Archaea and Bacteria have evolved different defence strategies that target virtually all steps of the viral life cycle. The diversified virion morphotypes and genome contents of archaeal viruses ...result in a highly complex array of archaea-virus interactions. However, our understanding of archaeal antiviral activities lags far behind our knowledges of those in bacteria. Here we report a new archaeal defence system that involves DndCDEA-specific DNA phosphorothioate (PT) modification and the PbeABCD-mediated halt of virus propagation via inhibition of DNA replication. In contrast to the breakage of invasive DNA by DndFGH in bacteria, DndCDEA-PbeABCD does not degrade or cleave viral DNA. The PbeABCD-mediated PT defence system is widespread and exhibits extensive interdomain and intradomain gene transfer events. Our results suggest that DndCDEA-PbeABCD is a new type of PT-based virus resistance system, expanding the known arsenal of defence systems as well as our understanding of host-virus interactions.
BRDs proteins that recognise chromatin acetylation regulate gene expression, are epigenetic readers and master transcription coactivators. BRDs proteins are now emerging as targets for new ...therapeutic development. Blocking the function of any of BRDs proteins can be a control agent for diseases, such as cancer. Traditional drugs like enzyme inhibitors and protein-protein inhibitors have many limitations. The therapeutic efficacy of them remains to be proven. Recently, Proteolysis-Targeting Chimaeras (PROTACs) have become an advanced tool in therapeutic intervention as they remove disease-causing proteins. Extremely potent and efficacious small-molecule PROTACs of the BRDs proteins, based on available, potent, and selective BRDs inhibitors, have been reported. This review presents a comprehensive overview of the development of PROTACs for BRDs proteins regulation in cancer, and the chances and challenges associated with this area are also highlighted.
Generally, a homogeneous catalyst exhibits good activity and defined active sites but it is difficult to recycle. Meanwhile, a heterogeneous catalyst can easily be reused but its active site is ...difficult to reveal. It is interesting to bridge the gap between homogeneous and heterogeneous catalysis via controllable construction of a heterogeneous catalyst containing defined active sites. Here, we report that a molecularly defined, single-active site heterogeneous catalyst has been designed and prepared via the oxidative polymerization of maleimide derivatives. These polymaleimide derivatives can be active catalysts for the selective oxidation of heterocyclic compounds to quinoline and indole via the recycling of -C=O and -C-OH groups, which was confirmed by tracing the reaction with GC-MS using maleimide as the catalyst and by FT-IR analysis with polymaleimide as the catalyst. These results might promote the development of heterogeneous catalysts with molecularly defined single active sites exhibiting a comparable activity to homogeneous catalysts.
Abstract Cell-derived microvesicles (MVs) have been recently shown as an efficient carrier to deliver small RNAs into the target cells. In the present study, we characterized the inhibitory effect of ...TGF-β1 siRNA delivered by mouse fibroblast L929 cell-derived MVs (L929 MVs) on the growth and metastasis of murine sarcomas 180 cells both in vitro and in vivo . We found that, comparing to the same concentration of free TGF-β1 siRNA, TGF-β1 siRNA delivered by L929 MVs much more efficiently decreased the level of TGF-β1 in the recipient tumor cells. Functionally, MVs containing TGF-β1 siRNA significantly decreased the viability and migration of sarcomas 180 cells and promoted the apoptosis of tumor cells. Co-immunoprecipitation with Argonaute 2 (AGO2) via anti-AGO2 antibody indicated that the majority of TGF-β1 siRNA in the MVs were associated with AGO2 complex. A tumor implantation mouse model further showed that intravenous injection of TGF-β1 siRNA-containing MVs strongly suppressed TGF-β1 expression and TGF-β1 signaling downstream in the implanted tumor cells, and thus inhibited the growth and lung metastases of tumor cells. In conclusion, our results collectively demonstrate that the delivery of therapeutic TGF-β1 siRNA by cell-derived MVs provides an effective strategy to control tumor cell growth and metastasis.
Contrast-induced encephalopathy (CIE) is an uncommon complication associated with contrast exposure during angiographic procedures that is usually transient but occasionally leads to permanent ...complications or death. Due to the low incidence of CIE, there are still insufficient reports. This study was used to summarize the clinical features of CIE through a case report and systematic review. We summarized and reviewed 127 patients with CIE, and we found that the total incidence of CIE between men and women had no difference (49.61 and 50.39%, respectively), but the average age in female patients with CIE was older than that in male patients (62.19 and 58.77 years, respectively). Interestingly, the incidence of female patients with CIE in the poor prognosis group was significantly higher than that in the good prognosis group (62.50 and 36.51%, respectively), and the average age of these female patients in the poor prognosis group was younger than that in the good prognosis group (61.39 and 62.82 years, respectively). The contrast medium types were mainly nonionic (79.69 and 73.02%, respectively) and low-osmolar (54.69 and 71.43%, respectively) in both groups. Importantly, the total contrast media administrated in patients with poor prognoses was greater than that administrated in patients with good prognoses (198.07 and 188.60 ml, respectively). In addition, comorbidities in both groups included hypertension (55.91%), diabetes mellitus (20.47%), previous contrast history (15.75%), renal impairment (11.81%), and hyperlipidemia (3.15%). The percentage of patients with cerebral angiography was significantly higher in the poor prognosis group than that in the good prognosis group (37.50 and 9.52%, respectively), whereas the percentage of patients with coronary angiography in both groups had the opposite results (35.94 and 77.78%, respectively). In conclusion, CIE may not always have a benign outcome and can cause permanent deficits. Female gender, younger age, the higher dose of contrast medium, and the procedure of cerebral angiography may be related to the patient's poor prognosis.
Recent studies by our group and others show that microRNAs can be actively secreted into the extracellular environment through microvesicles (MVs) and function as secretory signaling molecules that ...influence the recipient cell phenotypes. Here we investigate the role of monocyte-secreted miR-150 in promoting the capillary tube formation of endothelial cells and in enhancing angiogenesis. In vitro capillary tube formation and in vivo angiogenesis assays showed that monocyte-derived MVs have strong pro-angiogenic activities. By depleting miR-150 from monocytic MVs and increasing miR-150 in MVs derived from cells that normally contain low levels of miR-150, we further demonstrated that the miR-150 content accounted for the pro-angiogenic activity of monocytic MVs in these assays. Using tumor-implanted mice and ob/ob mice as models, we revealed that miR-150 secretion, which is increased for diseases such as cancers and diabetes, significantly promotes angiogenesis. The delivery of anti-miR-150 antisense oligonucleotides into tumor-implanted mice and ob/ob mice via MVs, however, strongly reduced angiogenesis in both types of mice. Our results collectively demonstrate that secretion of miR-150 via MVs can promote angiogenesis in vitro and in vivo, and we also present a novel microRNA-based therapeutic approach for disease treatment.
Background: The mechanism of secreted miRNA promoting angiogenesis is still unclear.
Results: Secreted miR-150 from monocyte induce endothelial cell tube formation in vitro and angiogenesis in vivo, and down-regulation of miR-150 inhibits angiogenesis caused by diabetes, cancer, and atherosclerosis.
Conclusion: Monocyte-derived miR-150 can induce angiogenesis via targeting endothelial cells.
Significance: Our study illustrates the new role of a secreted miRNA in angiogenesis.
Hexavalent chromium Cr(VI) is a common heavy metal pollutant that can cause a number of human disease, including inflammation and cancer. Senescent cells can secrete a variety of molecules known as ...senescence-associated secretory phenotype (SASP). Our previous studies have confirmed that Cr(VI) can induce premature senescence in L02 hepatocytes, but the composition and the function of the related SASP are still unknown. In order to understand the components of SASP secreted by senescent L02 hepatocytes under the action of Cr(VI), we applied LC-MS/MS-based label-free protein quantification. We found that three SASP components including Coactosin-like protein 1 (COTL1), Alpha-enolase (ENO1), and Peroxiredoxin 2 (PRDX2) were up-regulated, which were confirmed by western blotting and qRT-PCR. Evidence suggested that SASP may promote the development of tumor through chronic inflammatory response, therefore we identified and analyzed the potential biological functions and signaling pathways of these three SASP components using GO and KEGG methods. The interaction between SASP components was analyzed by STRING, and verified by Co-IP. We also found that ENO1 and PRDX2, which have direct interaction, can inhibit the growth and proliferation of wildtype hepatocytes and premature senescent hepatocytes, but can promote the proliferation and behavioral changes of liver tumor cells. The present study provides valuable clues for elucidation of the carcinogenic mechanism of Cr(VI), especially for further prevention and targeted treatment of Cr(VI)-related cancer.
•Cr(VI) induces premature senescence in L02 hepatocytes.•Cr(VI)-induced SASP components include COTL1, ENO1, PRDX2.•ENO1 directly interacts with PRDX2 in Cr(VI)-induced senescent hepatocytes.•ENO1 and PRDX2 regulate proliferation of wildtype/senescent hepatocytes and HCCLM3.
Autologous adipose tissue or adipose tissue with additive adipose-derived mesenchymal stem cells (ADSCs) is used in the breast reconstruction of breast cancer patients who undergo mastectomy. ADSCs ...play an important role in the angiogenesis and adipogenesis, which make it much better than other materials. However, ADSCs may promote residual tumor cells to proliferate or metastasize, and the mechanism is still not fully understood. In this study, we demonstrated that human ADSCs (hADSCs) could facilitate tumor cells growth after co-injection with MCF7 and ZR-75-30 breast cancer cells (BCCs) by promoting angiogenesis, but hADSCs showed limited effect on the growth of MDA-MB-231 BCCs. Intriguingly, compared with ZR-75-30 tumor cells, MCF7 tumor cells were more potentially promoted by hADSCs in the aspects of angiogenesis and proliferation. Consistent with this, cytokine and angiogenesis array analyses showed that after co-injection with hADSCs, the CXCL1 and CXCL8 concentration were significantly increased in MCF7 tumor, but only moderately increased in ZR-75-30 tumor and did not increase in MDA-MB-231 tumor. Furthermore, we found that CXCL1/8 were mainly derived from hADSCs and could increase the migration and tube formation of human umbilical vein endothelial cells (HUVECs) by signaling via their receptors CXCR1 and CXCR2. A CXCR1/2-specific antagonist (SCH527123) attenuated the angiogenesis and tumor growth in vivo. Our findings suggest that CXCL1/8 secreted by hADSCs could promote breast cancer angiogenesis and therefore provide better understanding of safety concerns regarding the clinical application of hADSCs and suggestion in further novel therapeutic options. Stem Cells 2017;35:2060-2070.
Immunotherapy based on the immune checkpoint blockade has emerged as the most promising approach for cancer therapy. However, the proportion of colorectal cancer patients who benefit from ...immunotherapy is small due to the immunosuppressive tumor microenvironment. Hence, combination immunotherapy is an ideal strategy to overcome this limitation. In this study, we developed a novel combination of CSF-1R (colony-stimulating factor 1 receptor) inhibitor (PLX3397), oncolytic viruses, and anti-PD-1 antibody. Our results demonstrated that the triple treatment synergistically conferred significant tumor control and prolonged the survival of mouse models of colon cancer. Approximately 43% and 82% of mice bearing the CT26 and MC38 tumor, respectively, survived long term following the triple treatment. This combination therapy reprogrammed the immunosuppressive tumor microenvironment toward a CD8+ T cell-biased anti-tumor immunity by increasing T cell infiltration in the tumor and augmenting anti-tumor CD8+ T cell function. Our results provide a robust strategy for clinical combination therapy.
The tumor microenvironment develops multiple immune escape mechanisms, thus limiting the immunotherapy efficacy of monotherapy. Deng and colleagues design a novel combination of oncolytic viruses, CSF-1R inhibitor (PLX3397), and anti-PD-1. This combination strategy reprograms the immunosuppressive microenvironment to facilitate anti-tumor immunity, and it induces tumor regression and long-term protection in mouse colon cancer models.
Neurodegenerative diseases, like Alzheimer's disease, Huntington's disease, Parkinson's disease, progressive supranuclear palsy, and frontotemporal dementia are among the refractory diseases that ...lack appropriate drugs and treatments. Numerous disease-causing proteins in neurodegenerative diseases are undruggable for traditional drugs. Many clinical studies of drugs for Alzheimer's disease have failed, and none of the substances that slowed the amyloid-β (Aβ) accumulation process have been approved for use in clinical trials. A novel approach to addressing this issue is Proteolysis targeting chimeras (PROTACs) technology. PROTACs are heterogeneous functional molecules joined by a chemical linker and include binding ligands for the target protein and recruitment ligands for the E3 ligand. When a PROTAC binds to a target protein, the E3 ligand enzyme is brought into close contact and the target protein begins to be polyubiquitinated, followed by proteasome-mediated degradation. Numerous neurodegenerative disease-related targets, including α-Synuclein, mHTT, GSK-3, LRRK2, Tau, TRKA, and TRKC have been successfully targeted by PROTACs to date. This article presents a comprehensive overview of the development of PROTACs in neurodegenerative diseases. These PROTACs' chemical structures, preparative routes, in vitro and in vivo activities, and pharmacodynamics are outlined. We also offer our viewpoint on PROTACs' probable challenges and future prospects.
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