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Retinoic acid inducible gene I (RIG-I) senses viral RNAs and triggers innate antiviral responses through induction of type I IFNs and inflammatory cytokines. However, whether RIG-I interacts with host cellular RNA remains undetermined. Here we report that Rig-I interacts with multiple cellular mRNAs, especially Nf-κb1 . Rig-I is required for NF-κB activity via regulating Nf-κb1 expression at posttranscriptional levels. It interacts with the multiple binding sites within 3′-UTR of Nf-κb1 mRNA. Further analyses reveal that three distinct tandem motifs enriched in the 3′-UTR fragments can be recognized by Rig-I. The 3′-UTR binding with Rig-I plays a critical role in normal translation of Nf-κb1 by recruiting the ribosomal proteins [ribosomal protein L13 (Rpl13) and Rpl8] and rRNAs (18S and 28S). Down-regulation of Rig-I or Rpl13 significantly reduces Nf-κb1 and 3′-UTR–mediated luciferase expression levels. These findings indicate that Rig-I functions as a positive regulator for NF-κB signaling and is involved in multiple biological processes in addition to host antivirus immunity.

Retinoic acid inducible gene I (RIG-I) senses viral RNAs and triggers innate antiviral responses through induction of type I IFNs and inflammatory cytokines. However, whether RIG-I interacts with host cellular RNA remains undetermined. Here we report that Rig-I interacts with multiple cellular mRNAs, especially Nf-Kb1. Rig-I is required for NF-KB activity via regulating Nf-Kb1 expression at posttranscriptional levels. It interacts with the multiple binding sites within 3'-UTR of Nf-Kb1 mRNA. Further analyses reveal that three distinct tandem motifs enriched in the 3'-UTR fragments can be recognized by Rig-I. The 3'-UTR binding with Rig-I plays a critical role in normal translation of Nf-Kb1 by recruiting the ribosomal proteins [ribosomal protein L13 (Rpl13) and Rpl8] and rRNAs (18S and 28S). Down-regulation of Rig-I or Rpl13 significantly reduces Nf-Kb1 and 3'-UTR-mediated luciferase expression levels. These findings indicate that Rig-I functions as a positive regulator for NF-KB signaling and is involved in multiple biological processes in addition to host antivirus immunity. [PUBLICATION ABSTRACT]

Retinoic acid inducible gene I (RIG-I) senses viral RNAs and triggers innate antiviral responses through induction of type I IFNs and inflammatory cytokines. However, whether RIG-I interacts with host cellular RNA remains undetermined. Here we report that Rig-I interacts with multiple cellular mRNAs, especially Nf-kb1. Rig-I is required for NF-kB activity via regulating Nf-kb1 expression at posttranscriptional levels. It interacts with the multiple binding sites within 3'-UTR of Nf-kb1 mRNA. Further analyses reveal that three distinct tandem motifs enriched in the 3'-UTR fragments can be recognized by Rig-I. The 3'-UTR binding with Rig-I plays a critical role in normal translation of Nf-kb1 by recruiting the ribosomal proteins [ribosomal protein L13 (Rpl13) and Rpl8] and rRNAs (18S and 28S). Down-regulation of Rig-I or Rpl13 significantly reduces Nf-kb1 and 3'-UTR-mediated luciferase expression levels. These findings indicate that Rig-I functions as a positive regulator for NF-kB signaling and is involved in multiple biological processes in addition to host antivirus immunity.

Vaccarin is a flavonoid glycoside, which has a variety of pharmacological properties and plays a protective role in diabetes and its complications, but its mechanism is unclear. In this study, we aim to investigate whether histone deacetylase 1(HDAC1), a gene that plays a pivotal role in regulating eukaryotic gene expression, is the target of miR-570-3p in diabetic vascular endothelium, and the potential molecular mechanism of vaccarin regulating endothelial inflammatory injury through miR-570-3p/HDAC1 pathway. The HFD and streptozotocin (STZ) induced diabetes mice model, a classical type 2 diabetic model, was established. The aorta of diabetic mice displayed a decrease of miR-570-3p, the elevation of HDAC1, and inflammatory injury, which were alleviated by vaccarin. Next, we employed the role of vaccarin in regulating endothelial cells miR-570-3p and HDAC1 under hyperglycemia conditions in vitro . We discovered that overexpression of HDAC1 counteracted the inhibitory effect of vaccarin on inflammatory injury in human umbilical vein endothelial cells (HUVECs). Manipulation of miRNA levels in HUVECs was achieved by transfecting cells with miR-570-3p mimic and inhibitor. Overexpression of miR-570-3p could decrease the expression of downstream components of HDAC1 including TNF-α, IL-1β, and malondialdehyde, while increasing GSH-Px activity in HUVECs under hyperglycemic conditions. Nevertheless, such phenomenon was completely reversed by miR-570-3p inhibitor, and administration of miR-570-3p inhibitor could block the inhibition of vaccarin on HDAC1 and inflammatory injury. Luciferase reporter assay confirmed the 3′- UTR of the HDAC1 gene was a direct target of miR-570-3p. In summary, our findings suggest that vaccarin alleviates endothelial inflammatory injury in diabetes by mediating miR-570-3p/HDAC1 pathway. Our study provides a new pathogenic link between deregulation of miRNA expression in the vascular endothelium of diabetes and inflammatory injury and provides new ideas, insights, and choices for the scope of application and medicinal value of vaccarin and some potential biomarkers or targets in diabetic endothelial dysfunction and vascular complications.

Background: Type 2 diabetes mellitus (T2DM) is a metabolic syndrome characterized by chronic inflammation, insulin resistance, and islet cell damage. The prevention of T2DM and its associated complications is an urgent public health issue that affects hundreds of millions of people globally. Numerous studies suggest that disturbances in gut metabolites are important driving forces for the pathogenesis of diabetes. However, the functions and mechanisms of action of most commensal bacteria in T2DM remain largely unknown. Methods: The quantification of bile acids (BAs) in fecal samples was performed using ultra-performance liquid chromatography–tandem mass spectrometer (UPLC-MS/MS). The anti-diabetic effects of Bacteroides uniformis (B. uniformis) and its metabolites cholic acid (CA) and chenodeoxycholic acid (CDCA) were assessed in T2DM mice induced by streptozocin (STZ) plus high-fat diet (HFD). Results: We found that the abundance of B. uniformis in the feces and the contents of CA and CDCA were significantly downregulated in T2DM mice. B. uniformis was diminished in diabetic individuals and this bacterium was sufficient to promote the production of BAs. Colonization of B. uniformis and intragastric gavage of CA and CDCA effectively improved the disorder of glucose and lipid metabolism in T2DM mice by inhibiting gluconeogenesis and lipolysis in the liver. CA and CDCA improved hepatic glucose and lipid metabolism by acting on the Takeda G protein-coupled receptor 5 (TGR5)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway since knockdown of TGR5 minimized the benefit of CA and CDCA. Furthermore, we screened a natural product—vaccarin (VAC)—that exhibited anti-diabetic effects by promoting the growth of B. uniformis in vitro and in vivo. Gut microbiota pre-depletion abolished the favorable effects of VAC in diabetic mice. Conclusions: These data suggest that supplementation of B. uniformis may be a promising avenue to ameliorate T2DM by linking the gut and liver.

Background Aberrant proliferation and inflammation of fibroblast-like synoviocytes (FLSs) significantly contribute to the pathogenesis of rheumatoid arthritis (RA). Deficiency of hydrogen sulfide (H 2 S) is a driving force for the development of RA, and the short half-life of the H 2 S-releasing donor sodium hydrosulfide (NaHS) limits its clinical application in RA therapy. Designing a targeted delivery system with slow-release properties for FLSs could offer novel strategies for treating RA. Methods Herein, we designed a strategy to achieve slow release of H 2 S targeted to the synovium, which was accomplished by synthesizing NaHS-CY5@mesoporous silic@LNP targeted peptide Dil (NaHS@Cy5@MS@SP) nanoparticles. Results Our results demonstrated that NaHS@Cy5@MS@SP effectively targets FLSs, upregulates H 2 S and its-producing enzyme cystathionine-γ-lyase (CSE) in the joints of arthritic mice. Overexpression of CSE inhibited the proliferation, migration, and inflammation of FLSs upon lipopolysaccharide (LPS) exposure, effects that were mimicked by NaHS@Cy5@MS@SP. In vivo studies showed that NaHS@Cy5@MS@SP achieved a threefold higher AUC inf than that of free NaHS, significantly improving the bioavailability of NaHS. Further, NaHS@Cy5@MS@SP inhibited synovial hyperplasia and reduced bone and cartilage erosion in the DBA/1J mouse model of collagen-induced arthritis (CIA), which was superior to NaHS. RNA sequencing and molecular studies validated that NaHS@Cy5@MS@SP inactivated the Hedgehog signaling pathway in FLSs, as evidenced by reductions in the protein expression of SHH, SMO, GLI1 and phosphorylated p38/MAPK. Conclusion This study highlights NaHS@Cy5@MS@SP as a promising strategy for the controlled and targeted delivery of H 2 S to synoviocytes, offering potential for RA management. Graphical Abstract

Chronic wound repair is a common complication in patients with diabetes mellitus, which causes a heavy burden on social medical resources and the economy. Hypaphorine (HYP) has good anti-inflammatory effect, and chitosan (CS) is used in the treatment of wounds because of its good antibacterial effect. The purpose of this research was to investigate the role and mechanism of HYP-nano-microspheres in the treatment of wounds for diabetic rats. The morphology of HYP-NPS was observed by transmission electron microscopy (TEM). RAW 264.7 macrophages were used to assess the bio-compatibility of HYP-NPS. A full-thickness dermal wound in a diabetic rat model was performed to evaluate the wound healing function of HYP-NPS. The results revealed that HYP-NPS nanoparticles were spherical with an average diameter of approximately 50 nm. The cell experiments hinted that HYP-NPS had the potential as a trauma material. The wound test in diabetic rats indicated that HYP-NPS fostered the healing of chronic wounds. The mechanism was through down-regulating the expression of pro-inflammatory cytokines IL-1β and TNF-α in the skin of the wound, and accelerating the transition of chronic wound from inflammation to tissue regeneration. These results indicate that HYP-NPS has a good application prospect in the treatment of chronic wounds.

Purpose - The purpose of this paper is to analyze and estimate the stray current corrosion hazard of a buried metallic pipeline using a predictive model for stray current density.Design methodology approach - A predictive model for stray current density of the buried metallic pipeline was built, using a back propagation (BP) neural network method and experimental data. The accuracy of the model was tested using test samples. The single sensitivity analysis predictive method was used to establish the relationship between stray current density with the soil resistivity. The effects of buried depth and the pipe-to-ground voltage offset were researched using this network model.Findings - The feasibility of the BP neural network to forecast stray current effects from the buried metallic pipeline was confirmed.Originality value - The paper provides a new method to analyze and estimate the stray current corrosion hazard of buried metallic pipelines.

Cardiovascular complications are a major leading cause of mortality in patients suffering from type 2 diabetes mellitus (T2DM). Vascular endothelial dysfunction is a core pathophysiological event in the early stage of T2DM and eventually leads to cardiovascular disease. Vaccarin (VAC), an active flavonoid glycoside extracted from vaccariae semen, exhibits extensive biological activities including vascular endothelial cell protection effects. However, little is known about whether VAC is involved in endothelial dysfunction regulation under high glucose (HG) or hyperglycemia conditions. Here, in an in vivo study, we found that VAC attenuated increased blood glucose, increased glucose and insulin tolerance, relieved the disorder of lipid metabolism and oxidative stress, and improved endothelium-dependent vasorelaxation in STZ/HFD-induced T2DM mice. Furthermore, in cultured human microvascular endothelial cell-1 (HMEC-1) cells, we showed that pretreatment with VAC dose-dependently increased nitric oxide (NO) generation and the phosphorylation of eNOS under HG conditions. Mechanistically, VAC-treated HMEC-1 cells exhibited higher AMPK phosphorylation, which was attenuated by HG stimulation. Moreover, HG-triggered miRNA-34a upregulation was inhibited by VAC pretreatment, which is in accordance with pretreatment with AMPK inhibitor compound C (CC). In addition, both reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) and VAC abolished HG-evoked dephosphorylation of AMPK and eNOS, increased miRNA-34a expression, and decreased NO production. These results suggest that VAC impedes HG-induced endothelial dysfunction via inhibition of the ROS/AMPK/miRNA-34a/eNOS signaling cascade.

Corrosion caused by sulfate-reducing prokaryotes (SRP) is an important cause of magnesium alloy anode failure in oil pipeline. In this study, the effects of Desulfovibrio sp. HQM3 on the corrosion behavior of AZ31B magnesium alloy anode in organic carbon sources with different contents in simulated tidal flat environment were analyzed using weight loss test, surface analysis and electrochemical analysis technologies. The results showed that the weight loss rate of coupons in low carbon sources contents (0%, 1%, 10%) was higher than that in 100% carbon sources. Electrochemical analyses showed that the corrosion current density ( J corr ) under low carbon sources contents was larger, while the charge transfer resistance ( R ct ) was lower, leading to a higher corrosion rate compared to those under 100% carbon sources content. Observations from scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) revealed more severe pitting corrosion on the alloy surface in the absence of carbon sources. In addition, a large number of nanowires were observed between bacteria on the alloy surface using SEM. Combined with thermodynamic calculations, it was demonstrated that the corrosion of coupons by Desulfovibrio sp. HQM3 in the absence of carbon sources was achieved through extracellular electron transfer.