Gastric cancer (GC) is one of the most pernicious tumors that seriously harm human healthcare. GC metastasis is one of the prime cause of failed cancer treatment, but correlation between ...N6-methyladenosine (m6A) and GC metastasis was less reported.
Methylated RNA immunoprecipitation sequencing (MeRIP-seq) of GC tissues was conducted. Quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry (IHC) were taken to determine the expression of ALKBH5 in GC tissues and cell lines. RNA-seq together with MeRIP-qRT-PCR was used to screen the target gene of ALKBH5. RNA pulldown, mass spectrometry and RNA immunoprecipitation (RIP) were used to search the "reader" protein of target gene. The mechanism was also validated via a tail vein injection method for lung metastasis model.
Decreased expression of ALKBH5 was detected in GC samples, and it was correlated with clinical tumor distal metastasis and lymph node metastasis. ALKBH5 interference promoted metastasis of GC cells and this effect was closely related to the demethylase activity of ALKBH5. PKMYT1, as a downstream target of ALKBH5, promoted invasion and migration in GC. Caused by ALKBH5 knockdown or its demethylase activity mutation, upregulated expression of PKMYT1 indicated that ALKBH5 modulates expression of PKMYT1 in an m6A-dependent manner. IGF2BP3 helped stabilize the mRNA stability of PKMYT1 via its m6A modification site.
This study established an ALKBH5-PKMYT1-IGF2BP3 regulation system in metastasis, representing a new therapeutic target for GC metastasis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Cancer stem cells (CSCs), which comprise a small proportion of total cancer cells, have special capacities for self-renewal, differentiation and tumor formation. Currently, CSCs are regarded ...as the major cause of the failure in anticancer therapy, such as chemoresistance and/or radioresistance, tumor recurrence and metastasis. Autophagy, a process of cellular self-digestion and response to stress, has a role in tumor formation and progression, and it may play a dual role in CSCs-related resistance to anticancer therapy. Most researchers believe that autophagy contributes to stemness maintenance of CSCs and is responsible for the failure of anticancer therapy. Unexpectedly, several studies have also suggested that loss of stemness in CSCs could be mediated by autophagy. Here, we review the recent advances in CSCs and autophagy, especially analyze the complex relationship between them, and hope to apply this new knowledge to the strategies for anticancer therapy.
Aberrant expression of circular RNAs contributes to the initiation and progression of cancers, but the underlying mechanism remains elusive.
RNA-seq and qRT-PCR were performed to screen differential ...expressed circRNAs between gastric cancer tissues and adjacent normal tissues. Candidate circRNA (circMRPS35) was screened out and validated by qRT-PCR. Cell proliferation and invasion ability were determined by CCK-8 and cell invasion assays. RNA-seq, GO-pathway, RNA pull-down and ChIRP were further applied to search for detailed mechanism.
Here, a novel circRNA named circMRPS35, was screened out by RNA-seq in gastric cancer tissues, whose expression is related to clinicopathological characteristics and prognosis in gastric cancer patients. Biologically, circMRPS35 suppresses the proliferation and invasion of gastric cancer cells in vitro and in vivo. Mechanistically, circMRPS35 acts as a modular scaffold to recruit histone acetyltransferase KAT7 to the promoters of FOXO1 and FOXO3a genes, which elicits acetylation of H4K5 in their promoters. Particularly, circMRPS35 specifically binds to FOXO1/3a promoter regions directly. Thus, it dramatically activates the transcription of FOXO1/3a and triggers subsequent response of their downstream target genes expression, including p21, p27, Twist1 and E-cadherin, resulting in the inhibition of cell proliferation and invasion. Moreover, circMRPS35 expression positively correlates with that of FOXO1/3a in gastric cancer tissues.
Our findings not only reveal the pivotal roles of circMRPS35 in governing histone modification in anticancer treatment, but also advocate for triggering circMRPS35/KAT7/FOXO1/3a pathway to combat gastric cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited. We developed a genome-editing approach to target a dominantly ...inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9-guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth) mouse model, even though the mutant Tmc1
allele differs from the wild-type allele at only a single base pair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1
allele into the cochlea of neonatal Tmc1
mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1
mice. These findings suggest that protein-RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.
Road traffic sensors provide rich multivariable datastreams about the current traffic conditions. Occasionally, there are unusual traffic events (such as accidents, jams, and severe weather) that ...disrupt the expected road traffic conditions. Detecting the occurrence of such events in an online and real-time manner is useful to drivers in planning their routes and in the management of the transportation infrastructure. We propose a new method for detecting traffic events that impact road traffic conditions by extending the Bayesian robust principal component analysis (RPCA) approach. Our method couples multiple traffic datastreams so that they share a certain sparse structure. This sparse structure is used to localize traffic events in space and time. The traffic datastreams are measurements of different physical quantities (e.g., traffic flow and road occupancy) by different nearby sensors. Our proposed method processes datastreams in an incremental way with small computational cost; hence, it is suitable to detect events in an online and real-time manner. We experimentally analyze the detection performance of the proposed coupled Bayesian RPCA (BRPCA) using real data from loop detectors on the Minnesota I-494. We find that our method significantly improves the detection accuracy when compared with the traditional PCA and noncoupled BRPCA.
Intrahepatic cholestasis of pregnancy (ICP) is a female pregnancy-specific disorder that is characterized by increased serum bile acid and adverse fetal outcomes. The aetiology and mechanism of ICP ...are poorly understood; thus, existing therapies have been largely empiric. Here we show that the gut microbiome differed significantly between individuals with ICP and healthy pregnant women, and that colonization with gut microbiome from ICP patients was sufficient to induce cholestasis in mice. The gut microbiomes of ICP patients were primarily characterized by Bacteroides fragilis (B. fragilis), and B. fragilis was able to promote ICP by inhibiting FXR signaling via its BSH activity to modulate bile acid metabolism. B. fragilis-mediated FXR signaling inhibition was responsible for excessive bile acid synthesis and interrupted hepatic bile excretion to ultimately promote the initiation of ICP. We propose that modulation of the gut microbiota-bile acid-FXR axis may be of value for ICP treatment.
The endoglycosidase heparanase which degrades heparan sulfate proteoglycans, exerts a pro-inflammatory mediator in various inflammatory disorders. However, the function and underlying mechanism of ...heparanase in acute pancreatitis remain poorly understood. Here, we investigated the interplay between heparanase and the gut microbiota in the development of acute pancreatitis.
Acute pancreatitis was induced in wild-type and heparanase-transgenic mice by administration of caerulein. The differences in gut microbiota were analyzed by 16S ribosomal RNA sequencing. Antibiotic cocktail experiment, fecal microbiota transplantation, and cohousing experiments were used to assess the role of gut microbiota.
As compared with wild-type mice, acute pancreatitis was exacerbated in heparanase-transgenic mice. Moreover, the gut microbiota differed between heparanase-transgenic and wild-type mice. Heparanase exacerbated acute pancreatitis in a gut microbiota-dependent manner. Specially, the commensal Parabacteroides contributed most to distinguish the differences between wild-type and heparanase-transgenic mice. Administration of Parabacteroides alleviated acute pancreatitis in wild-type and heparanase-transgenic mice. In addition, Parabacteroides produced acetate to alleviate heparanase-exacerbated acute pancreatitis through reducing neutrophil infiltration.
The gut-pancreas axis played an important role in the development of acute pancreatitis and the acetate produced by Parabacteroides may be beneficial for acute pancreatitis treatment. Video abstract.
lncRNA may be involved in the occurrence, metastasis, and chemical reaction of hepatocellular carcinoma (HCC) through various pathways associated with autophagy. Therefore, it is urgent to reveal ...more autophagy-related lncRNAs, explore these lncRNAs' clinical significance, and find new targeted treatment strategies.
The corresponding data of HCC patients and autophagy genes were obtained from the TCGA database, and the human autophagy database respectively. Based on the co-expression and Cox regression analysis to construct prognostic prediction signature.
Finally, a signature containing seven autophagy-related lncRNAs (PRRT3-AS1, RP11-479G22.8, RP11-73M18.8, LINC01138, CTD-2510F5.4, CTC-297N7.9, RP11-324I22.4) was constructed. Based on the risk score of signature, Overall survival (OS) curves show that the OS of high-risk patients is significantly lower than that of low-risk patients (P = 2.292e-10), and the prognostic prediction accuracy of risk score (AUC = 0.786) is significantly higher than that of ALBI (0.532), child_pugh (0.573), AFP (0.5751), and AJCC_stage (0.631). Moreover, multivariate Cox analysis and Nomogram of risk score are indicated that the 1-year and 3-year survival rates of patients are obviously accuracy by the combined analysis of the risk score, child_pugh, age, M_stage, and Grade (The AUC of 1- and 3-years are 0.87, and 0.855). Remarkably, the 7 autophagy-related lncRNAs may participate in Spliceosome, Cell cycle, RNA transport, DNA replication, and mRNA surveillance pathway and be related to the biological process of RNA splicing and mRNA splicing.
In conclusion, the 7 autophagy-related lncRNAs might be promising prognostic and therapeutic targets for HCC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, we investigate the potential for repurposing disulfiram (DSF), a drug commonly used to treat chronic alcoholism, for ...NASH. Using a mouse model, we show that DSF ameliorates NASH in a gut microbiota-dependent manner. DSF modulates the gut microbiota and directly inhibits the growth of Clostridium. Administration of Clostridium abolishes the ameliorating effects of DSF on NASH. Mechanistically, DSF reduces Clostridium-mediated 7α-dehydroxylation activity to suppress secondary bile acid biosynthesis, which in turn activates hepatic farnesoid X receptor signaling to ameliorate NASH. To assess the effect of DSF on human gut microbiota, we performed a self-controlled clinical trial (ChiCTR2100048035), including 23 healthy volunteers who received 250 mg-qd DSF for 7 days. The primary objective outcomes were to assess the effects of the intervention on the diversity, composition and functional profile of gut microbiota. The pilot study shows that DSF also reduces Clostridium-mediated 7α-dehydroxylation activity. All volunteers tolerated DSF well and there were no serious adverse events in the 7-day follow-up period. Transferring fecal microbiota obtained from DSF-treated humans into germ-free mice ameliorates NASH. Collectively, the observations of similar ameliorating effects of DSF on mice and humans suggest that DSF ameliorates NASH by modulating the gut microbiota and bile acid metabolism.
Ca2+-sensing receptor (CaSR), a member of G protein-coupled receptor family, is widely expressed in the vascular system, including perivascular neurons, vascular endothelial cells (VECs) and vascular ...smooth muscle cells (VSMCs). When stimulated, CaSR can further increase the cytosolic Ca2+ concentration (Ca2+cyt) in two ways: intracellular Ca2+ release from endo/sarcoplasmic reticulum (ER/SR) and extracellular Ca2+ entry through Ca2+-permeable cation channels. In endothelium, increased Ca2+ subsequently activate nitric oxide synthase (NOS) and intermediate conductance Ca2+-activated K+ channels (IKCa), resulting in vasodilation through NOS-mediated NO release or membrane hyperpolarization. In VSMCs, CaSR-induced intracellular Ca2+ increase causes blood vessel constriction. CaSR activation predominantly induces vasorelaxation of whole vascular tissues through VECs-dependent mechanisms; however, CaSR-induced Ca2+ signaling in VSMCs may play a braking role in CaSR-mediated vasorelaxation. Emerging evidence reveals the importance of CaSR in the regulation of vascular tone and blood pressure. Here, we summarized recent advances in CaSR-mediated vascular reaction and the underlying mechanisms in different species, including humans. In addition, several studies have demonstrated that CaSR dysfunction may be associated with some fatal vascular diseases, such as pulmonary arterial hypertension, primary hypertension, diabetes, acute myocardial infarction and vascular calcification. With the advance of studies on CaSR in vascular health and disease, it is expected positive modulators or negative modulators of CaSR used for the treatment of specific diseases may be promising therapeutic options for the prevention and/or treatment of vascular diseases.
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