查看更多>>摘要：Small drug-like molecules that can block the function of serotonin 5-HT2A receptors have garnered considerable attention due to their ability to inhibit platelet aggregation and the possible prevention of atherosclerotic lesions. Although clinical data provided compelling evidence for the efficacy of this approach in the prevention of various cardiovascular conditions, the chemical space of 5-HT2A receptor antagonists is limited to ketanserin and sar-pogrelate. To expand the portfolio of novel chemical motifs with potential antiplatelet activity, we evaluated the antiplatelet activity of a series of 6-fluorobenzo[d]isoxazole derivatives that possess a high affinity for 5-HT2a receptor. Here we describe in vitro studies showing that 6-fluorobenzo[d]isoxazole derivatives exert promising antiplatelet activity in three various in vitro models of platelet aggregation, as well as limit serotonin-induced vasoconstriction. Compound AZ928 showed in vitro activity greater than the clinically approved drug sarpog-relate. In addition to promising antiplatelet activity, the novel series was characterized by a favorable safety profile. Our findings show that the novel series exerts promising antiplatelet efficacy while being deprived of potential side effects, such as hemolytic activity, which render these compounds as potential substances for further investigation in the field of cardiovascular research.
Lucía PinillaIvan D. BenítezFerno Santamaria-MartosAdriano Targa...
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查看更多>>摘要：Introduction: Obstructive sleep apnea (OSA) is a chronic, heterogeneous and multicomponent disorder with associated cardiovascular and metabolic alterations. Despite being the most common sleep-disordered breathing, it remains a significantly undiagnosed condition. Objective: We examined the plasma metabolome and lipidome of patients with suspected OSA, aiming to identify potential diagnosis biomarkers and to provide insights into the pathophysiological mechanisms underlying the disease. Additionally, we evaluated the impact of continuous positive airway pressure (CPAP) treatment on the circulating metabolomic and lipidomic profile. Material and methods: Observational-prospective-longitudinal study including 206 consecutive subjects referred to the sleep unit. OSA was defined as an apnea-hypopnoea index > 15 events/h after polysomnography (PSG). Patients treated with CPAP were followed-up for 6 months. Untargeted plasma metabolomic and lipidomic profiling was performed using liquid chromatography coulpled to massspectrometry. Results: A plasma profile composed of 33 metabolites (mainly glycerophospholipids and bile acids) was identified in OSA vs. non-OSA patients. This profile correlated with specific PSG measures of OSA severity related to sleep fragmentation and hypoxemia. Machine learning analyses disclosed a 4-metabolites-signature that provided an accuracy (95% CI) of 0.98 (0.95-0.99) for OSA detection. CPAP treatment was associated with changes in 5 plasma metabolites previously altered by OSA. Conclusions: This analysis of the circulating metabolome and lipidome reveals a molecular fingerprint of OSA, which was modulated after effective CPAP treatment. Our results suggest blood-based biomarker candidates with potential application in the personalized management of OSA and suggest the activation of adaptive mechanisms in response to OSA-derived hypoxia.
Elsa M. MateronFlavio M. ShimizuKevin Figueiredo dos SantosGustavo F. Nascimento...
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查看更多>>摘要：Glutathione-s-transferase is believed to be involved in the resistance to chemotherapeutic drugs, which depends on the interaction with the cell membranes. In this study, we employed Langmuir monolayers of a mixture of phospholipids and cholesterol (MIX) as models for tumor cell membranes and investigated their interaction with the anticancer drugs cisplatin (CDDP) and doxorubicin (DOX). We found that both DOX and CDDP expand and affect the elasticity of MIX monolayers, but these effects are hindered when glutathione-s-transferase (GST) and its cofactor glutathione (GSH) are incorporated. Changes are induced by DOX or CDDP on the polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS) data for MIX/GST/GSH monolayers, thus denoting some degree of interaction that is not sufficient to alter the monolayer mechanical properties. Overall, the results presented here give support to the hypothesis of the inactivation of DOX and CDDP by GST and point to possible directions to detect and fight drug resistance.
查看更多>>摘要：Colon cancer is one of the leading causes of death in the world. The search for effective and minimally invasive methods of treating colon cancer is the aim of modern medicine. Chalcones and their derivatives have shown an anticancer activity. The aim of the study was to evaluate the effect of methoxy-derivatives of 2'-hydrox-ychalcones: 2'-hydroxy-3"-methoxychalcone (TJ3), 2'-hydroxy-2"-methoxychalcone (TJ6) and 2'-hydroxy-4"-metoxychalcone (TJ7) at the concentrations of 10 μM and 25 μM on the release of IL-8, MIF, VCAM-1, ICAM-1 by colon cancer SW480 and SW620 cell lines. The cytokines and adhesion molecules were detected using the Bio-Plex Magnetic Luminex Assay and the Bio-Plex Suspension Array System. Our results showed that all tested methoxy-derivatives of 2'-hydroxychalcone compounds significantly reduced ICAM-1 released by SW480 cancer cells. The tested compounds at both concentrations did not significantly affect VCAM-1 released by SW480 and SW620 cancer cell lines. All methoxy-derivatives significantly reduced the concentration of MIF in dose dependent manner on SW480 cells. The TJ3 at the concentration of 25 μM significantly decreased IL-8 secreted by SW480 and SW620 cancer cells. Our results demonstrated that tested methoxy-derivatives of 2'-hydrox-ychalcones showed modulating effect on colon cancer cells.
查看更多>>摘要：The human contact system consists of plasma proteins, which - after contact to foreign surfaces - are bound to them, thereby activating the zymogens of the system into enzymes. This activation mechanism gave the system its name - contact system. It is considered as a procoagulant and proinflammatory response mechanism, as activation finally leads to the generation of fibrin and bradykinin. To date, no physiological processes have been described that are mediated by contact activation. However, contact system factors play a pathophysiological role in numerous diseases, such as cardiovascular diseases, arthritis, colitis, sepsis, and cancer. Contact system factors are therefore an interesting target for new therapeutic options in different clinical conditions.
查看更多>>摘要：Spinal cord injury (SCI) is the most common disabling spinal injury, and the complex pathological process can eventually lead to severe neurological dysfunction. Many studies have reported that the mammalian target of rapamycin (mTOR) signaling pathway plays an important role in synaptogenesis, neuron growth, differentiation, and survival after central nervous system injury. It is also involved in various traumatic and central nervous system diseases, including traumatic brain injury, neonatal hypoxic-ischemic brain injury, Alzheimer's disease, Parkinson's disease, and cerebral apoplexy. mTOR has also been reported to play an important regulatory role in various pathophysiological processes following SCI. Activation of mTOR signals after SCI can regulate physiological and pathological processes, such as proliferation and differentiation of neural stem cells, regeneration of nerve axons, neuroinflammation, and glial scar formation, through various pathways. Inhibition of mTOR activity has been confirmed to promote repair in SCI. At present, many studies have reported that Chinese herbal medicine can inhibit the SCI-activated mTOR pathway to improve the microenvironment and promote nerve repair after SCI. Due to the role of the mTOR pathway in SCI, it may be a potential therapeutic target for SCI. This review is focused on the pathophysiological process of SCI, characteristics of the mTOR pathway, role of the mTOR pathway in SCI, role of inhibition of mTOR on SCI, and role and significance of inhibition of mTOR by related Chinese herbal medicine inhibitors in SCI. In addition, the review discusses the deficiencies and solutions to mTOR and SCI research shortcomings. This study hopes to provide reference for mTOR and SCI research and a theoretical basis for SCI biotherapy.
查看更多>>摘要：Background: There is currently a growing interest in the roles of epigenetic mechanisms in the diagnosis, prognosis, and therapies associated with precision oncology for breast cancer (BC). This study aimed to demonstrate the clinical significance of euchromatic histone lysine methyltransferase 2 (EHMT2), histone deacetylase 1 (HDAC1) and HDAC2 in BC, to evaluate the antitumor effectiveness of a combination of the selective inhibitors UNC0638 and CI-994 (U+C), and to clarify the underlying mechanisms. Methods: Multi-omic analysis was used to study the clinical significance of the biomarkers of interest. The effects of U+C treatment were evaluated by detecting cell viability, cell cycle, apoptosis, and representative gene expressions. RNA-Seq and Gene Set Enrichment Analysis (GSEA) were employed to identify over-represented genes associated with the treatment. Chromatin immunoprecipitation and qPCR (ChIP-qPCR) assay were applied to verify epigenetic profiling on the identified promoters. Results: The significance of elevated expressions of EHMT2, HDAC1, and HDAC2 in tumor tissue and BC basal-like subtype in predicting a poor prognosis was noted. The U+C combined treatment showed an enhanced sup-pressive effect as compared to single agent treatment, perturbed the cell cycle, induced apoptosis, reduced expressions of the genes representing anti-apoptosis, stemness, drug resistance and basal-like state, while increasing luminal-like state genes. In addition, the combined U+C treatment suppressed xenograft tumor growth. The epigenetic reprogramming of histones was identified in the down-regulated BIRC5 and upregulated GADD45A. Conclusion: These findings demonstrate that selectively targeting EHMT2, HDAC1, and HDAC2 by concurrent U+C treatment suppresses BC tumor progression via epigenetic remodeling of BIRC5 and GADD45A.
查看更多>>摘要：Calenduloside E (CE) is a saponin isolated from Aralia elata (Miq) Seem, which has anti-cardiovascular disease effects. This study aims to evaluate the anti-myocardial ischemia-reperfusion injury (MIRI) mechanisms of CE and regulation of BAG3 on calcium overload. We adopted siRNA to interfere with BAG3 expression in H9c2 cardiomyocytes and used adenovirus to interfere with BAG3 expression (Ad-BAG3) in primary neonatal rat cardiomyocytes (PNRCMs) to clarify the role of BAG3 in mitigating MIRI by CE. The results showed that CE reduced calcium overload, and Ad-BAG3 had a significant regulatory effect on L-type Ca~2+ channels (LTCC) but no effects on other calcium-related proteins. And BAG3 and LTCC were colocalized in myocardial tissue and BAG3 inhibited LTCC expression. Surprisingly, CE had no regulatory effect on LTCC mRNA, but CE promoted LTCC degradation through the autophagy-lysosomal pathway rather than the ubiquitination-protease pathway. Autophagy inhibitor played a negative regulation of cardiomyocyte contraction rhythm and field potential signals. Ad-BAG3 inhibited autophagy by regulating the expression of autophagy-related proteins and autophagy agonist treatment suppressed calcium overload. Therefore, CE promoted autophagy through BAG3, thereby regulating LTCC expression, inhibiting calcium overload, and ultimately reducing MIRI.
查看更多>>摘要：Lipoxygenases (ALOX-isoforms) are lipid peroxidizing enzymes, which have been implicated in cell differentiation and maturation but also in the biosynthesis of lipid mediators playing important roles in the pathogenesis of inflammatory, hyperproliferative and neurological diseases. In mammals these enzymes are widely distributed and the human genome involves six functional genes encoding for six distinct human ALOX paralogs. In mice, there is an orthologous enzyme for each human ALOX paralog but the catalytic properties of human and mouse ALOX orthologs show remarkable differences. ALOX inhibitors are frequently employed for deciphering the biological role of these enzymes in mouse models of human diseases but owing to the functional differences between mouse and human ALOX orthologs the uncritical use of such inhibitors is sometimes misleading. In this study we evaluated the paralog- and ortholog-specificity of 13 frequently employed ALOX-inhibitors against four recombinant human and mouse ALOX paralogs (ALOX15, ALOX15B, ALOX12, ALOX5) under different experimental conditions. Our results indicated that except for zileuton, which exhibits a remarkable paralog-specificity for mouse and human ALOX5, no other inhibitor was strictly paralog specific but some compounds exhibit an interesting ortholog-specificity. Because of the variable isoform specificities of the currently available ALOX inhibitors care must be taken when the biological effects of these compounds observed in complex in vitro and in vivo systems are interpreted.
查看更多>>摘要：Introduction: Cold ischemia-reperfusion injury (IRI) is an inevitable event that increases post-transplant complications. We have previously demonstrated that supplementation of University of Wisconsin (UW) solution with non-FDA-approved hydrogen sulfide (H2S) donor molecules minimizes cold IRI and improves renal graft function after transplantation. The present study investigates whether an FDA-approved H2S donor molecule, sodium thiosulfate (STS), will have the same or superior effect in a clinically relevant rat model of syngeneic orthotopic kidney transplantation. Method: Thirty Lewis rats underwent bilateral nephrectomy followed by syngeneic orthotopic transplantation of the left kidney after 24-hour preservation in either UW or UW+STS solution at 4 °C. Rats were monitored to post-transplant day 14 and sacrificed to assess renal function (urine output, serum creatinine and blood urea nitrogen). Kidney sections were stained with H&E, TUNEL, CD68, and myeloperoxidase (MPO) to detect acute tubular necrosis (ATN), apoptosis, macrophage infiltration, and neutrophil infiltration. Result: UW+STS grafts showed significantly improved graft function immediately after transplantation, with improved recipient survival compared to UW grafts (p < 0.05). Histopathological examination revealed significantly reduced ATN, apoptosis, macrophage and neutrophil infiltration and downregulation of pro-inflammatory and pro-apoptotic genes in UW+STS grafts compared to UW grafts (p < 0.05). Conclusion: We show for the first time that preservation of renal grafts in STS-supplemented UW solution protects against prolonged cold IRI by suppressing apoptotic and inflammatory pathways, and thereby improving graft function and prolonging recipient survival. This could represent a novel clinically applicable therapeutic strategy to minimize the detrimental clinical outcome of prolonged cold IRI in kidney transplantation.
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