Ana GutierrezAngel Marquez-GaleraRaquel LinaresEsther Caparros...
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查看更多>>摘要：Background: Crohn's disease (CD) exacerbation is marked by an intense cellular trafficking. We set out to determine the specific impact of biologic therapies on regulating chemokine network gene expression in healthy, mildly and severely inflamed tissue of CD patients. Methods: Twenty CD patients on biologics (adalimumab, ustekinumab, vedolizumab) or untreated undergoing colonoscopy due to clinical symptoms of flare. Healthy, mildly and severely inflamed ileum biopsies from each patient were collected. Chemokines and receptors gene expression was analyzed and a STRING analysis for functional enrichment was performed. Results: The chemokine network exhibited wide transcriptional differences among tissues in active untreated patients, whereas all biologic treatments reduced these differences and homogenized their transcriptional activity. In mildly inflamed tissue, all treatments showed gene upregulation while ustekinumab additionally maintained the downregulation of genes such as CCL2, CCL3, CCL17 or CCL23, involved in T cell chemotaxis, inflammatory monocyte and NK trafficking. In severely inflamed tissue, all treatments shared a downregulatory effect on chemokines controlling T cell response (i.e. CXCL16, CXCR3). Adalimumab and vedolizumab significantly reduced the expression of genes promoting antigen presentation by DCs and the initiation of leukocyte extravasation (i.e. CXCL12, CCL25, CCR7). Ustekinumab significantly reduced genes positively regulating Th1 cytokine production and IL-8 mediated signaling (i.e. IL1B, XCL1, CXCR1, CXCR2). Conclusion: Biologic therapies differentially target the chemokine network gene expression profile in the ileal tissue of active CD patients. These results may contribute to better understanding cell homing and to defining future personalized therapeutic strategies for CD patients.
查看更多>>摘要：As the important active ingredients of Astragali Radix (AR), Astragalus polysaccharides (APs) have therapeutic potential for multiple diseases including nervous system diseases, cardiovascular diseases, diabetes mellitus, and cancer. A large number of cell experiments combined with animal experiments have shed light on the therapeutic mechanisms and therapeutic effects of APs on a variety of diseases. However, the clinical application of APs is not widespread, except for the use of injected APs in the clinical adjuvant therapy of cancer. Due to the excessive molecular weight, bulky, low solubility and negatively charged characteristics, APs have low bio availability which limits their clinical application. With the deepening of researches on the pharmaceutics of APs, the nanocrystals and moderate structural modification enormously boost the bioavailability, which may expand the application of APs. This review summarizes the studies in pharmacodynamic properties and pharmaceutics of APs, with the purpose of providing experimental researches and clinical application data for expanding the clinical development through expounding the therapeutic mechanisms and pharmaceutical researches of APs.
查看更多>>摘要：Cardiovascular diseases (CVDs) are now the leading cause of mortality and morbidity worldwide , resulting in a large global economic burden. Recently, complementary and alternative medicine, such as traditional Chinese medicine (TCM) have received great attention. Puerarin (Pue) is an isoflavone isolated from the roots ofPueraria lobata (Willd.) Ohwi (also named "Ge gen" in China), and is a versatile TCM herb used for the treatment of fever, diarrhea, diabetes mellitus CVDs and cerebrovascular diseases. Numerous lines ofin vitro studies, as well as in vivo animal experiments have established that Pue offers beneficial roles against the progression of atherosclerosis, ischemic heart diseases, heart failure hypertension and arrhythmia by inhibiting pathological processes, such as the mitigation of endothelium injury, protection against inflammation, the disturbance of lipid metabolism, protection against ischemic reperfusion injury, anti-myocardial remodeling and other effects. Here, we provide a systematic overview of the pharmacological actions and molecular targets of Pue in cardiovascular disease prevention and treatment, to provide insights into the therapeutic potential of Pue in treating cardiovascular diseases.
查看更多>>摘要：Mitochondrial uncoupling proteins (UCP) are a part of the large family of mitochondrial solute carriers (SLC25s), concentrated in the inner mitochondrial membrane that carries protons from intermembrane space to the matrix. Further, some UCPs are also involved in the transportation of the fatty acid anions and catalyzed the proton transport by fatty acid cycling across the membrane. Out of the 5 UCPs, UCP 2, 4, and 5 are localized in the central nervous system (CNS), and alteration within the expression of these UCPs results in neuronal dysfunction and, ultimately, death of neurons. UCPs play a vital role in regulating mitochondrial membrane potential, preventing reactive oxygen species (ROS) production, alteration in neuronal activity, and the regulation of calcium homeostasis that ultimately results in the prevention of neuronal loss. These changes in mitochondria impact the function and survival of neurons playing a critical role in the progression of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). Additionally, UCP2 regulates the microglia response towards neuroinflammation by modulating microglia's M1 and M2 phenotypes. These microglia cells are further involved in regulating inflammatory response and synaptic functions. Moreover, UCP2, 4, and 5 are ubiquitously present in all brain regions that negatively regulate ROS production and inflammation, leading to the prevention of neuronal cell death. Increased ROS production is a common symptom reported in neurodegenerative diseases that affect several pathways concerned with neuronal death, either apoptosis or autophagy. These accumulating evidence suggested UCPs as a possible therapeutic target for the management of neurodegenerative diseases.
查看更多>>摘要：Tumour-derived exosomes (TDEs) are actively produced and released by tumour cells and carry messages from tumour cells to normal or abnormal cells residing at close or distant sites. TDEs participate in every process of tumour metastasis. However, the occurrence and development of tumours depend on the specific functions acquired by tumour cells on the primary and metastatic foci. In this review, we discussed that TDEs regulate the initial mechanism of metastasis, the formation of a pre-metastatic niche, immunosuppression and angiogenesis. In addition, we investigated the signalling pathways and effective components of TDEs and discussed that inhibition of exosomes can inhibit tumour progression. Finally, we discussed the application and future development of TDEs. An understanding of several molecular players and processes involved in metastasis can lead to the development of effective, targeted approaches to prevent metastasis and treat cancer.
查看更多>>摘要：The unexpected emergence of the new Coronavirus disease (COVID-19) has affected more than three hundred million individuals and resulted in more than five million deaths worldwide. The ongoing pandemic has underscored the urgent need for effective preventive and therapeutic measures to develop anti-viral therapy. The natural compounds possess various pharmaceutical properties and are reported as effective anti-virals. The interest to develop an anti-viral drug against the novel severe acute respiratory syndrome Coronavirus (SARS-CoV-2) from natural compounds has increased globally. Here, we investigated the anti-viral potential of selected promising natural products. Sources of data for this paper are current literature published in the context of therapeutic uses of phytoconstituents and their mechanism of action published in various reputed peer-reviewed journals. An extensive literature survey was done and data were critically analyzed to get deeper insights into the mechanism of action of a few important phytoconstituents. The consumption of natural products such as thy-moquinone, quercetin, caffeic acid, ursolic acid, ellagic acid, vanillin, thymol, and rosmarinic acid could improve our immune response and thus possesses excellent therapeutic potential. This review focuses on the anti-viral functions of various phytoconstituent and alkaloids and their potential therapeutic implications against SARS-CoV-2. Our comprehensive analysis provides mechanistic insights into phytoconstituents to restrain viral infection and provide a better solution through natural, therapeutically active agents.
查看更多>>摘要：Background: Diabetes mellitus (DM)-related corneal epithelial dysfunction is a severe ocular disorder; however, the effects of nicotinamide mononucleotide (NMN) on high-glucose (HG)-treated human corneal epithelial cells (HCECs) remain unclear. Methods: We conducted an in-vitro study to examine the effects of NMN treatment on HG-treated HCECs. Cell viability was measured using trypan blue stain, mitochondrial membrane potential was measured using JC-1 stain, and intracellular reactive oxygen species and apoptosis assays were conducted using flow cytometry. Transepithelial electrical resistance (TEER) and zonula occludens-1 (ZO-1) immunofluorescence for tight junction examinations were conducted. Immunoblot analyses were conducted to analyze the expression of silent information regulator-1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) of the SIRT1/Nrf2/HO-1 pathway. Results: NMN increased cell viability by reducing cell damage, reducing apoptosis, increasing cell migration, and restoring tight junctions in HG-treated HCECs. By analyzing the expressions of SIRT1, Nrf2, HO-1, NMN demonstrated protective effects via the SIRT1/Nrf2/HO-1 pathway. Conclusions: NMN increases cell viability by reversing cell damage, reducing apoptosis, increasing cell migration, and restoring tight junctions in HG-treated HCECs, and these effects may be mediated by the SIRT1/Nrf2/HO-1 pathway.
查看更多>>摘要：Oral squamous cells carcinoma (OSCC) is the most common oral malignancy that majorly originated from oral cavity. Though the prognostic and predictive value of targeting checkpoint molecules has been reported on OSCC, the treatment efficacy of monotherapy is remaining limited. Several studies suggested that multikinase inhibitors may show potential to facilitate anti-PD-L1-induced anti-tumor immunity. Regorafenib, an oral multikinase inhibitor has been approved by FDA for various types of cancer treatment. Here, we aim to identify whether regorafenib may boost anti-tumor immunity of anti-PD-L1 in MOC1-bearing OSCC animal model. The alteration of immune cells such as M1/M2-like macrophages (MΦ), cytotoxicity T cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) after combination of anti-PD-L1 and regorafenib was validated by flow cytometry and immunohistochemistry staining. The combination index analysis (CI=0.89) supported that regorafenib effectively induce anti-OSCC efficacy of anti-PD-L1. Combination of anti-PD-L1 and regorafenib may not only trigger the polarization of M1-like MΦ (CD11b~+CD86~+) in mice bone marrow (BM) and spleen (SP), but also induce the accumulation and function of CD8+ T cells in tumor-draining lymph node (TDLN) and tumor. In addition, immunosuppressive related cells (MDSCs and Treg) and factors were all decreased by combination therapy in BM, SP and tumor. In sum, regorafenib may improve anti-OSCC efficacy of anti-PD-L1 through sys-temically and locally upregulating the immunostimulation immunity and suppressing immunosuppression immunity.
查看更多>>摘要：Acquired drug resistance and metastasis in breast cancer (BC) are coupled with epigenetic deregulation of gene expression. Epigenetic drugs, aiming to reverse these aberrant transcriptional patterns and sensitize cancer cells to other therapies, provide a new treatment strategy for drug-resistant tumors. Here we investigated the ability of DNA methyltransferase (DNMT) inhibitor decitabine (DAC) to increase the sensitivity of BC cells to anthracycline antibiotic doxorubicin (DOX). Three cell lines representing different molecular BC subtypes, JIMT-1, MDA-MB-231 and T-47D, were used to evaluate the synergy of sequential DAC -+- DOX treatment in vitro. The cytotoxicity, genotoxicity, apoptosis, and migration capacity were tested in 2D and 3D cultures. Moreover, genome-wide DNA methylation and transcriptomic analyses were employed to understand the differences underlying DAC responsiveness. The ability of DAC to sensitize trastuzumab-resistant HER2-positive JIMT-1 cells to DOX was examined in vivo in an orthotopic xenograft mouse model. DAC and DOX synergistic effect was identified in all tested cell lines, with JIMT-1 cells being most sensitive to DAC. Based on the whole-genome data, we assume that the aggressive behavior of JIMT-1 cells can be related to the enrichment of epithelial-to-mesenchymal transition and stemness-associated pathways in this cell line. The four-week DAC + DOX sequential administration significantly reduced the tumor growth, DNMT1 expression, and global DNA methylation in xenograft tissues. The efficacy of combination therapy was comparable to effect of pegylated liposomal DOX, used exclusively for the treatment of metastatic BC. This work demonstrates the potential of epigenetic drugs to modulate cancer cells' sensitivity to other forms of anticancer therapy.
查看更多>>摘要：Memory-enhancing agents have long been required for various reasons such as for obtaining a good score in a test in the young and for retaining memory in the aged. Although many studies have found that several natural products may be good candidates for memory enhancement, there is still a need for better agents. The present study investigated whether rubrofusarin, an active ingredient in Cassiae semen, enhances learning and memory in normal mice. Passive avoidance and Morris water maze tests were performed to determine the memory-enhancing ability of rubrofusarin. To investigate synaptic function, hippocampal long-term potentiation (LTP) was measured. Western blotting was performed to determine protein levels. To investigate neurite outgrowth, DCX immunohistochemistry and cell culture were utilised. Rubrofusarin (1, 3, 10, 30 mg/kg) enhanced memory in passive avoidance and Morris water maze tests. Moreover, rubrofusarin ameliorated scopolamine-induced memory impairment. In the rubrofusarin-treated group, high-frequency stimulation induced higher LTP in the hippocampal Schaffer-collateral pathway compared to the control group. The rubrofusarin-treated group showed a higher number of DCX-positive immature neurons with an increase in the length of dendrites compared to the control group in the hippocampal dentate gyrus region. In vitro experiments showed that rubrofusarin facilitated neurite outgrowth in neuro2a cells through extracellular signal-regulated kinase (ERK). Finally, we found that extracellular signal-regulated kinase (ERK) is required for rubrofusarin-induced enhancement of neurite outgrowth, learning and memory. These results demonstrate that rubrofusarin enhances learning and memory and neurite outgrowth, and these might need activation of ERK pathway.
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