Enzyme Inhibitor
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Author(s):  
Patrik Keringer ◽  
Nora Furedi ◽  
Balazs Gaszner ◽  
Alexandra Miko ◽  
Eszter Pakai ◽  
...  

Cholecystokinin (CCK) increases core body temperature via CCK2 receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the fever response to systemic inflammation. We studied the interaction between central CCK signaling and the cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with intraperitoneal infusion of the nonselective COX enzyme inhibitor metamizol (120 mg/kg) or a selective COX-2 inhibitor, meloxicam or etoricoxib (10 mg/kg for both) and, 30 minutes later, treated with icv CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by ~0.4°C from 10 min post-infusion, which was attenuated by metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by ~70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by ~50% in both); all these changes were all completely blocked with metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by metamizol. CCK-induced hyperthermia was also completely blocked with both selective COX-2 inhibitors studied. Finally, the CCK2 receptor antagonist YM022 (10 µg/kg; icv) attenuated the late phases of fever induced by bacterial lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes hyperthermia through changes in the activity of "classical" thermoeffector pathways, and that the activation of COX-2 is required for the development of this response.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Thanuja D. Sudasinghe ◽  
Michael T. Banco ◽  
Donald R. Ronning

AbstractErgothioneine (EGT) is a low molecular weight histidine betaine essential in all domains of life but only synthesized by selected few organisms. Synthesis of EGT by Mycobacterium tuberculosis (M. tb) is critical for maintaining bioenergetic homeostasis and protecting the bacterium from alkylating agents, oxidative stress, and anti-tubercular drugs. EgtD, an S-adenosylmethionine-dependent methyltransferase (AdoMet), catalyzes the trimethylation of L-Histidine to initiate EGT biosynthesis and this reaction has been shown to be essential for EGT production in mycobacteria and for long-term infection of murine macrophages by M. tb. In this work, library screening and structure-guided strategies identified multiple classes of M. tb EgtD inhibitors that bind in various regions of the enzyme active site. X-ray crystal structures of EgtD-inhibitor complexes confirm that L-Histidine analogs bind solely to the L-Histidine binding site while drug-like inhibitors, such as TGX-221, and S-Glycyl-H-1152 span both the L-Histidine and AdoMet binding sites. These enzyme-inhibitor complexes provide detailed structural information of compound scaffolds useful for developing more potent inhibitors that could shorten Tuberculosis treatment regimens by weakening important bacterial defenses.


2021 ◽  
pp. 096032712110563
Author(s):  
Hai-Yan Jiang ◽  
Yan-Ni Bao ◽  
Feng-Mei Lin ◽  
Yong Jin

Triptolide (TP), the main active compound extracted from medicine— tripterygium wilfordii Hook f. (TWHF). It has anti-tumor and immunomodulatory properties. Our study aimed to investigate the mechanisms of hepatotoxicity treated with TP in vivo and in vitro, as well as their relationship with the NF-κB (p65) signal pathway; and to assess TP-induced hepatotoxicity after CYP2E1 modulation by the known inhibitor, clomethiazole, and the known inducer, pyrazole. Mice were given TP to cause liver injury and IHHA-1 cells were given TP to cause hepatocyte injury. The enzyme activity and hepatotoxicity changed dramatically when the CYP2E1 inhibitor and inducer were added. In comparison to the control group, the enzyme inducer increased the activity of CYP2E1, whereas the enzyme inhibitor had the opposite effect. Our findings suggest that TP is an inducer of CYP2E1 via a time-dependent activation mechanism. In addition, TP can promote oxidative stress, inflammatory and involving the NF-κB (p65) signal pathway. Therefore, we used triptolide to stimulate C57 mice and IHHA-1 cells to determine whether TP can promote oxidative stress and inflammation by activating CYP2E1 in response to exacerbated liver damage and participate in NF-κB (p65) signaling pathway.


2021 ◽  
Vol 5 (11) ◽  
pp. 1211-1218
Author(s):  
Rina Kriswiastiny ◽  
Radiyati Umi Partan ◽  
Hermansyah ◽  
Surya Darma ◽  
Muhammad Reagan

Rheumatoid Arthritis or RA disease is a chronic inflammatory and systemic disease associated with broad synovitis resulting in erosion of the articular cartilage and marginal bone causing joint damage. RA is an autoimmune disease with the discovery of an autoantibody, namely rheumatoid factor. The relevant antibody is anti-citrullinated protein (ACPA) antibody. Citullination on the introduction of several proteins such as fibrin, vimentin, fibronectin, collagen type II, which is expressed in the synovial membrane during inflammation by ACPA. In a recent study increased HDAC activity in the synovial tissue of RA patients has increased. Histone deacetylase or abbreviated as HDAC is an enzyme that is important in regulating gene transcription by altering the acetylation of histone proteins which results in an important regulation of repression in the implementation of inflammation. HDAC enzyme inhibitor (HDACi) is an HDAC enzyme inhibitor that can provide benefits for the treatment of various diseases including malignancy and inflammation. In inflammatory disease HDACi overcomes inflammatory cytokines such as TNF-α, IL-6 and IL-1β. One of the HDAC classes is HDAC1 which is highly expressed in the synovial fibroblasts of RA patients. HDACi can burden swollen joints, reduce mononuclear cell infiltration, request pannus orders, inhibit bone and cartilage damage.


Author(s):  
Richard K. Cheng ◽  
Alexi Vasbinder ◽  
Wayne C. Levy ◽  
Parag Goyal ◽  
Jan M. Griffin ◽  
...  

Background Despite the belief that heart failure therapies are not effective in transthyretin cardiac amyloidosis, data are limited. We tested the association of neurohormonal blockade use with survival. Methods and Results A total of 309 consecutive patients with transthyretin cardiac amyloidosis were identified. Medication inventory was obtained at baseline and subsequent visits. Exposure included a neurohormonal blockade class (β‐blocker [βB], angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker, and mineralocorticoid antagonist) at baseline and subsequent visits. βB was modeled as baseline use, time‐varying use, and in an inverse probability treatment weighted model. Primary outcome was all‐cause mortality analyzed with adjusted Cox proportional hazards models. Continuing compared with stopping βB during follow‐up was tested. Mean age was 73.2 years, 84.1% were men, and 17.2% had atrial fibrillation/flutter at baseline. At the time of study entry, 49.8% were on βBs, 35.0% were on angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers, and 23.9% were on mineralocorticoid antagonists. For the total cohort, there was a trend toward harm in the unadjusted model for baseline βB use, but this was neutral after adjustment. When βB use was analyzed as a time‐varying exposure, there was no association with mortality. βB discontinuation was associated with decreased mortality for the total cohort. Findings were consistent in inverse probability treatment weighted models. For angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker or mineralocorticoid antagonist use, there was no association with mortality after adjustment for the total cohort. Conclusions There was no association of neurohormonal blockade use with survival in transthyretin cardiac amyloidosis. For the total cohort, deprescribing βB may be associated with improved survival. Additional studies are needed to confirm these findings.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi54-vi54
Author(s):  
Miri Kim ◽  
Erik Ladomersky ◽  
Lijie Zhai ◽  
Lakshmi Bollu ◽  
April Bell ◽  
...  

Abstract INTRODUCTION We previously determined that advanced age plays a negative role in the survival outcome of human recurrent glioblastoma (GBM) patients treated with immune checkpoint blockade. Here we investigate the immunologic “signature” of younger patients who are < 65 years of age and older adult GBM patients who are ≥ 65 years of age that undergo simultaneous treatment with standard radiation, nivolumab (anti-PD-1 mAb), and BMS-986205 (a potent IDO enzyme inhibitor) and are newly diagnosed with O6-methylguanine-DNA methyl-transferase (MGMT) unmethylated GBM. Our objective was to identify age-dependent immunologic changes before and after treatment with immunotherapy. METHODS Patients ≥ 18 years old with newly diagnosed MGMT unmethylated GBM, KPS ≥ 70, and minimal steroid use were eligible for enrollment in this phase 1 trial. PBMCs and serum were drawn at baseline and routine post-treatment time points followed by mass spec analysis of kynurenine (Kyn) and tryptophan (Trp) metabolites, RNAseq, and 18-color flow cytometric analysis. RESULTS 8 younger adults with a median age of 50 years old and 4 older adults with a median age of 68.5 years old were studied. The median overall survival of younger and older adults was 368 and 108.5 days, respectively (p=0.032, HR 4.8 for age). BMS-986205 treatment decreased the Kyn/Trp ratio of all patients irrespective of age. RNAseq analysis found significant age-related changes using Gene Ontology pathway analysis of T cell related immunity, lymphocyte activation, and NK cell mediated immunity. Flow cytometric analysis is ongoing. CONCLUSIONS Similar to what was reported in older adult mice treated with simultaneous RT, anti-PD-1 mAb, and IDO enzyme inhibitor, advanced age negatively affected the survival in older adult human GBM patients treated with an analogous clinical approach. Future determination of whether the age-related biomarker profile can be used diagnostically and therapeutically is now under investigation.


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