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Exosomes are emerging mediators of intercellular communication; whether the release of exosomes has an effect on the exosome donor cells in addition to the recipient cells has not been investigated to any extent. Here, we examine different exosomal miRNA expression profiles in primary mouse colon tumour, liver metastasis of colon cancer and naive colon tissues. In more advanced disease, higher levels of tumour suppressor miRNAs are encapsulated in the exosomes. miR-193a interacts with major vault protein (MVP). Knockout of MVP leads to miR-193a accumulation in the exosomal donor cells instead of exosomes, inhibiting tumour progression. Furthermore, miR-193a causes cell cycle G1 arrest and cell proliferation repression through targeting of Caprin1, which upregulates Ccnd2 and c-Myc. Human colon cancer patients with more advanced disease show higher levels of circulating exosomal miR-193a. In summary, our data demonstrate that MVP-mediated selective sorting of tumour suppressor miRNA into exosomes promotes tumour progression. Exosomes are involved in the development of metastasis but how their composition is regulated is not well known. Here the authors propose that major vault protein-dependent loading of miR-193a into exosomes could be a general mechanism by which cancer cells get rid of oncosuppressor miRNAs.

Key Points Urinary extracellular vesicles comprise a wide range of biologically distinct structures with contents that are a snapshot of the life of a cell Urine is a dynamic biofluid, which changes over hours and days within an individual; therefore, at present, no single approach for the isolation of urinary extracellular vesicles is likely to comprehensively distinguish between healthy and disease states Alterations in the composition of urinary extracellular vesicles are useful experimentally and may provide information about disease pathophysiology as well as provide diagnostic end points for the study of renal disease Perhaps the greatest promise of this 'extracellular organelle' is to open a window for science into a greater understanding of cellular therapeutics Extracellular vesicles in the urine have potential as disease biomarkers. This Review discusses the different types of extracellular vesicles and the optimization of approaches to enable their isolation and purification, and to characterize their composition by high-throughput 'omics' technologies. Urine is a valuable diagnostic medium and, with the discovery of urinary extracellular vesicles, is viewed as a dynamic bioactive fluid. Extracellular vesicles are lipid-enclosed structures that can be classified into three categories: exosomes, microvesicles (or ectosomes) and apoptotic bodies. This classification is based on the mechanisms by which membrane vesicles are formed: fusion of multivesicular bodies with the plasma membranes (exosomes), budding of vesicles directly from the plasma membrane (microvesicles) or those shed from dying cells (apoptotic bodies). During their formation, urinary extracellular vesicles incorporate various cell-specific components (proteins, lipids and nucleic acids) that can be transferred to target cells. The rigour needed for comparative studies has fueled the search for optimal approaches for their isolation, purification, and characterization. RNA, the newest extracellular vesicle component to be discovered, has received substantial attention as an extracellular vesicle therapeutic, and compelling evidence suggests that ex vivo manipulation of microRNA composition may have uses in the treatment of kidney disorders. The results of these studies are building the case that urinary extracellular vesicles act as mediators of renal pathophysiology. As the field of extracellular vesicle studies is burgeoning, this Review focuses on primary data obtained from studies of human urine rather than on data from studies of laboratory animals or cultured immortalized cells.

High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets. High-fat diet plays a role in development of insulin resistance. Here, the authors report a mechanism that underlies the development of diet induced insulin resistance through the activation of an aryl hydrocarbon receptor mediated signalling pathway in the liver by faecal exosomes derived from intestinal cells.

Diet has emerged as a key impact factor for gut microbiota function. However, the complexity of dietary components makes it difficult to predict specific outcomes. Here we investigate the impact of plant-derived nanoparticles (PNP) on gut microbiota and metabolites in context of cancer immunotherapy with the humanized gnotobiotic mouse model. Specifically, we show that ginger-derived exosome-like nanoparticle (GELN) preferentially taken up by Lachnospiraceae and Lactobacillaceae mediated by digalactosyldiacylglycerol (DGDG) and glycine, respectively. We further demonstrate that GELN aly-miR159a-3p enhances anti-PD-L1 therapy in melanoma by inhibiting the expression of recipient bacterial phospholipase C (PLC) and increases the accumulation of docosahexaenoic acid (DHA). An increased level of circulating DHA inhibits PD-L1 expression in tumor cells by binding the PD-L1 promoter and subsequently prevents c-myc-initiated transcription of PD-L1. Colonization of germ-free male mice with gut bacteria from anti-PD-L1 non-responding patients supplemented with DHA enhances the efficacy of anti-PD-L1 therapy compared to controls. Our findings reveal a previously unknown mechanistic impact of PNP on human tumor immunotherapy by modulating gut bacterial metabolic pathways. The impact of diet on gut microbiota and metabolites in context of cancer immunotherapy remains elusive. Here the authors reveal ginger-derived exosome-like nanoparticle (GELN) aly-miR159a-3p enhances anti-PD-L1 therapy by increasing microbiota-dependent docosahexaenoic acid (DHA) level thus limiting tumor cell PD-L1 expression.

Obesity is becoming a global epidemic and reversing the pathological processes underlying obesity and metabolic co-morbidities is challenging. Obesity induced chronic inflammation including brain inflammation is a hallmark of obesity via the gut-brain axis. The objective of this study was to develop garlic exosome-like nanoparticles (GaELNs) that inhibit systemic as well as brain inflammatory activity and reverse a HFD induced obesity in mice. GELNs were isolated and administrated orally into HFD fed mice. GaELNs were fluorescent labeled for monitoring their trafficking route after oral administration and quantified the number particles in several tissues. The brain inflammation was determined by measuring inflammatory cytokines by ELISA and real-time PCR. Mitochondrial membrane permeability of microglial cells was determined using JC-10 fluorescence dye. The apoptotic cell death was quantified by TUNEL assay. The brain metabolites were identified and quantified by LC-MS analysis. Memory function of the mice was determined by several memory functional analysis. The effect of GaELNs on glucose and insulin response of the mice was determined by glucose and insulin tolerance tests. c-Myc localization and interaction with BASP1 and calmodulin was determined by confocal microscopy. Our results show that GaELNs is preferentially taken up microglial cells and inhibits the brain inflammation in HFD mice. GaELN phosphatidic acid (PA) (36:4) is required for the uptake of GaELNs via interaction with microglial BASP1. Formation of the GaELNs/BASP1 complex is required for inhibition of c-Myc mediated expression of STING. GaELN PA binds to BASP1, leading to inhibition of c-Myc expression and activity through competitively binding to CaM with c-Myc transcription factor. Inhibition of STING activity leads to reducing the expression of an array of inflammatory cytokines including IFN-γ and TNF-α. IFN-γ induces the expression of IDO1, which in turn the metabolites generated as IDO1 dependent manner activate the AHR pathway that contributes to developing obesity. The metabolites derived from the GaELNs treated microglial cells promote neuronal differentiation and inhibit mitochondrial mediated neuronal cell death. GaELNs treated HFD mice showed improved memory function and increased glucose tolerance and insulin sensitivity in these mice. : Collectively, these results demonstrate how nanoparticles from a healthy diet can inhibit unhealthy high-fat diet induced brain inflammation and reveal a link between brain microglia/diet to brain inflammatory disease outcomes via diet-derived exosome-like nanoparticles.

Developments in the genome organisation field has resulted in the recent methodology to infer spatial conformations of the genome directly from experimentally measured genome contacts (Hi-C data). This provides a detailed description of both intra- and inter-chromosomal arrangements. Chromosomal intermingling is an important driver for radiation-induced DNA mis-repair. Which is a key biological endpoint of relevance to the fields of cancer therapy (radiotherapy), public health (biodosimetry) and space travel. For the first time, we leverage these methods of inferring genome organisation and couple them to nano-dosimetric radiation track structure modelling to predict quantities and distribution of DNA damage within cell-type specific geometries. These nano-dosimetric simulations are highly dependent on geometry and are benefited from the inclusion of experimentally driven chromosome conformations. We show how the changes in Hi-C contract maps impact the inferred geometries resulting in significant differences in chromosomal intermingling. We demonstrate how these differences propagate through to significant changes in the distribution of DNA damage throughout the cell nucleus, suggesting implications for DNA repair fidelity and subsequent cell fate. We suggest that differences in the geometric clustering for the chromosomes between the cell-types are a plausible factor leading to changes in cellular radiosensitivity. Furthermore, we investigate changes in cell shape, such as flattening, and show that this greatly impacts the distribution of DNA damage. This should be considered when comparing in vitro results to in vivo systems. The effect may be especially important when attempting to translate radiosensitivity measurements at the experimental in vitro level to the patient or human level.

Idiopathic membranous nephropathy is associated with autoantibodies against the phospholipase A2 receptor (PLA2R1) in about 70% of patients. This study identifies another antigen, thrombospondin type-1 domain-containing 7A (THSD7A), which accounts for about 10% of cases. Idiopathic membranous nephropathy is an autoimmune disease and a common cause of the nephrotic syndrome in adults. 1 In 2009, the phospholipase A2 receptor 1 (PLA2R1), a protein that is expressed in glomerular podocytes, was discovered as the major antigen involved in the pathogenesis of adult idiopathic membranous nephropathy. 2 As confirmed by a number of subsequent studies, about 70% of patients with idiopathic membranous nephropathy have circulating autoantibodies against PLA2R1. 2 – 6 The remaining patients, approximately 30% of those with idiopathic membranous nephropathy, have no obvious secondary cause of the disease, and it is thought that other endogenous glomerular antigens may be . . .

Improved methods for the accurate identification of both the presence and severity of cervical intraepithelial neoplasia (CIN) and extent of spread of invasive carcinomas of the cervix (IC) are needed. Differential scanning calorimetry (DSC) has recently been shown to detect specific changes in the thermal behavior of blood plasma proteins in several diseases. This methodology is being explored to provide a complementary approach for screening of cervical disease. The present study evaluated the utility of DSC in differentiating between healthy controls, increasing severity of CIN and early and advanced IC. Significant discrimination was apparent relative to the extent of disease with no clear effect of demographic factors such as age, ethnicity, smoking status and parity. Of most clinical relevance, there was strong differentiation of CIN from healthy controls and IC, and amongst patients with IC between FIGO Stage I and advanced cancer. The observed disease-specific changes in DSC profiles (thermograms) were hypothesized to reflect differential expression of disease biomarkers that subsequently bound to and affected the thermal behavior of the most abundant plasma proteins. The effect of interacting biomarkers can be inferred from the modulation of thermograms but cannot be directly identified by DSC. To investigate the nature of the proposed interactions, mass spectrometry (MS) analyses were employed. Quantitative assessment of the low molecular weight protein fragments of plasma and urine samples revealed a small list of peptides whose abundance was correlated with the extent of cervical disease, with the most striking plasma peptidome data supporting the interactome theory of peptide portioning to abundant plasma proteins. The combined DSC and MS approach in this study was successful in identifying unique biomarker signatures for cervical cancer and demonstrated the utility of DSC plasma profiles as a complementary diagnostic tool to evaluate cervical cancer health.

Polychlorinated biphenyls (PCBs) have been associated with sex-dependent liver disease outcomes. Current mechanisms only partially explain these sex differences and alternative mechanisms including gut-liver toxicity warrant investigation. This study aims to identify PCB-induced changes in the hepatic proteome and gut microbiome and determine their contributions to sex-specific PCB toxicity. Male and female C57BL/6J mice were exposed to Aroclor1260 (20 mg/kg) and PCB126 (20 μg/kg) via oral gavage. After two weeks, hepatic and intestinal tissues were collected for peptide measurements (LC/MS) and 16S sequencing respectively. Proteomic analysis revealed that biological sex largely drove differences seen in the hepatic proteome and dictated PCB liver responses. PCB-exposed females manifested higher abundance of aryl hydrocarbon receptor (AHR) targets including CD36 vs. PCB-exposed males. Computational analysis also demonstrated enhanced AHR and liver-X-receptor (LXR) activation (higher z -scores) in PCB-exposed females vs. males. With regards to gut microbiome, both exposure and sex impacted the composition of microbial communities. Intriguingly, only PCB-exposed males exhibited increased Dehalobacterium abundance, and decreased mRNA levels for genes encoding gut barrier and antimicrobial proteins ( Ocln , Reg3g ). Overall, PCB-exposed females exhibited an altered proteome relevant to AHR and LXR responses, while PCB-exposed males exhibited more distinct changes in gut microbiota coupled with altered ileal gene expression. The findings suggest that, in addition to biological sex, organ-organ interactions should be considered when predicting toxicity outcomes, particularly for persistent compounds such as PCBs that can impact multiple organs simultaneously yet have tissue-specific toxic effects.

The obesity epidemic has expanded globally, due in large part to the increased consumption of high-fat diets (HFD), and has increased the risk of major chronic diseases, including type 2 diabetes. Diet manipulation is the foundation of prevention and treatment of obesity and diabetes. The molecular mechanisms that mediate the diet-based prevention of insulin resistance, however, remain to be identified. Here, we report that treatment with orally administered ginger-derived nanoparticles (GDNP) prevents insulin resistance by restoring homeostasis in gut epithelial Foxa2 mediated signaling in mice fed a high-fat diet (HFD). Ginger-derived nanoparticles (GDNP) were added into drinking water to treat high-fat diet fed mice for at least one year or throughout their life span. A micro array profile of intestinal, liver and fat tissue of GDNP treated mice was used to analyze their gene expression profile. Genes associated with metabolism or insulin signaling were further quantified using the real time polymerase chain reaction (RT-PCR). Surface plasmon resonance (SPR) was used for determining the interaction between Foxa2 protein and phosphatic acid lipid nanoparticles. HFD-feeding inhibited the expression of Foxa2; the GDNPs increased the expression of Foxa2 and protected Foxa2 against Akt-1 mediated phosphorylation and subsequent inactivation of Foxa2. Increasing expression of Foxa2 leads to altering the composition of intestinal epithelial cell (IEC) exosomes of mice fed a HFD and prevents IEC exosome mediated insulin resistance. Collectively, oral administration of GDNP prevents insulin resistance in HFD mice. Interestingly, oral administration of GDNP also extended the life span of the mice and inhibited skin inflammation. Our findings showed that GDNP treatment can prevent HFD-induced obesity and insulin resistance via protecting the Foxa2 from Akt-1 mediated phosphorylation. GDNP treatment provides an alternative approach based on diet manipulation for the development of therapeutic interventions for obesity.