL3A1 expression and collagen deposition, were paralleled by siRNA-mediated depletion of BRD4. Together, these data reveal that BRD4-mediated epigenetic events support TGFβ1-mediated myofibroblast differentiation and collagen deposition as seen in arthrofibrosis. To our knowledge, these are the first studies that assess epigenetic regulators and their downstream events in the context of arthrofibrosis. Future studies may reveal clinical utility for drugs that target epigenetic pathways, specifically BET proteins, in the prevention and treatment of arthrofibrosis.
Topics: Humans; Azepines; Cell Cycle Proteins; Collagen; Epigenesis, Genetic; Fibroblasts; Knee; Myofibroblasts; Nuclear Proteins; RNA, Messenger; Transcription Factors
PubMed: 36648754
DOI: 10.1002/jcb.30368 -
Journal of Nuclear Medicine : Official... Dec 2017The purpose of this study was to assess safety, biodistribution, and radiation dosimetry in humans for the highly selective σ-1 receptor PET agent...
The purpose of this study was to assess safety, biodistribution, and radiation dosimetry in humans for the highly selective σ-1 receptor PET agent F-6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[]thiazol-2(3H)-one (F-FTC-146). Ten healthy volunteers (5 women, 5 men; age ± SD, 34.3 ± 6.5 y) were recruited, and written informed consent was obtained from all participants. Series of whole-body PET/MRI examinations were acquired for up to 3 h after injection (357.2 ± 48.8 MBq). Blood samples were collected, and standard vital signs (heart rate, pulse oximetry, and body temperature) were monitored at regular intervals. Regions of interest were delineated, time-activity curves were calculated, and organ uptake and dosimetry were estimated. All subjects tolerated the PET/MRI examination well, and no adverse reactions to F-FTC-146 were reported. High accumulation of F-FTC-146 was observed in σ-1 receptor-dense organs such as the pancreas and spleen, moderate uptake in the brain and myocardium, and low uptake in bone and muscle. High uptake was also observed in the kidneys and bladder, indicating renal tracer clearance. The effective dose of F-FTC-146 was 0.0259 ± 0.0034 mSv/MBq (range, 0.0215-0.0301 mSv/MBq). First-in-human studies with clinical-grade F-FTC-146 were successful. Injection of F-FTC-146 is safe, and absorbed doses are acceptable. The potential of F-FTC-146 as an imaging agent for a variety of neuroinflammatory diseases is currently under investigation.
Topics: Adult; Azepines; Benzothiazoles; Female; Healthy Volunteers; Humans; Isotope Labeling; Magnetic Resonance Imaging; Male; Multimodal Imaging; Radiometry; Radiopharmaceuticals; Receptors, sigma; Tissue Distribution; Whole Body Imaging; Sigma-1 Receptor
PubMed: 28572487
DOI: 10.2967/jnumed.117.192641 -
Journal of Clinical Hypertension... Jun 2019
Topics: Azepines; Blood Pressure; Humans; Hypertension; Sleep Initiation and Maintenance Disorders; Triazoles
PubMed: 30874341
DOI: 10.1111/jch.13519 -
Organic Letters Apr 2020(-)-Aurantioclavine (), which contains a characteristic seven-membered ring fused to an indole ring, belongs to the azepinoindole class of fungal clavine alkaloids. Here...
(-)-Aurantioclavine (), which contains a characteristic seven-membered ring fused to an indole ring, belongs to the azepinoindole class of fungal clavine alkaloids. Here we show that starting from a 4-dimethylallyl-l-tryptophan precursor, a flavin adenine dinucleotide (FAD)-binding oxidase and a catalase-like heme-containing protein are involved in the biosynthesis of . The function of these two enzymes was characterized by heterologous expression, characterization, and deuterium labeling experiments.
Topics: Azepines; Biocatalysis; Ergot Alkaloids; Indoles; Molecular Conformation; Oxidoreductases; Penicillium; Tryptophan
PubMed: 32243182
DOI: 10.1021/acs.orglett.0c01132 -
Journal of Gastroenterology and... May 2022Elobixibat is a locally acting inhibitor of the ileal bile acid transporter. We compared bile acid metabolism between healthy subjects and patients with chronic...
BACKGROUND AND AIM
Elobixibat is a locally acting inhibitor of the ileal bile acid transporter. We compared bile acid metabolism between healthy subjects and patients with chronic constipation and assessed changes in the bile acid profile after elobixibat administration in the latter group.
METHODS
Healthy subjects (n = 10) and patients with chronic constipation (n = 19) were assessed as inpatients for 7 days, during which they received meals containing ~60 g/day of fat. Patients with chronic constipation remained as inpatients for a further 7 days for once-daily elobixibat administration. Assessments included concentrations of fecal and serum bile acids, serum 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19, and bowel movements and constipation symptoms.
RESULTS
Fecal total and primary bile acids were significantly lower in patients with chronic constipation versus healthy subjects. Serum C4 and fibroblast growth factor 19 levels were comparable between groups. Elobixibat treatment increased fecal total and primary bile acids and decreased levels of fecal lithocholic acid and serum total as well as secondary bile acids in patients with chronic constipation. Bowel movements and other constipation-related symptoms were also improved by elobixibat to levels almost comparable with those of healthy subjects.
CONCLUSIONS
Despite comparable C4 levels, patients with chronic constipation demonstrated decreased levels of fecal bile acids versus healthy subjects. Elobixibat treatment increased fecal bile acid excretion and reduced serum bile acid concentrations. The improvement of constipation after elobixibat treatment was associated with increased total bile acids, particularly primary bile acids.
Topics: Bile Acids and Salts; Constipation; Dipeptides; Feces; Fibroblast Growth Factors; Humans; Thiazepines
PubMed: 35168298
DOI: 10.1111/jgh.15800 -
Marine Drugs Dec 2021From the marine-derived fungus (Trichocomaceae), a pair of enantiomers [(+)- and (-)-] were isolated with identical 1D NMR data to drazepinone, which was originally...
From the marine-derived fungus (Trichocomaceae), a pair of enantiomers [(+)- and (-)-] were isolated with identical 1D NMR data to drazepinone, which was originally reported to have a trisubstituted naphthofuroazepinone skeleton. In this study, we confirmed the structures of the two enantiomers as drazepinone and revised their structures by detailed analysis of extensive 2D NMR data and a comparison of the calculated C chemical shifts, ECD, VCD, and ORD spectra with those of the experiment ones. (+)- and (-)- were evaluated for their PTP inhibitory activity in vitro. (-)- showed selective PTP inhibitory activity against PTP1B and TCPTP with IC values of 1.56 and 12.5 μg/mL, respectively.
Topics: Animals; Aquatic Organisms; Azepines; Enzyme Inhibitors; Naphthalenes; Penicillium; Protein Tyrosine Phosphatases; Structure-Activity Relationship
PubMed: 34940713
DOI: 10.3390/md19120714 -
PloS One 2023The decidua undergoes proinflammatory activation in late pregnancy, promoting labor. Bromodomain and Extra-Terminal (BET) family proteins interact with acetylated...
The decidua undergoes proinflammatory activation in late pregnancy, promoting labor. Bromodomain and Extra-Terminal (BET) family proteins interact with acetylated histones and may control gene expression in inflammation. Here, we assessed whether BETs are involved in inflammatory gene regulation in human decidual cells. We have treated primary cultures of decidual stromal cells (DSCs) from term pregnancies with endotoxin (LPS) and measured the expression of a panel of pro-and anti-inflammatory genes. BET involvement was assessed using the selective BET inhibitors (+)-JQ1 and I-BET-762 or the negative control compound (-)-JQ1. Histone 3 and -4 acetylation and BETs binding at the target gene promoters were determined to assess whether these processes are involved in the actions of LPS, BETs, and BET inhibitors. LPS increased the expression of the proinflammatory (PTGS2, IL6, CXCL8/IL8, TNF) and the anti-inflammatory (IL10, IDO1) genes of the panel. The constitutively expressed inflammatory genes (PTGS1, PTGES) were unaffected. The BET inhibitors, but not the control compound, reduced the basal and LPS-induced expression of PTGS1, PTGS2, IL6, CXCL8/IL8, IL10, and IDO1. TNF expression was not changed by BET inhibition. The dominant BETs were Bromodomain-containing protein -2 (BRD2) and -4L (BRD4L) in DSCs. LPS increased histone 4 acetylation at the CXCL8/IL8 and TNF promoters and histone 3 and -4 acetylation at the IDO1 promoter, while (+)-JQ1 abrogated histone acetylation at several promoters. Overall, histone acetylation and promoter binding of BETs showed no consistent relationship with gene expression across the gene panel and the treatments. BET proteins, predominantly BRD2 and BRD4L, control critical pro- and anti-inflammatory genes in DSCs. TNF induction exemplifies a BET-independent pathway. Changing histone acetylation at the promoters is not a general obligatory requirement for inflammatory gene expression in response to LPS. BETs likely act at chromatin loci separate from the examined promoters. BET inhibitors may block decidual activation at labor.
Topics: Female; Humans; Pregnancy; Histones; Interleukin-8; Interleukin-6; Lipopolysaccharides; Cyclooxygenase 2; Interleukin-10; Transcription Factors; Anti-Inflammatory Agents; Azepines
PubMed: 36897880
DOI: 10.1371/journal.pone.0280645 -
Acta Pharmacologica Sinica Sep 2021Immune checkpoint blockade therapy has become a first-line treatment in various cancers. But there are only a small percent of colorectal patients responding to...
Immune checkpoint blockade therapy has become a first-line treatment in various cancers. But there are only a small percent of colorectal patients responding to PD-1/PD-L1 blockage immunotherapy. How to increase their treatment efficacy is an urgent and clinically unmet need. It is acknowledged that immunogenic cell death (ICD) induced by some specific chemotherapy can enhance antitumor immunity. Chemo-based combination therapy can yield improved outcomes by activating the immune system to eliminate the tumor, compared with monotherapy. Here, we develop a PD-L1-targeting immune liposome (P-Lipo) for co-delivering irinotecan (IRI) and JQ1, and this system can successfully elicit antitumor immunity in colorectal cancer through inducing ICD by IRI and interfering in the immunosuppressive PD-1/PD-L1 pathway by JQ1. P-Lipo increases intratumoral drug accumulation and promotes DC maturation, and thereby facilitates adaptive immune responses against tumor growth. The remodeling tumor immune microenvironment was reflected by the increased amount of CD8 T cells and the release of IFN-γ, and the reduced CD4Foxp3 regulatory T cells (Tregs). Collectively, the P-Lipo codelivery system provides a chemo-immunotherapy strategy that can effectively remodel the tumor immune microenvironment and activate the host immune system and arrest tumor growth.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Azepines; B7-H1 Antigen; Cell Line, Tumor; Female; Immune Checkpoint Inhibitors; Irinotecan; Mice; Mice, Inbred BALB C; Neoplasms; Programmed Cell Death 1 Receptor; T-Lymphocytes, Regulatory; Triazoles; Tumor Microenvironment
PubMed: 33311600
DOI: 10.1038/s41401-020-00570-8 -
American Family Physician Jun 2016
Topics: Azepines; Education, Medical, Continuing; Humans; Practice Guidelines as Topic; Practice Patterns, Physicians'; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles
PubMed: 27304771
DOI: No ID Found -
Chemistry (Weinheim An Der Bergstrasse,... Jul 2017A set of multivalent polyhydroxylated acetamidoazepanes based on ethylene glycol, glucoside, or cyclodextrin scaffolds was prepared. The compounds were assessed against...
A set of multivalent polyhydroxylated acetamidoazepanes based on ethylene glycol, glucoside, or cyclodextrin scaffolds was prepared. The compounds were assessed against plant, mammalian, and therapeutically relevant hexosaminidases. Multimerization was shown to improve the inhibitory potency with synergy, and to fine tune the selectivity profile between related hexosaminidases.
Topics: Animals; Anti-Bacterial Agents; Azepines; Cyclodextrins; Enzyme Inhibitors; Ethylene Glycol; Glucosides; Hexosaminidases; Imino Sugars; Plants
PubMed: 28548311
DOI: 10.1002/chem.201701756