Epigenetic modifiers of the histone deacetylase (HDAC) family contribute to autoimmunity, cancer, HIV infection, inflammation, and neurodegeneration. Hence, histone deacetylase inhibitors (HDACi), which alter protein acetylation, gene expression patterns, and cell fate decisions, represent promising new drugs for the therapy of these diseases. Whereas pan-HDACi inhibit all 11 Zn-dependent histone deacetylases (HDACs) and cause a broad spectrum of side effects, specific inhibitors of histone deacetylase 6 (HDAC6i) are supposed to have less side effects. We present the synthesis and biological evaluation of Marbostats, novel HDAC6i that contain the hydroxamic acid moiety linked to tetrahydro-β-carboline derivatives. Our lead compound Marbostat-100 is a more potent and more selective HDAC6i than previously established well-characterized compounds in vitro as well as in cells. Moreover, Marbostat-100 is well tolerated by mice and effective against collagen type II induced arthritis. Thus, Marbostat-100 represents a most selective known HDAC6i and the possibility for clinical evaluation of a HDAC isoform-specific drug.
Our findings support the use of TNFRII-selective therapeutics as an effective approach to the treatment of arthritic disease and possibly other inflammatory and autoimmune diseases.
Previously, we reported that cervical vagal nerve stimulation (VNS) increases blood glucose levels and inhibits insulin secretion in anesthetized rats through afferent signaling. Since afferent signaling is also thought to mediate the therapeutic effects of VNS in patients with therapy‐refractory epilepsy and major depression, the question arises if patients treated with VNS develop impaired glucose tolerance. Thus, we hypothesized that cervical VNS impairs glucose tolerance in conscious rats. Rats (n = 7) were instrumented with telemetric blood pressure sensors and right‐ or left‐sided cervical vagal nerve stimulators (3 V, 5 Hz, 1 msec pulse duration, 1 h on 1 h off). Glucose tolerance tests (GTTs, 1.5 g dextrose/kg BW, i.p.) were performed after overnight fasting with the stimulators on or off (sham stimulation) in randomized order separated by 3–4 days. Overnight VNS did not alter mean levels of blood pressure or heart rate, but increased fasted blood glucose levels (140 ± 13 mg/dL vs. 109 ± 8 mg/dL, P < 0.05). The area under the blood glucose concentration curves of the GTTs was larger during VNS than sham stimulation (3499 ± 211 mg/dL*h vs. 1810 ± 234 mg/dL*h, P < 0.05). One hour into the GTTs, the serum insulin concentrations had decreased during VNS (−0.57 ± 0.25 ng/mL, P < 0.05) and increased during sham stimulation (+0.71 ± 0.15 ng/mL, P < 0.05) compared to the fasted baseline levels. These results demonstrate that chronic cervical VNS elevates fasted blood glucose levels and impairs glucose tolerance likely through inhibition of glucose‐induced insulin release in conscious rats. It remains to be determined if patients treated with VNS are at greater risk of developing glucose intolerance and type 2 diabetes.
Blacklegged ticks (Ixodes scapularis) transmit the causative agent of Lyme disease in the Northeastern and upper Midwestern US. Current research focuses on elucidating biochemical pathways which may be disrupted to prevent pathogen transmission, thereby preventing disease. A genome screening process reported transcripts coding for two putative sulfotransferases in salivary glands of adult Ixodes scapularis and in whole tick extracts of the nymphal and larval stages. Sulfotransferases are known to sulfonate phenolic and alcoholic receptor agonists such as 17β-estradiol, thereby inactivating the receptor ligands. We used bioinformatic approaches to predict substrates for these two sulfotransferases (designated Ixosc Sult 1 and Ixosc Sult 2), and tested the predictions with biochemical assays. Amino acid sequence analysis showed that Ixosc Sult 1 and 2 are members of the cytosolic sulfotransferase superfamily. Homology models of 3D-protein structure were prepared for each tick sulfotransferase based on sulfotransferase X-ray crystal structures. Visualization of the electrostatic surface of the ligand binding cavities showed regions of negative electrostatic charge. Molecular docking identified potential substrates including dopamine, R-octopamine and S-octopamine, which docked into Ixosc Sult 1 with favorable binding affinity and correct conformation for sulfonation. Dopamine, but not R-or S-octopamine, also docked into Ixosc Sult 2 in a catalytic binding mode. Other molecules including 17β-estradiol, pregnenolone and serotonin, did not dock in catalytically active position to either protein. The predictions were tested and confirmed using cytosolic fractions of extracts of whole ticks. Dopamine was found to be a good substrate (K m 0.1 -0.4 μM) for the native Ixodes scapularis sulfotransferases from larval and nymphal stages regardless of their fed/unfed status. Octopaminesulfonation was only detected after feeding when gene expression data suggests that only Ixosc Sult 1 is present. These results agree with the docking predictions that octopamine is sulfonated only by Ixosc Sult 1, whereas dopamine is sulfonated by both Ixosc Sult 1 and Sult 2. Because dopamine is known to stimulate salivation in ticks through receptor stimulation, these results imply that the function/s of Ixosc Sult 1 or Sult 2 in the Ixodid tick may include inactivation of the salivation signal via sulfonation of dopamine and/or octopamine. 15/2010). This tick species serves as the vector for the pathogen, Borrelia burgdorferi, which is a spirochete bacterium responsible for Lyme disease in humans. Small animals such as wild mice, chipmunks and other wild rodents provide the reservoir and seem not to be adversely affected by presence of the bacterium. The spirochete can be passed to humans after a tick, which has previously fed on an infected small animal, subsequently feeds on an individual. Blacklegged ticks (also known as deer ticks) have three life stages (larval, nymphal, adult) and feed once at each life stage. A single infect...
BackgroundSo far, there exists no golden standard for the treatment of arthrofibrosis (AF) following total knee arthroplasty (TKA). Although pain is a hallmark of AF, nociceptive nerve fibers have never been investigated in affected joint tissue.MethodsA total of 24 patients with osteoarthritis (OA) of the knee (n = 12) and post-TKA AF of the knee (n = 12) were included. Along evaluation of typical clinical signs and symptoms by using the Knee Society Clinical Rating System (KSS), the Knee Injury and Osteoarthritis Outcome Score (KOOS), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC index), the innervation of joint tissue was studied by semiquantitative immunofluorescence of nerve fibers.ResultsPatients with AF compared to OA had a lower KSS and lower KOOS. In all compartments (anterior, medial, and lateral recesses), the density of synovial sympathetic nerve fibers was significantly higher in OA compared to AF, which was also true for the density of sensory nerve fibers in the medial and lateral recesses. In synovial tissue of the anterior recess of patients with AF compared to OA, the density of nociceptive sensory nerve fibers was significantly higher relative to sympathetic nerve fibers. This was similarly observed in the neighboring infrapatellar fat pad of the knee.ConclusionsSimilar as in many painful musculoskeletal diseases, this study indicates that patients with arthrofibrosis of the knee after TKA demonstrate a preponderance of profibrotic sensory nerve fibers over antifibrotic sympathetic nerve fibers. This could serve as a starting point for AF therapy with specific antifibrotic pain medication or regional anesthetic techniques.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.