查看更多>>摘要：Lecithin: cholesterol acyltransferase (LCAT) is the only enzyme in plasma which is able to esterify cholesterol and boost cholesterol esterify with phospholipid-derived acyl chains. In order to better understand the progress of LCAT research, it is always inescapable that it is linked to high-density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT). Because LCAT plays a central role in HDL metabolism and RCT, many animal studies and clinical studies are currently aimed at improving plasma lipid metabolism by increasing LCAT activity in order to find better treatment options for familial LCAT deficiency (FLD), fish eye disease (FED), and cardiovascular disease. Recombinant human LCAT (rhLCAT) injections, cells and gene therapy, and small molecule activators have been carried out with promising results. Recently rhLCAT therapies have entered clinical phase II trials with good prospects. In this review, we discuss the diseases associated with LCAT and therapies that use LCAT as a target hoping to find out whether LCAT can be an effective therapeutic target for coronary heart disease and atherosclerosis. Also, probing the mechanism of action of LCAT may help better understand the heterogeneity of HDL and the action mechanism of dynamic lipoprotein particles.
查看更多>>摘要：The obesity epidemic has become a global public health crisis in recent years and is continuing to worsen at an alarming rate. However, the pathophysiological mechanisms involved in the development of obesity and obesity-related diseases are still being unraveled. In the past ten years, the gut microbiota has been identified as a crucial player affecting the onset and progression of obesity and obesity-related diseases, especially with respect to changes in its composition and metabolites during obesity progression. Herein, we summarize the roles and mechanisms of gut microbiota's composition and metabolite changes in the gut play in obesity and obesity related diseases. Furthermore, we discuss potential therapeutic treatments that can be used to modulate the gut microbiome composition and target the relevant metabolic pathways of obesity and obesity-related metabolic diseases.
查看更多>>摘要：Recent data showed that dabigatran can reduce not only procoagulatory effects but also block pro inflammatory stimuli by inhibiting the expression of cytokines and chemokines and reducing thrombin-induced endothelial permeability. The aim of our study was to assess the effect of dabigatran on the integrity and inflammatory properties of endothelial cells stimulated by 25-hydroxycholesterol (25-OHC, oxysterol). HUVECs (Human Umbilical Vein Endothelial Cells) were stimulated with 25-hydroxycholesterol 10 μg/ml, dabigatran 100 ng/ml or 500 ng/ml and 25-hydroxycholesterol -+- dabigatran (100 ng/ml, 500 ng/ml). HUVEC integrity and permeability was measured in the RTCA-DP xCELLigence system and by the paracellular flux system. The mRNA expression of ICAM-1, VEGF, IL-33, MCP-1 and TNF-α was analyzed by Real-time PCR. Cell apoptosis and viability was measured by flow cytometry. VEGF protein concentration was assessed in supernatants by ELISA. VE-cadherin expression in endothelial cells was evaluated by confocal microscopy. Pre-stimulation of HUVECs with 25-OHC decreased endothelial cell integrity (p < 0.001) and increased the expression of IL-33, ICAM-1, MCP-1, VEGF, TNF-α mRNA (p < 0.01) compared to unstimulated controls. Following stimulation of HUVECs with dabigatran 100 ng/ml or 500 ng/ml restored HUVEC integrity interrupted by 25-OHC (p < 0.001). In HUVECs pre-stimulated with oxysterol, dabigatran stimulation decreased mRNA expression of the proin-flammatory cytokines IL-33 and TNF-α, chemokines MCP-1 ICAM-1 and VEGF (p < 0.01). Dabigatran 500 mg/ ml+ 25-OHC increased the endothelial expression of VE-cadherin as compared to 25-OHC (p < 0.01).Our findings suggest that dabigatran stabilizes the endothelial barrier and inhibits the inflammation caused by oxysterol.
查看更多>>摘要：This study aimed to explore the effects of endometriosis (EMS)-derived exosomes and miR-301a-3p on the polarization of macrophages and investigate the involved molecular mechanism. The exosomes were isolated from ectopic endometrial tissues of EMS patients and normal human serum (NHS). Results of transmission electron microscope and Nanoparticle Tracking Analysis showed that both EMS-exosomes and NHS-exosomes are about 80 nm microvesicles. Exosomal markers CD63 and TSG101 were abundantly expressed in both EMS-exosomes and NHS-exosomes. No negative marker Calnexin was detected in NHS-exosomes. A small amount of Calnexin was detected in EMS-exosomes. THP-1 cells differentiatee to macrophages by incubating with phorbol-12-myristate-13-acetate. Effects of the exosomes on the phagocytosis and polarization of macrophages were evaluated by PKH26 fluorescent labeling and flow cytometry, respectively. Compared with the NHS-exosomes group, the phagocytic capacity of macrophages was reduced and the polarization of macrophages to M2 macrophages was promoted after EMS-exosomes treatment. Results of western blot showed that compared with the NHS-exosomes group, the EMS-exosomes treatment significantly up-regulated the expression of phosphatidylinosi-tol 3-kinase (PI3K) and down-regulated the expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN). miR-301a-3p mimic, negative control (NC) mimic, miR-301a-3p inhibitor and NC inhibitor were transfected into cells. Transfection efficiency was confirmed by RT-qPCR. Effects of the miR-301a-3p expression on the macrophages polarization and the expression of Arg-1, PTEN and PI3K in the macrophages were evaluated by flow cytometry and western blot, respectively. miR-301a-3p overexpression significantly enhanced the ability of EMS-exosomes-inducing M2 transformation of macrophages, promoted the expression of Arg-1 and PI3K, and inhibited the PTEN expression. miR-301a-3p inhibitor significantly reduced the expression of Arg-1 and PI3K and promoted the PTEN expression. In conclusion, EMS derived exosomal miR-301a-3p mediated macrophage polarization via regulating PTEN-PI3K axis.
查看更多>>摘要：Viral infections have a great impact on human health. The urgent need to find a cure against different viruses led us to investigations in a vast range of drugs. Azithromycin (AZT), classified as a macrolide, showed various effects on different known viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV), Zika, Ebola, Enterovirus (EVs) and Rhinoviruses (RVs), and Influenza A previously; namely, these viruses, which caused global concerns, are considered as targets for AZT different actions. Due to AZT background in the treatment of known viral infections mentioned above (which is described in this study), in the early stages of COVID-19 (a new zoonotic disease caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) development, AZT drew attention to itself due to its antiviral and immunomodu-latory effects as a valuable candidate for COVID-19 treatment. AZT usage instructions for treating different viral infections have always been under observation, and COVID-19 is no exception. There are still debates about the use of AZT in COVID-19 treatment. However, eventually, novel researches convinced WHO to announce the discontinuation of AZT use (alone or in combination with hydroxychloroquine) in treating SARS-CoV-2 infection. This research aims to study the structure of all of the viruses mentioned above and the molecular and clinical effects of AZT against the virus.
查看更多>>摘要：Compelling evidence supports the therapeutic benefit of extracellular vesicles (EVs). EVs are nanostructures with a lipid bilayer membrane that are secreted by multiple cells, including mesenchymal stromal cells (MSCs), as means of cellular communication. MSC-EVs, resembling their MSC origin, carry protected immunomodulatory and pro-regenerative cargoes to targeted neighboring or distant cells and tissues. Though treatments focused on MSC-EVs have emerged as greatly versatile approaches to modulate multiple inflammatory-related conditions, crucial concerns, including the possibility of increasing therapeutic outcomes by pre-conditioning parental MSCs or engineering derived EVs and clarification of the most relevant mechanisms of action, remain. Here, we summarize the large amount of preclinical research surrounding the modulation of beneficial effects by MSC-EVs.
查看更多>>摘要：Cancer is one of the main causes of human mortality and brain tumors, including invasive pituitary adenomas, medulloblastomas and glioblastomas are common brain malignancies with poor prognosis. Therefore, the development of innovative management strategies for refractory cancers and brain tumors is important. In states of mitochondrial dysfunction - commonly encountered in malignant cells - cells mostly shift to anaerobic glycolysis by increasing the expression of LDHA (Lactate Dehydrogenase-A) gene. Oxamate, an isosteric form of pyruvate, blocks LDHA activity by competing with pyruvate. By blocking LDHA, it inhibits protumorigenic cascades and also induces ROS (reactive oxygen species)-induced mitochondrial apoptosis of cancer cells. In preclinical studies, oxamate blocked the growth of invasive pituitary adenomas, medulloblastomas and glioblastomas. Oxamate also increases temozolomide and radiotherapy sensitivity of glioblastomas. Oxamate is highly polar, which may preclude its clinical utilization due to low penetrance through cell membranes. However, this obstacle could be overcome with nanoliposomes. Moreover, different oxamate analogs were developed which inhibit LDHC4, an enzyme also involved in cancer progression and germ cell physiology. Lastly, phen-formin, an antidiabetic agent, exerts anticancer effects via complex I inhibition in the mitochondria and leading the overproduction of ROS. Oxamate combination with phenformin reduces the lactic acidosis-causing side effect of phenformin while inducing synergistic anticancer efficacy. In sum, oxamate as a single agent and more efficiently with phenformin has high potential to slow the progression of aggressive cancers with special emphasis to brain tumors.
查看更多>>摘要：Background: Several serious attempts to treat colorectal cancer have been made in recent decades. However, no effective treatment has yet been discovered due to the complexities of its etiology. Methods: we used Weighted Gene Co-expression Network Analysis (WGCNA) to identify key modules, hub-genes, and mRNA-miRNA regulatory networks associated with CRC. Next, enrichment analysis of modules has been performed using Cluepedia. Next, quantitative real-time PCR (RT-qPCR) was used to validate the expression of selected hub-genes in CRC tissues. Results: Based on the WGCNA results, the brown module had a significant positive correlation (r = 0.98, p-value=9e-07) with CRC. Using the survival and DEGs analyses, 22 genes were identified as hub-genes. Next, three candidate hub-genes were selected for RT-qPCR validation, and 22 pairs of cancerous and non-cancerous tissues were collected from CRC patients referred to the Gastroenterology and Liver Clinic. The RT-qPCR results revealed that the expression of GUCA2B was significantly reduced in CRC tissues, which is consistent with the results of differential expression analysis. Finally, top miRNAs correlated with GUCA2B were identified, and ROC analyses revealed that GUCA2B has a high diagnostic performance for CRC. Conclusions: The current study discovered key modules and GUCA2B as a hub-gene associated with CRC, providing references to understand the pathogenesis and be considered a novel candidate to CRC target therapy.
查看更多>>摘要：Naegleria fowleri is the causative agent the primary amoebic meningoencephalitis (PAM), a fatal disease in more than the 90% of the reported cases that affects the central nervous system. The amoeba infects the nasal cavity of mostly children and young adults who report previous aquatic exposure in warm water sources. The rapid progression of the disease and the lack of effective and safety therapeutic options make the search of new anti-amoebic compounds an urgent issue. In this study, twelve sesquiterpene lactones isolated from the zoanthid Palythoa aff. clavata were tested against the trophozoite stage of Naegleria fowleri. Anhydroartemorin (2) and 1 (10)Z,4E,14-acetoxy-costunolide (3) showed the best anti-amoeboid activity values with IC50 23.02 ± 1.26 and 28.34 ± 6.27, respectively. In addition, the mechanisms of programmed cell death induction of these two molecules were evaluated with positive results for both compounds. Finally, a structure-activity relationship was analyzed to reveal the dependence of reactivity and lipophilicity on the biological activity. The log P values of the compounds were calculated to postulate them as good candidates to cross the blood-brain barrier, a limiting factor in the development of new anti-Naegleria treatments. Therefore, the mentioned sesquiterpene lactones could be considered as potential PAM therapeutic options in the future.
Paul Andrei NegruAndrei-Flavius RaduCosmin Mihai VesaTapan Behl...
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查看更多>>摘要：Coronavirus disease 2019 (COVID-19) represents an unmet clinical need, due to a high mortality rate, rapid mutation rate in the virus, increased chances of reinfection, lack of effectiveness of repurposed drugs and economic damage. COVID-19 pandemic has created an urgent need for effective molecules. Clinically proven efficacy and safety profiles have made favipiravir (FVP) and remdesivir (RDV) promising therapeutic options for use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Even though both are prodrug molecules with an antiviral role based on a similar mechanism of action, differences in pharmacological, pharmacokinetic and pharmacotoxicological mechanisms have been identified. The present study aims to provide a comprehensive comparative assessment of FVP and RDV against SARS-CoV-2 infections, by centralizing medical data provided by significant literature and authorized clinical trials, focusing on the importance of a better understanding of the interactions between drug molecules and infectious agents in order to improve the global management of COVID-19 patients and to reduce the risk of antiviral resistance.
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