Characteristics of Exosomes and the Vascular Landscape Regulate Exosome Sequestration by Peripheral Tissues and Brain

Exosomes mediate intercellular communication, shuttling messages between cells and tissues. We explored whether exosome tissue sequestration is determined by the exosomes or the tissues using ten radiolabeled exosomes from human or murine, cancerous or noncancerous cell lines. We measured sequestration of these exosomes by the liver, kidney, spleen, and lung after intravenous injection into male CD-1 mice. Except for kidney sequestration of three exosomes, all exosomes were incorporated by all tissues, but sequestration levels varied greatly among exosomes and tissues. Species of origin (mouse vs. human) or source (cancerous vs. noncancerous cells) did not influence tissue sequestration. Sequestration of J774A.1 exosomes by liver involved the mannose-6 phosphate (M6P) receptor. Wheatgerm agglutinin (WGA) or lipopolysaccharide (LPS) treatments enhanced sequestration of exosomes by brain and lung but inhibited sequestration by liver and spleen. Response to LPS was not predictive of response to WGA. Path and heat map analyses included our published results for brain and found distinct clusters among the exosomes and the tissues. In conclusion, we found no evidence for a universal binding site controlling exosome-tissue interactions. Instead, sequestration of exosomes by tissues is differentially regulated by both exosomes and tissues and may be stimulated or inhibited by WGA and inflammation.     

PRMT7 Inhibitor SGC8158 Enhances Doxorubicin-Induced DNA Damage and Its Cytotoxicity

Protein arginine methyltransferase 7 (PRMT7) regulates various cellular responses, including gene expression, cell migration, stress responses, and stemness. In this study, we investigated the biological role of PRMT7 in cell cycle progression and DNA damage response (DDR) by inhibiting PRMT7 activity with either SGC8158 treatment or its specific siRNA transfection. Suppression of PRMT7 caused cell cycle arrest at the G₁ phase, resulting from the stabilization and subsequent accumulation of p21 protein. In addition, PRMT7 activity is closely associated with DNA repair pathways, including both homologous recombination and non-homologous end-joining. Interestingly, SGC8158, in combination with doxorubicin, led to a synergistic increase in both DNA damage and cytotoxicity in MCF7 cells. Taken together, our data demonstrate that PRMT7 is a critical modulator of cell growth and DDR, indicating that it is a promising target for cancer treatment.     

Microbiota and Serum Metabolic Profile Changes in Korean Native Hanwoo Steer in Response to Diet Feeding Systems

The diversity of bacteria and their function in cattle gastrointestinal tracts can influence animal welfare. Next-generation sequencing (NGS) was used to investigate microbial diversity in the feces of Hanwoo steers reared under natural grazing (GS) and housing (HS) systems. Additionally, serum metabolic parameters, such as liver and kidney markers and mineral and lipid content changes, as well as their correlation with pyrotags, were studied. A total of 6468 ± 87.86 operational taxonomic units (OTUs) were identified in both steer groups, of which 3538 ± 38.17 OTUs were from grazing steer and 2930 ± 94.06 OTUs were from GS. Chao1 index analysis revealed a higher bacterial richness in GS. The dominant bacterial taxa were Bacteroidetes and Firmicutes. GS showed lower Bacteroidetes and higher Firmicutes abundance than HS. The serum of HS showed consistent increases in gamma-glutamyl transpeptidase (γGTP), glucose (GLU), total cholesterol (T-CHO), and triglyceride (TG) levels. The impact of GS on animal health and serum metabolic markers was strongly correlated with microbiota. As shown in this study, grazing has a significant impact on the fecal microbiota at the phylum and family levels, as well as the serum biochemical metabolites of Hanwoo steers.     

Hybrid Carbon Supports Composed of Small Reduced Graphene Oxide and Carbon Nanotubes for Durable Oxygen Reduction Catalysts in Proton Exchange Membrane Fuel Cells

We demonstrated highly active and durable hybrid catalysts (HCs) composed of small reduced graphene oxide (srGO) and carbon nanotubes (CNTs) for use as oxygen reduction reaction (ORR) catalysts in proton exchange membrane fuel cells. Pt/srGO and Pt/CNTs were prepared by loading Pt nanoparticles onto srGO and CNTs using a polyol process, and HCs with different Pt/CNT and Pt/srGO ratios were prepared by mechanically mixing the two components. The prepared HCs consisted of Pt/CNTs well dispersed on Pt/srGO, with catalyst HC55, which was prepared using Pt/srGO and Pt/CNTs in a 5:5 ratio, exhibiting excellent oxygen reduction performance and high stability over 1000 cycles of the accelerated durability test (ADT). In particular, after 1000 cycles of the ADT, the normalized electrochemically active surface area of Pt/HC55 decreased by 11.9%, while those of Pt/srGO and Pt/C decreased by 21.2% and 57.6%, respectively. CNTs have strong corrosion resistance because there are fewer defect sites on the surface, and the addition of CNTs in rGO further improved the durability and the electrical conductivity of the catalyst. A detailed analysis of the structural and electrochemical properties of the synthesized catalysts suggested that the synergetic effects of the high specific surface area of srGO and the excellent electrical conductivity of CNTs were responsible for the enhanced efficiency and durability of the catalysts.     

An ErbB Lineage Co-Regulon Harbors Potentially Co-Druggable Targets for Multimodal Precision Therapy in Head and Neck Squamous Cell Carcinoma

The ErbB lineage of oncogenic receptor tyrosine kinases is frequently overexpressed in head and neck squamous cell carcinomas. A common co-regulon triggered by the ErbB proteins; involving shared signaling circuitries; may harbor co-druggable targets or response biomarkers for potential future multimodal precision therapy in ErbB-driven head and neck squamous cell carcinoma. We here present a cohort-based; genome-wide analysis of 488 head and neck squamous cell carcinomas curated as part of The Cancer Genome Atlas Project to characterize genes that are significantly positively co-regulated with the four ErbB proteins and those that are shared among all ErbBs denoting a common ErbB co-regulon. Significant positive gene correlations involved hundreds of genes that were co-expressed with the four ErbB family members (q < 0.05). A common; overlapping co-regulon consisted of a core set of 268 genes that were uniformly co-regulated with all four ErbB genes and highly enriched for functions in chromatin organization and histone modifications. This high-priority set of genes contained ten putative antineoplastic drug-gene interactions. The nature and directionality of these ten drug-gene associations was an inhibiting interaction for seven (PIK3CB; PIK3C2B; HDAC4; FRK; PRKCE; EPHA4; and DYRK1A) of them in which the drug decreases the biological activity or expression of the gene target. For three (CHD4; ARID1A; and PBRM1) of the associations; the directionality of the interaction was such that the gene predicted sensitivit y to the drug suggesting utility as potential response biomarkers. Drug-gene interactions that predicted the gene product to be reduced by the drug included a variety of potential targeted molecular agent classes. This unbiased genome-wide analysis identified a target-rich environment for multimodal therapeutic approaches in tumors that are putatively ErbB-driven. The results of this study require preclinical validation before ultimately devising lines of combinatorial treatment strategies for ErbB-dependent head and neck squamous cell carcinomas that incorporate these findings.     

Polymer Electrolyte Membranes Containing Functionalized Organic/Inorganic Composite for Polymer Electrolyte Membrane Fuel Cell Applications

To mitigate the dependence on fossil fuels and the associated global warming issues, numerous studies have focused on the development of eco-friendly energy conversion devices such as polymer electrolyte membrane fuel cells (PEMFCs) that directly convert chemical energy into electrical energy. As one of the key components in PEMFCs, polymer electrolyte membranes (PEMs) should have high proton conductivity and outstanding physicochemical stability during operation. Although the perfluorinated sulfonic acid (PFSA)-based PEMs and some of the hydrocarbon-based PEMs composed of rationally designed polymer structures are found to meet these criteria, there is an ongoing and pressing need to improve and fine-tune these further, to be useful in practical PEMFC operation. Incorporation of organic/inorganic fillers into the polymer matrix is one of the methods shown to be effective for controlling target PEM properties including thermal stability, mechanical properties, and physical stability, as well as proton conductivity. Functionalization of organic/inorganic fillers is critical to optimize the filler efficiency and dispersion, thus resulting in significant improvements to PEM properties. This review focused on the structural engineering of functionalized carbon and silica-based fillers and comparisons of the resulting PEM properties. Newly constructed composite membranes were compared to composite membrane containing non-functionalized fillers or pure polymer matrix membrane without fillers.     

Effects of Loganin on Bone Formation and Resorption In Vitro and In Vivo

Osteoporosis is a disease caused by impaired bone remodeling that is especially prevalent in elderly and postmenopausal women. Although numerous chemical agents have been developed to prevent osteoporosis, arguments remain regarding their side effects. Here, we demonstrated the effects of loganin, a single bioactive compound isolated from Cornus officinalis, on osteoblast and osteoclast differentiation in vitro and on ovariectomy (OVX)-induced osteoporosis in mice in vivo. Loganin treatment increased the differentiation of mouse preosteoblast cells into osteoblasts and suppressed osteoclast differentiation in primary monocytes by regulating the mRNA expression levels of differentiation markers. Similar results were obtained in an osteoblast–osteoclast co-culture system, which showed that loganin enhanced alkaline phosphatase (ALP) activity and reduced TRAP activity. In in vivo experiments, the oral administration of loganin prevented the OVX-induced loss of bone mineral density (BMD) and microstructure in mice and improved bone parameters. In addition, loganin significantly increased the serum OPG/RANKL ratio and promoted osteogenic activity during bone remodeling. Our findings suggest that loganin could be used as an alternative treatment to protect against osteoporosis.     

Tamalin Function Is Required for the Survival of Neurons and Oligodendrocytes in the CNS

Tamalin is a post-synaptic scaffolding protein that interacts with group 1 metabotropic glutamate receptors (mGluRs) and several other proteins involved in protein trafficking and cytoskeletal events, including neuronal growth and actin reorganization. It plays an important role in synaptic plasticity in vitro by controlling the ligand-dependent trafficking of group 1 mGluRs. Abnormal regulation of mGluRs in the central nervous system (CNS) is associated with glutamate-mediated neurodegenerative disorders. However, the pathological consequences of tamalin deficiency in the CNS are unclear. In this study, tamalin knockout (KO) zebrafish and mice exhibited neurodegeneration along with oligodendrocyte degeneration in the post-embryonic CNS to adulthood without any developmental defects, thus suggesting the function of tamalin is more important in the postnatal stage to adulthood than that in CNS development. Interestingly, hypomyelination was independent of axonal defects in the CNS of tamalin knockout zebrafish and mice. In addition, the loss of Arf6, a downstream signal of tamalin scaffolding protein, synergistically induced neurodegeneration in tamalin KO zebrafish even in the developing CNS. Furthermore, tamalin KO zebrafish displayed increased mGluR5 expression. Taken together, tamalin played an important role in neuronal and oligodendrocyte survival and myelination through the regulation of mGluR5 in the CNS.     

ERK Inhibition Increases RANKL-Induced Osteoclast Differentiation in RAW 264.7 Cells by Stimulating AMPK Activation and RANK Expression and Inhibiting Anti-Osteoclastogenic Factor Expression

Bone absorption is necessary for the maintenance of bone homeostasis. An osteoclast (OC) is a monocyte–macrophage lineage cell that absorbs bone tissue. Extracellular signal-regulated kinases (ERKs) are known to play important roles in regulating OC growth and differentiation. In this study, we examined specific downstream signal pathways affected by ERK inhibition during OC differentiation. Our results showed that the ERK inhibitors PD98059 and U0126 increased receptor activator of NF-κB ligand (RANKL)-induced OC differentiation in RAW 264.7 cells, implying a negative role in OC differentiation. This is supported by the effect of ERK2-specific small interfering RNA on increasing OC differentiation. In contrast to our findings regarding the RAW 264.7 cells, the ERK inhibitors attenuated the differentiation of bone marrow-derived cells into OCs. The ERK inhibitors significantly increased the phosphorylation of adenosine 5′-monophosphate-activated protein kinase (AMPK) but not the activation of p38 MAPK, Lyn, and mTOR. In addition, while the ERK inhibition increased the expression of the RANKL receptor RANK, it decreased the expression of negative mediators of OC differentiation, such as interferon regulatory factor-8, B-cell lymphoma 6, and interferon-γ. These dichotomous effects of ERK inhibition suggest that while ERKs may play positive roles in bone marrow-derived cells, ERKs may also play negative regulatory roles in RAW 264.7 cells. These data provide important information for drug development utilizing ERK inhibitors in OC-related disease treatment.