Small ubiquitin-like modifier (SUMO) binding (termed SUMOylation) emerged as the inducer for the sorting of bioactive molecules into extracellular vesicles (EVs), triggering lymphangiogenesis and ...further driving tumor lymph node (LN) metastasis, but the precise mechanisms remain largely unclear. Here, we show that bladder cancer (BCa) cell-secreted EVs mediated intercellular communication with human lymphatic endothelial cells (HLECs) through transmission of the long noncoding RNA ELNAT1 and promoted lymphangiogenesis and LN metastasis in a SUMOylation-dependent manner in both cultured BCa cell lines and mouse models. Mechanistically, ELNAT1 induced UBC9 overexpression to catalyze the SUMOylation of hnRNPA1 at the lysine 113 residue, which mediated recognition of ELNAT1 by the endosomal sorting complex required for transport (ESCRT) and facilitated its packaging into EVs. EV-mediated ELNAT1 was specifically transmitted into HLECs and epigenetically activated SOX18 transcription to induce lymphangiogenesis. Importantly, blocking the SUMOylation of tumor cells by downregulating UBC9 expression markedly reduced lymphatic metastasis in EV-mediated, ELNAT1-treated BCa in vivo. Clinically, EV-mediated ELNAT1 was correlated with LN metastasis and a poor prognosis for patients with BCa. These findings highlight a molecular mechanism whereby the EV-mediated ELNAT1/UBC9/SOX18 regulatory axis promotes lymphangiogenesis and LN metastasis in BCa in a SUMOylation-dependent manner and implicate ELNAT1 as an attractive therapeutic target for LN metastatic BCa.
Patients with lymph node (LN)-positive pancreatic ductal adenocarcinoma (PDAC) have extremely poor survival rates. Circular RNAs (circRNAs), a newly discovered type of endogenous noncoding RNAs, have ...been proposed to mediate the progression of diverse types of tumors. However, the role and underlying regulatory mechanisms of circRNAs in the LN metastasis of PDAC remain unknown.
Next-generation sequencing was used to identify differentially expressed circRNAs between PDAC and normal adjacent tissues. In vitro and in vivo experiments were conducted to evaluate the functional role of circNFIB1. RNA pulldown and luciferase assays were performed to examine the binding of circNFIB1 and miR-486-5p.
In the present study, we identified that a novel circRNA (circNFIB1, hsa_circ_0086375) was downregulated in PDAC and negatively associated with LN metastasis in PDAC patients. Functionally, circNFIB1 knockdown promoted lymphangiogenesis and LN metastasis of PDAC both in vitro and in vivo. Mechanistically, circNFIB1 functioned as a sponge of miR-486-5p, and partially reversed the effect of miR-486-5p. Moreover, circNFIB1 attenuated the oncogenic effect of miR-486-5p and consequently upregulated PIK3R1 expression, which further downregulated VEGF-C expression through inhibition of the PI3K/Akt pathway, and ultimately suppressed lymphangiogenesis and LN metastasis in PDAC.
Our findings provide novel insight into the underlying mechanism of circRNA-mediated LN metastasis of PDAC and suggest that circNFIB1 may serve as a potential therapeutic target for LN metastasis in PDAC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Vitamin D deficiency is identified as a risk factor for gestational diabetes mellitus (GDM). Forkhead box class O1 (FoxO1) is closely related to GDM; however, the role of vitamin D deficiency and the ...underlying pathogenesis of GDM has not been elucidated. Serum vitamin D level was detected using chemiluminescence immunoassay. FOXO1 expression was examined using Real-time polymerase chain reaction (PCR), western blot and immunocytochemistry analysis. Apoptosis of cells was assessed by flow cytometry. Mitochondrial function was assessed via reactive oxygen species (ROS) generation and changes in the mitochondrial membrane potential (ΔΨm). Our study demonstrated that vitamin D levels were significantly lower in 40 GDM patients. The silencing of the vitamin D receptor (VDR) decreased cell survival and increased both FoxO1 mRNA and protein expression. Overexpression of FoxO1 could cause the mitochondrial dysfunction (including production of ROS and decrease of mitochondrial membrane potential (ΔΨm)) and cell apoptosis. However, Overexpression of VDR and vitamin D treatment could induce the cell survival and alleviate the FoxO1-induced cell apoptosis, furthermore, vitamin D treatment or silencing of FoxO1 gene could reverse the ROS-induced cell apoptosis. Therefore, our results support that vitamin D may protect FoxO1-induced pancreatic beta cell apoptosis, which suggests that vitamin D may have beneficial effects in preventing and treating GDM.
Aims
Microbial inoculation has been proposed as a potential approach for rhizosphere engineering. However, it is still unclear to what extent successful plant growth-promoting effects are driven by ...the origin of the microbial inocula and which taxa are responsible for the plant-beneficial effects.
Methods
We conducted a microbial transplant experiment by using different microbial inocula (and nutrient controls) isolated from forest, soybean and tomato field soils and determined their effects on tomato plant biomass and nutrient assimilation in sterilized tomato soil. Rhizosphere bacterial communities were compared at the end of the experiment and correlative and machine learning analyses used to identify potential keystone taxa associated with the plant growth-promotion.
Results
Microbial inoculants had a clear positive effect on plant growth compared to control nutrient inoculants. Specifically, positive effects on the plant biomass were significantly associated with microbial inoculants from the forest and soybean field soils, while microbial inoculants from the forest and tomato field soils had clear positive effects on the plant nutrient assimilation. Soil nutrients alone had relatively minor effects on rhizosphere bacterial communities. However, the origin of microbial inoculants had clear effects on the structure of bacterial community structure with tomato and soybean inoculants having positive effects on the diversity and abundance of bacterial communities, respectively. Specifically,
Streptomyces
,
Luteimonas
and
Enterobacter
were identified as the potential keystone genera affecting plant growth.
Conclusions
The origin of soil microbiome inoculant can predictably influence plant growth and nutrient assimilation and that these effects are associated with certain key bacterial genera.
Accumulating evidence suggests that circular RNAs (circRNAs) are important participants in cancer progression. However, the biological processes and underlying mechanisms of circRNAs in pancreatic ...ductal adenocarcinoma (PDAC) are unclear.
CircRNAs were verified by Sanger sequencing. Colony formation, 5-Ethynyl-2'-deoxyuridine (EdU), and Transwell assays were performed to investigate the effect of circBFAR on the proliferation, invasion, and migration of PDAC cells in vitro. RNA pull-down assays were conducted to verify the binding of circBFAR with microRNA miR-34b-5p.
In the present study, we identified a novel circRNA (termed as circBFAR, hsa_circ_0009065) that was upregulated in a 208-case cohort of patients with PDAC. The ectopic expression of circBFAR correlated positively with the tumor-node-metastasis (TNM) stage and was related to poorer prognosis of patients with PDAC. Moreover, circBFAR knockdown dramatically inhibited the proliferation and motility of PDAC cells in vitro and their tumor-promoting and metastasis properties in in vivo models. Mechanistically, circBFAR upregulated mesenchymal-epithelial transition factor (MET) expression via sponging miR-34b-5p. Additionally, circBFAR overexpression increased the expression of MET and activated downstream phosphorylation of Akt (Ser 473) and further activated the MET/PI3K/Akt signaling pathway, which ultimately promoted the progression of PDAC cells. Importantly, application of MET inhibitors could significantly attenuate circBFAR-mediated tumorigenesis in vivo.
Our findings showed that circBFAR plays an important role in the proliferation and metastasis of PDAC, which might be explored as a potential prognostic marker and therapeutic target for PDAC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study examines the mobile phone practices of rural left-behind children (LBC) whose one or both parents migrate to cities for better earnings and the impact of such practices on migrant families ...in China. The study has used ethnographic approach by conducting participant observations and interviews of 21 LBC, residing in Guangren village, south China's Guangxi Autonomous Region. The study uses domestication theory to analyze these LBC's adoption of mobile phones in their daily routines and spaces in and out of their households. The key findings are as follows: (a) the LBC used mobile phones primarily to engage with their distant parent(s); (b) through collaborative efforts, they tried to enhance familial connections; and (c) they overcome the separation issue by co-participating in ongoing events, thus making the domestication of mobile phone a distant solving of real-world problems faced by migrant parent(s) and their LBC. The study concludes that LBC's innovative uses of mobile phones empowered them by building shared virtual space with their migrant parent(s),
via
which they handled the separation issue. In such shared virtual spaces, LBC's families have developed rich expressions of familial connections in various forms based on the limited perpetuate connectedness.
AbstractAn experimental test is proposed to investigate the interface shear strength between carbonated concrete substrate and self-compacting concrete (SCC) overlay. Thirty-nine Z-type specimens ...consisting of two L-type concrete members were designed and subjected to direct shear test. One L-type concrete member was cast as substrate and carbonated. Then the SCC was cast as overlay. The effects of carbonation of substrate, strength of SCC overlay, and interfacial treatment on shear strength were discussed and clarified. A coefficient was developed to consider the influence of carbonation on the shear strength prediction between old concrete substrate and new SCC overlay. Results showed that carbonation of substrate affects both the interface shear strength and cracking. The shear strength increased by 30% when the carbonation depth of substrate was deeper than 20 mm. The location of shear crack was changed from the bonding interface to the interface between the carbonated and uncarbonated layers within the substrate. The strength of new self-compacting concrete and the interface treatment also affected the interface shear strength. For specimens without interfacial planted bars, the shear strength increased with the strength of SCC overlay until it was more than 5 MPa greater than that of the substrate. The strength of SCC overlay, however, had negligible effect on the shear strength of specimens reinforced with interfacial planted bars.
The activation of NF-κB signaling pathway is regarded as the dominant process that correlates with tumorigenesis. Recently, increasing evidence shows that long noncoding RNAs (lncRNAs) play crucial ...roles in sustaining the NF-κB signaling pathway. However, the underlying mechanisms have not yet been elucidated.
The expression and clinical features of PLACT1 were analyzed in a 166-case cohort of PDAC by qRT-PCR and in situ hybridization. The functional role of PLACT1 was evaluated by both in vitro and in vivo experiments. Chromatin isolation by RNA purification assays were utilized to examine the interaction of PLACT1 with IκBα promoter.
We identified a novel lncRNA-PLACT1, which was significantly upregulated in tumor tissues and correlated with progression and poor survival in PDAC patients. Moreover, PLACT1 promoted the proliferation and invasion of PDAC cells in vitro. Consistently, PLACT1 overexpression fostered the progression of PDAC both in orthotopic and lung metastasis mice models. Mechanistically, PLACT1 suppressed IκBα expression by recruiting hnRNPA1 to IκBα promoter, which led to increased H3K27me3 that decreased the transcriptional level of IκBα. Furthermore, E2F1-mediated overexpression of PLACT1 modulated the progression of PDAC by sustained activation of NF-κB signaling pathway through forming a positive feedback loop with IκBα. Importantly, administration of the NF-κB signaling pathway inhibitor significantly suppressed PLACT1-induced sustained activation of NF-κB signaling pathway, leading to reduced tumorigenesis in vivo.
Our findings suggest that PLACT1 provides a novel epigenetic mechanism involved in constitutive activation of NF-κB signaling pathway and may represent a new therapeutic target of PDAC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lymph node (LN) metastasis occurs frequently in pancreatic ductal adenocarcinoma (PDAC) and predicts poor prognosis for patients. The KRASG12D mutation confers an aggressive PDAC phenotype that is ...susceptible to lymphatic dissemination. However, the regulatory mechanism underlying KRASG12D mutation-driven LN metastasis in PDAC remains unclear. Herein, we found that PDAC with the KRASG12D mutation (KRASG12D PDAC) sustained extracellular vesicle-mediated (EV-mediated) transmission of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) in a SUMOylation-dependent manner and promoted lymphangiogenesis and LN metastasis in vitro and in vivo. Mechanistically, hnRNPA1 bound with SUMO2 at the lysine 113 residue via KRASG12D-induced hyperactivation of SUMOylation, which enabled its interaction with TSG101 to enhance hnRNPA1 packaging and transmission via EVs. Subsequently, SUMOylation induced EV-packaged-hnRNPA1 anchoring to the adenylate- and uridylate-rich elements of PROX1 in lymphatic endothelial cells, thus stabilizing PROX1 mRNA. Importantly, impeding SUMOylation of EV-packaged hnRNPA1 dramatically inhibited LN metastasis of KRASG12D PDAC in a genetically engineered KrasG12D/+ Trp53R172H/+ Pdx-1-Cre (KPC) mouse model. Our findings highlight the mechanism by which KRAS mutant-driven SUMOylation triggers EV-packaged hnRNPA1 transmission to promote lymphangiogenesis and LN metastasis, shedding light on the potential application of hnRNPA1 as a therapeutic target in patients with KRASG12D PDAC.
Stroke is deemed a worldwide leading cause of neurological disability and death, however, there is currently no promising pharmacotherapy for acute ischemic stroke aside from intravenous or ...intra-arterial thrombolysis. Yet because of the narrow therapeutic time window involved, thrombolytic application is very restricted in clinical settings. Accumulating data suggest that non-pharmaceutical therapies for stroke might provide new opportunities for stroke treatment. Here we review recent research progress in the mechanisms and clinical implications of non-pharmaceutical therapies, mainly including neuroprotective approaches such as hypothermia, ischemic/hypoxic conditioning, acupuncture, medical gases and transcranial laser therapy. In addition, we briefly summarize mechanical endovascular recanalization devices and recovery devices for the treatment of the chronic phase of stroke and discuss the relative merits of these devices.
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