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BACKGROUND: Arglabin is a plant alkaloid (sesquiterpene lactone) that is used as an anticancer drug. It has potential anti-diabetic and anti-atherogenic effects. PURPOSE: Arglabin has drawn particular attention because of its therapeutic effects as an anti-inflammatory agent in multiple diseases. Since arglabin inhibits Epidermal Growth Factor Receptor (EGFR) tyrosine kinase, concerns for cardiotoxic effects are valid. The present study was designed to investigate the protective effects of arglabin on the myocardium. STUDY DESIGN: This study was designed to evaluate the effect of arglabin on the myocardium in an experimental model of myocardial necrosis in rats. Different doses of arglabin (2.5, 5, and 10 µg/kg) were investigated as pre-treatment for 21 days in the isoproterenol (ISO) model of myocardial necrosis groups and per se groups. METHODS: On the 22nd day, hemodynamic, histopathological, electron microscopy, oxidative stress markers, inflammatory mediators, apoptotic markers, inflammasome mediators, and Western blot analysis were performed to evaluate the effects of arglabin. RESULTS: Arglabin pre-treatment showed improvement in hemodynamic parameters and histopathological findings at low doses in isoproterenol-induced myocardial necrosis model of rats. Arglabin administration altered myocardial structure and modulated myocardial function via activation of NFκB/MAPK pathway that led to myocardial injury with an increase in dose. CONCLUSION: Arglabin imparted partial cardio-protection via an inflammasome-dependent pathway and mediated injury through the inflammasome-independent pathway.

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BACKGROUND: At present, more than 8000 sesquiterpene lactones have been isolated and described from natural sources, a significant part of which has cytotoxicity and antitumor activity. One of the practically available sesquiterpene lactones is arglabin, which, as a renewable material, is used for the synthesis of new compounds. The article presents data on the study of cytotoxicity and antitumor activity of the arglabin and its derivatives using molecular modeling methods and, in the experiment in vitro and in vivo. AIM: The aim of this work is to study the cytotoxicity and antitumor activity of new compounds based on the sesquiterpene lactone arglabin using molecular modeling and experimental pharmacology. METHODS: ChemDraw programs and a set of AutoDock programs were used for computer simulation. Molecular docking was carried out using the Maestro graphical interface of the Schrödinger Suite software package (Schrödinger, LLC, New York, NY, 2017). Docking modes standard precision and XP (extra precision) were used. In in vitro experiments, the antitumor activity of compound samples was studied in models of 60 human tumor cell lines, and clonogenic C6 rat glioma cells. The antitumor activity of the samples was studied in experiments in vivo on white outbred rats with transplanted tumors and was evaluated by the inhibition of tumor growth and the magnitude of the increase in average life expectancy. CONCLUSION: When studying the antitumor activity on 60 cell lines of tumor cells (NCI60), clonogenic cells of C6 rat glioma, a high antitumor activity of some arglabin derivatives was established. The connection between the structure of arglabin derivatives and their inhibitory effect on farnesyl protein transferase, topoisomerases -I and -II was studied.

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Chronic subclinical inflammation is a key process in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Along with lipids, inflammation is essential for the initiation and progression of atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine secretion. Several pro-inflammatory cytokines have been described in the primary and secondary prevention of ASCVD. Although extensive work over the past decades has established the role of lipid-lowering medications in the prevention and treatment of ASCVD, modulation of inflammation is a subject of active debate. It remains to be confirmed whether targeting the residual cardiovascular risk by adding anti-inflammatory agents to the conventional cardiovascular treatment becomes a shifting paradigm for ASCVD management. This review aims to discuss novel therapeutic agents targeting inflammatory pathways in ASCVD in light of the canakinumab anti-inflammatory thrombosis outcomes study (CANTOS) trial results. Further we discuss the effects of different anti-inflammatory agents administered in patients with ASCVD and their potential to change clinical practice in preventive cardiology.

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Arglabin (Arg) is a derivative of parthenolide. At present, there are few reports on the pharmacological effects and targets of Arg. In this study, we aimed to explore the relationship between Arg and NF-κB (P50) and the intervention effects of Arg on neuroinflammation. BV2 cells were cultured in vitro. LPS/IFN-γ was used to induce M1 polarization. After Arg intervention, the cytokine expression of M1 and M2 cell marker was detected, the expression of CD86 was detected by immunofluorescence (IF) staining, the levels of P50 and p-P50 were detected by Western blot and the expression of ROS was by DCFH-DA. AfterP50 knockout, we investigated the effect of P50 on the polarization of BV2 cells. Four-month-old APP/PS1 (AD) mice were treated with Arg by intragastric administration, followed by detection of the expression of CD86, CD206, and IBA-1 by IF staining, Finally, molecular-protein docking and Pull-down assays were used to validate the targeted binding relationship between P50 and Arg. Arg could inhibit the M1 polarization of BV2 cells, decrease the levels of TNF-α, IL-1ß, IL-6, iNOS, and IL-12, and simultaneously inhibit the expression of P50 and p-P50. P50 knockout could inhibit the M1 polarization of BV2 cells, and P50 played an important role in the polarization of BV2 cells. Molecular docking and pull-down assays revealed that Arg and P50 had a targeted binding relationship. Animal experiments showed that Arg could regulate the polarization level of M1-M2 cells, increase the proportion of M2 cells, decrease the degree of nerve injury and suppress the expression of P50 and p-P50. In this study, we found that Arg could target P50 to regulate reprogramming of BV2 cells, inhibit M1 polarization, and increase the level of M2 cells, thereby exerting a neuroprotective effect.

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Arglabin (l(R),10(S)-epoxy-5(S),5(S),7(S)-guaia-3(4),ll(13)-dien-6,12-olide), is a natural sesquiterpene γ-lactone which was first isolated from Artemisia glabella. The compound has been shown to possess anti-inflammatory activity through inhibition of the NLR Family pyrin domain-containing 3 (NLRP3) inflammasome and production of proinflammatory cytokines including interleukin (IL)-1ß and IL-18. A more hydrophilic derivative of the compound also exhibited antitumor activity in the breast, colon, ovarian, and lung cancer. Some other synthetic derivatives of the compound have also been synthesized with antitumor, cytotoxic, antibacterial, and antifungal activities. Since both NLRP3 inflammasome and cytokine storm are associated with the pathogenesis of COVID-19 and its lethality, compounds like arglabin might have therapeutic potential to attenuate the inflammasome-induced acute respiratory distress syndrome and/or the cytokine storm associated with COVID-19.

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INTRODUCTION: The chemical modification of arglabin, a natural sesquiterpene lactone, has garnered significant attention because it comprises a guaianolide structure that exhibits antitumour and immunomodulating properties. Its primarily derived from Artemisia glabella Kar. et Kir. Physicochemical characterisation of commercial anititumour drugs based on arglabin can be time-consuming and expensive; thus, high-performance liquid chromatography (HPLC) is an optimal method to identify arglabin and its derivatives. AIM: This study has a two-fold objective: to develop a unified HPLC method for quality control of arglabin and its new hybrid molecules with alkaloids (cytisine, anabasine), and to study the relationship between their structures and chromatographic behaviours. MATERIALS AND METHODS: To develop a selective method that ensures the quality of arglabin and its derivatives, HPLC was used with the Zorbax SB-C18 analytical column. Dipole moments were calculated via the restricted Hartree-Fock method (RHF/6-31G(d, p)) and the B3LYР density functional theory with full geometry optimisation by using the GAUSSIAN 03 W program. RESULTS: A novel analytical method has been developed using reversed-phase (RP) HPLC, which is selective and allows reliable as well as quantitative determination of arglabin and its derivatives. To confirm the selectivity of the developed method, the chromatographic capacity factors and column selectivity were calculated. The relationship between retention time and structure (particularly, the nature of the substituent) was studied for the first time for arglabin and its derivatives using the B3LYP/6-31G(d) quantum chemical method. The influence of the dipole moment on the retention time of arglabin and its derivatives was confirmed. CONCLUSION: A novel unified quality control method using HPLC was developed to analyse arglabin, and its new hybrid molecules with alkaloids (cytisine and anabasine). For the first time, the relationship between the chromatographic behaviour in RP-HPLC and the dipole moment for arglabin and its derivatives was revealed.

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BACKGROUNDS: In breast cancer, blocking of Ras signaling and inhibition of H-Ras is quite promising. H-Ras may become a target for farnesyl transferase inhibitors, and in combination with other immunohistochemical factors it will contribute to the progression of a breast tumor. PURPOSE: The aim of this study was to evaluate the effectiveness of neoadjuvant therapy for breast cancer with the inclusion of farnesyl transferase inhibitor, arglabin interfering with the expression and concentration of H-Ras oncoproteins. METHODS: Depending on the presence of H-Ras oncoproteins after Western-blot hybridization, the patients were divided a negative and positive expression of H-Ras groups. RESULTS: Correlation analysis of methods used for determining the expression ability and concentration of H-Ras oncoproteins (immunohistochemistry and Western-blot analysis) demonstrated substantial statistical relationship Rs=0.71, p=0.03. The H-Ras oncoproteins were absent in patients receiving either "Arglabin" or standard AC regimen. However, in the AC + Arglabin group, there was a varying degrees of positive concentration of H-Ras oncoproteins (Kruskal-Wallis=6.92; p=0.03). CONCLUSION: These results indicate that Arglabin attenuates H-Ras oncoproteins expression which is a promising therapeutic target for breast cancer.

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This review summarizes the results of own research on chemical modification of the molecule of sesquiterpene lactone arglabin from Artemisia glabella Kar. et Kir. Over 70 new arglabin derivatives were obtained which are polyfunctional compounds with oxy functions, atoms of haloids, phosphorus, nitrogen, and cyclopropane fragments. For the first time the results of bioscreening of new arglabin derivatives are reported.

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Arglabin belongs to guaianolide class of sesquiterpene lactones, isolated from Artemisia species. The molecule bears a 5,7,5-tricyclic ring system having five contiguous stereo centers in which the two five membered rings are trans-annulated. Arglabin shows promising antitumor activity against different tumor cell lines. The antitumor activity of arglabin proceeds through its inhibition of farnesyl transferase which leads to the activation of RAS proto-oncogene, a process that is believed to play a pivotal role in 20-30% of all human tumors. It actually inhibits the incorporation of farnesyl pyrophosphate into human H-ras proteins by the enzyme farnesyl transferase (FTase). The present review is an attempt to summarize the chemistry and biology of this molecule since its isolation in 1982. It embodies the isolation, structure elucidation, stereo chemical description, structural classification, chemical synthesis, structural modifications and antitumor evaluation reported till date.

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BACKGROUND: This study was designed to evaluate the effect of arglabin on the NLRP3 inflammasome inhibition and atherosclerotic lesion in ApoE2Ki mice fed a high-fat Western-type diet. METHODS AND RESULTS: Arglabin was purified, and its chemical identity was confirmed by mass spectrometry. It inhibited, in a concentration-dependent manner, interleukin (IL)-1ß and IL-18, but not IL-6 and IL-12, production in lipopolysaccharide and cholesterol crystal-activated cultured mouse peritoneal macrophages, with a maximum effect at ≈50 nmol/L and EC50 values for both cytokines of ≈ 10 nmol/L. Lipopolysaccharide and cholesterol crystals did not induce IL-1ß and IL-18 production in Nlrp3(-/-) macrophages. In addition, arglabin activated autophagy as evidenced by the increase in LC3-II protein. Intraperitoneal injection of arglabin (2.5 ng/g body weight twice daily for 13 weeks) into female ApoE2.Ki mice fed a high-fat diet resulted in a decreased IL-1ß plasma level compared with vehicle-treated mice (5.2±1.0 versus 11.7±1.1 pg/mL). Surprisingly, arglabin also reduced plasma levels of total cholesterol and triglycerides to 41% and 42%, respectively. Moreover, arglabin oriented the proinflammatory M1 macrophages into the anti-inflammatory M2 phenotype in spleen and arterial lesions. Finally, arglabin treatment markedly reduced the median lesion areas in the sinus and whole aorta to 54% (P=0.02) and 41% (P=0.02), respectively. CONCLUSIONS: Arglabin reduces inflammation and plasma lipids, increases autophagy, and orients tissue macrophages into an anti-inflammatory phenotype in ApoE2.Ki mice fed a high-fat diet. Consequently, a marked reduction in atherosclerotic lesions was observed. Thus, arglabin may represent a promising new drug to treat inflammation and atherosclerosis.

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