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Essential amino acids (EAA) and microRNAs (miRs) control biological activity of a cell. Whether EAA regulates the activity of miR has never been demonstrated. Here, as proof‐of‐concept, a tryptophan (Trp, an EAA) complex containing Argonaute 2 (Ago2) and miRs including miR‐193a (Trp/Ago2/miR‐193a) is identified. Trp binds miR‐193a‐3p and interacts with Ago2. Trp/Ago2/miR‐193a increases miR‐193a‐3p activity via enhancing Argonaute 2 (Ago2) RNase activity. Other miRs including miR‐103 and miR‐107 in the Trp complex enhance miR‐193a activity by targeting the same genes. Mechanistically, the Trp/Ago2/miR‐193a complex interacts with Trp‐binding pockets of the PIWI domain of Ago2 to enhance Ago2 mediated miR activity. This newly formed Ago2/Trp/miR‐193a‐3p complex is more efficient than miR‐193a‐3p alone in inhibiting the expression of targeted genes and inhibiting colon cancer liver metastasis. The findings show that Trp regulates miR activity through communication with the RNA‐induced silencing complexes (RISC), which provides the basis for tryptophan based miR therapy. [ABSTRACT FROM AUTHOR]

Investigating Na‐ion battery (SIB) materials is complicated by the absence of a well‐performing (reference) electrode material since sodium metal cannot be considered as a quasi‐reference electrode. Taking advantage of the activity of both Ni and Mn, herein, the P2‐type and Mn‐rich Na0.6Ni0.22Al0.11Mn0.66O2 (NAM) material, known to be an excellent positive electrode, is investigated as a negative electrode. To prove NAM stability as both positive and negative electrode, symmetric cells have been assembled without pre‐sodiation, which showed a reversible capacity of 73 mA h g−1 and a remarkable capacity retention of 82.6 % after 500 cycles. The outstanding cycling performance is ascribed to the high stability of the active material at both the highest and lowest Na‐ion storage plateaus and the rather limited electrolyte decomposition and solid‐electrolyte‐interphase (SEI) formation occurring. The long‐term stability of NAM at both electrodes enables its use as a "reference" electrode for the investigation of other positive and negative electrode materials for SIBs, resembling the role played by lithium titanate (LTO) and lithium iron phosphate (LFP) in LIBs. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) contain more than 100 proteins. Whether there are EVs proteins that act as an 'organiser' of protein networks to generate a new or different biological effect from that identified in EV‐producing cells has never been demonstrated. Here, as a proof‐of‐concept, we demonstrate that EV‐G12D‐mutant KRAS serves as a leader that forms a protein complex and promotes lung inflammation and tumour growth via the Fn1/IL‐17A/FGF21 axis. Mechanistically, in contrast to cytosol derived G12D‐mutant KRAS complex from EVs‐producing cells, EV‐G12D‐mutant KRAS interacts with a group of extracellular vesicular factors via fibronectin‐1 (Fn1), which drives the activation of the IL‐17A/FGF21 inflammation pathway in EV recipient cells. We show that: (i), depletion of EV‐Fn1 leads to a reduction of a number of inflammatory cytokines including IL‐17A; (ii) induction of IL‐17A promotes lung inflammation, which in turn leads to IL‐17A mediated induction of FGF21 in the lung; and (iii) EV‐G12D‐mutant KRAS complex mediated lung inflammation is abrogated in IL‐17 receptor KO mice. These findings establish a new concept in EV function with potential implications for novel therapeutic interventions in EV‐mediated disease processes. [ABSTRACT FROM AUTHOR]

Bark protects the tree against environmental insults. Here, we analyzed whether this defensive strategy could be utilized to broadly enhance protection against colitis. As a proof of concept, we show that exosome‐like nanoparticles (MBELNs) derived from edible mulberry bark confer protection against colitis in a mouse model by promoting heat shock protein family A (Hsp70) member 8 (HSPA8)‐mediated activation of the AhR signaling pathway. Activation of this pathway in intestinal epithelial cells leads to the induction of COP9 Constitutive Photomorphogenic Homolog Subunit 8 (COPS8). Utilizing a gut epithelium‐specific knockout of COPS8, we demonstrate that COPS8 acts downstream of the AhR pathway and is required for the protective effect of MBELNs by inducing an array of anti‐microbial peptides. Our results indicate that MBELNs represent an undescribed mode of inter‐kingdom communication in the mammalian intestine through an AhR‐COPS8‐mediated anti‐inflammatory pathway. These data suggest that inflammatory pathways in a microbiota‐enriched intestinal environment are regulated by COPS8 and that edible plant‐derived ELNs may hold the potential as new agents for the prevention and treatment of gut‐related inflammatory disease. Synopsis: Mulberry bark derived exosome‐like nanoparticles (MBELNs) prevent gut inflammation via plant heat shock protein HSPA8‐mediated activation of AhR/COPS8 pathways. Treatment with MBELNs promotes the restoration of gut microbiome homeostasis, ameliorating intestinal inflammatory pathologies. Mulberry bark derived exosome‐like nanoparticles (MBELNs) prevent mouse colitis via the AhR/COPS8 pathway.Binding of MBELN‐derived heat shock protein HSPA8 to AhR leads to the activation of AhR signaling.Activation of AhR leads to the induction of an array of anti‐microbial peptides (AMPs) via COP9/COPS8.AhR/COPS8‐dependent induction of AMPs inhibits intestinal inflammation and alters fecal gut microbiota composition. [ABSTRACT FROM AUTHOR]

Daily exposure of humans to nanoparticles from edible plants is inevitable, but significant advances are required to determine whether edible plant nanoparticles are beneficial to our health. Additionally, strategies are needed to elucidate the molecular mechanisms underlying any beneficial effects. Here, as a proof of concept, we used a mouse model to show that orally given nanoparticles isolated from ginger extracts using a sucrose gradient centrifugation procedure resulted in protecting mice against alcohol-induced liver damage. The ginger-derived nanoparticle (GDN)–mediated activation of nuclear factor erythroid 2-related factor 2 (Nrf2) led to the expression of a group of liver detoxifying/antioxidant genes and inhibited the production of reactive oxygen species, which partially contributes to the liver protection. Using lipid knock-out and knock-in strategies, we further identified that shogaol in the GDN plays a role in the induction of Nrf2 in a TLR4/TRIF-dependent manner. Given the critical role of Nrf2 in modulating numerous cellular processes, including hepatocyte homeostasis, drug metabolism, antioxidant defenses, and cell-cycle progression of liver, this finding not only opens up a new avenue for investigating GDN as a means to protect against the development of liver-related diseases such as alcohol-induced liver damage but sheds light on studying the cellular and molecular mechanisms underlying interspecies communication in the liver via edible plant–derived nanoparticles. [ABSTRACT FROM AUTHOR]

The NIH Extracellular RNA Communication Program's initiative on clinical utility of extracellular RNAs and therapeutic agents and developing scalable technologies is reviewed here. Background information and details of the projects are presented. The work has focused on modulation of target cell fate by extracellular vesicles (EVs) and RNA. Work on plant-derived vesicles is of intense interest, and non-mammalian sources of vesicles may represent a very promising source for different therapeutic approaches. Retro-viral-like particles are intriguing. Clearly, EVs share pathways with the assembly machinery of several other viruses, including human endogenous retrovirals (HERVs), and this convergence may explain the observation of viral-like particles containing viral proteins and nucleic acid in EVs. Dramatic effect on regeneration of damaged bone marrow, renal, pulmonary and cardiovascular tissue is demonstrated and discussed. These studies show restoration of injured cell function and the importance of heterogeneity of different vesicle populations. The potential for neural regeneration is explored, and the capacity to promote and reverse neoplasia by EV exposure is described. The tremendous clinical potential of EVs underlies many of these projects, and the importance of regulatory issues and the necessity of general manufacturing production (GMP) studies for eventual clinical trials are emphasized. Clinical trials are already being pursued and should expand dramatically in the near future. [ABSTRACT FROM AUTHOR]

A quantitative trait locus (QTL) that affects heading date (HD) and the number of spikelets per panicle (SPP) was previously identified in a small region on chromosome 7 in rice ( Oryza sativa L.). In order to further characterize the QTL region, near isogenic lines (NILs) were quickly obtained by self-crossing recombinant inbred line 189, which is heterozygous in the vicinity of the target region. The pleiotropic effects of QTL Ghd7.1 on plant height (PH), SPP, and HD, were validated using an NIL-F2 population. Ghd7.1 explained 50.2%, 45.3%, and 76.9% of phenotypic variation in PH, SPP, and HD, respectively. Ghd7.1 was precisely mapped to a 357-kb region on the basis of analysis of the progeny of the NIL-F2 population. Day-length treatment confirmed that Ghd7.1 is sensitive to photoperiod, with long days delaying heading up to 12.5 d. Identification of panicle initiation and development for the pair of NILs showed that Ghd7.1 elongated the photoperiod-sensitive phase more than 10 d, but did not change the basic vegetative phase and the reproductive growth phase. These findings indicated that Ghd7.1 regulates SPP by controlling the rate of panicle differentiation rather than the duration of panicle development. [ABSTRACT FROM AUTHOR]

Numerous studies have been performed in vitro and in various animal models to modulate the interaction of dendritic cells (DC) and T cells by Fas (CD95/Apo-1) signalling to delete activated T cells via induction of activation-induced cell death (AICD). Previously, we could demonstrate that Fas ligand (FasL/CD95L)-expressing 'killer-antigen-presenting cells' can be generated from human monocyte-derived mature DC (mDC) using adenoviral gene transfer. To evaluate whether these FasL-expressing mDC (mDC-FasL) could eliminate alloreactive primary human T cells in vitro, co-culture experiments were performed. Proliferation of human T cells was markedly reduced in primary co-cultures with allogeneic mDC-FasL, whereas a strong proliferative T-cell response could be observed in co-cultures with enhanced green fluorescent protein-transduced mDC. Inhibition of T-cell proliferation was related to the transduction efficiency, and the numbers of mDC-FasL present in co-cultures. In addition, proliferation of pre-activated alloreactive CD4 and CD8 T cells could be almost completely inhibited in secondary co-cultures using mDC-FasL as stimulatory cells, which was the result of induction of apoptosis in the majority of preactivated T cells. The specific deletion of alloreactive T cells by mDC-FasL was confirmed by an unaffected proliferative response of surviving T cells towards allogeneic 'third-party' peripheral blood mononuclear cells in a third stimulation, or upon unspecific stimulation with anti-CD3/CD28 beads. The results of this study demonstrate that allospecifically activated T cells are efficiently eliminated by mDC-FasL, supporting further investigations to apply FasL-expressing 'killer-DC' as a novel strategy for the treatment of allograft rejection. [ABSTRACT FROM AUTHOR]

Objective: To determine novel genes regulated by tumor necrosis factor alpha (TNFalpha) signaling in primary rheumatoid arthritis synovial fibroblasts (RASFs)., Methods: Oligonucleotide microarrays were used to measure gene expression levels in 6 independent replicate samples of RASFs. RASFs were transfected for 18 hours with AdIkappaB-dominant negative (AdIkappaB-DN) (n = 3) or with control AdTet expressing the reverse tetracycline trans-activator (n = 3). The cells were stimulated for 3 hours with TNFalpha, and total RNA was prepared. Several novel parametric and nonparametric methods were used to rank genes in terms of the magnitude and significance of intergroup differences. Microarray expression differences were confirmed by real-time quantitative reverse transcription-polymerase chain reaction. Small interfering RNA (siRNA) was used to specifically down-modulate microarray-identified genes to demonstrate their role in the promotion of apoptosis, proliferation, or matrix metalloproteinase (MMP) expression., Results: Blocking of NF-kappaB by AdIkappaB-DN was associated with a down-modulation of antiapoptosis genes, including BIRC-3, and several novel genes, including GG2-1, a TNFalpha-inducible FLIP-like gene. Other families of genes that were significantly down-regulated by AdIkappaB-DN included cytokines/chemokines (interleukin-1beta [IL-1beta], IL-8, IL-15, and RANTES), adhesion molecule (vascular cell adhesion molecule 1, intercellular adhesion molecule 1), and unique genes that have not previously been reported to be regulated by TNFalpha in RA. Inhibition of the GG2-1 gene using the siRNA technique resulted in significantly enhanced apoptosis, decreased proliferation, and decreased production of MMP-1 in TNFalpha-stimulated RASFs., Conclusion: These studies provide a comprehensive analysis of genes that are differentially regulated by TNFalpha signaling and NF-kappaB nuclear translocation in RASFs and demonstrate methods for confirming the expression and functional significance of such genes.