Extracellular vesicles (EVs) are heterogeneous lipid containers with a complex molecular cargo comprising several populations with unique roles in biological processes. These vesicles are closely associated with specific physiological features, which makes them invaluable in the detection and monitoring of various diseases. EVs play a key role in pathophysiological processes by actively triggering genetic or metabolic responses. However, the heterogeneity of their structure and composition hinders their application in medical diagnosis and therapies. This diversity makes it difficult to establish their exact physiological roles, and the functions and composition of different EV (sub)populations. Ensemble averaging approaches currently employed for EV characterization, such as western blotting or ‘omics’ technologies, tend to obscure rather than reveal these heterogeneities. Recent developments in single-vesicle analysis have made it possible to overcome these limitations and have facilitated the development of practical clinical applications. In this review, we discuss the benefits and challenges inherent to the current methods for the analysis of single vesicles and review the contribution of these approaches to the understanding of EV biology. We describe the contributions of these recent technological advances to the characterization and phenotyping of EVs, examination of the role of EVs in cell-to-cell communication pathways and the identification and validation of EVs as disease biomarkers. Finally, we discuss the potential of innovative single-vesicle imaging and analysis methodologies using microfluidic devices, which promise to deliver rapid and effective basic and practical applications for minimally invasive prognosis systems. Understanding the heterogeneity of extracellular vesicles is crucial for unraveling their functions. This review describes the benefits, challenges and contributions of the state-of-the art methods used in single-vesicle analysis.

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Using single-vesicle technologies to unravel the heterogeneity of extracellular vesicles.

To evaluate the effects of therapy on the vascular complications of adult diabetes, the University Group Diabetes Program (UGDP) carried out a prospective double-blind study in 12 centers ...

Sulfonylureas: Effects in Vivo and in Vitro

The microflora and pH of gastric contents were determined in breast-fed and in bottle-fed normal infants, in well nourished infants with acute diarrhoea and in infants with chronic diarrhoea and protein-calorie malnutrition. The last group of infants was reevaluated after recovery from diarrhoea and protein-calorie malnutrition. A bactericidal pH effect below 2-5 was observed. Bottle-fed controls had low pH values and low bacterial concentrations, whereas infants with chronic diarrhoea and protein-calorie malnutrition had high pH values and bacterial overgrowth, essentially of Gram-negative bacilli. After recovery, the only remaining alteration was the frequent isolation of yeast-like fungi in low concentrations. Infants with acute diarrhoea, except for the isolation more frequently of yeast-like fungi, presented no alterations; this seems to indicate that pH alterations and Gram-negative bacilli overgrowth occurred during the evolution of the disease to a chronic state. Breast-fed normal infants had hydrogen-ion concentrations similar to those of the chronic diarrhoea group, but without Gram-negative bacilli overgrowth, suggesting that other factors, besides pH, regulate bacterial growth in the gastric contents of these groups of infants.

https://gut.bmj.com/content/gutjnl/16/9/719.full.pdf

Gastric pH and microflora of normal and diarrhoeic infants.

Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) expressed on a variety of cell types. These receptors play an important role in the regulation of inflammatory reactions and sensing cellular damage. They have also been implicated in the pathogenesis of various diseases, including neurodegenerative diseases, cataract formation, and atherogenesis. Thus, FPR ligands, both agonists and antagonists, may represent novel therapeutics for modulating host defense and innate immunity. A variety of molecules have been identified as receptor subtype-selective and mixed FPR agonists with potential therapeutic value during last decade. This review describes our efforts along with recent advances in the identification, optimization, biological evaluation, and structure-activity relationship (SAR) analysis of small molecule non-peptide FPR agonists and antagonists, including chiral molecules. Questions regarding the interaction at the molecular level of benzimidazoles, pyrazolones, pyridazin-3(2H)-ones, N-phenylureas and other derivatives with FPR1 and FPR2 are discussed. Application of computational models for virtual screening and design of FPR ligands is also considered.

/pdf/development-of-small-molecule-non-peptide-formyl-peptide-cze8prse3z.pdf

Development of small molecule non-peptide formyl peptide receptor (FPR) ligands and molecular modeling of their recognition.

Introduction: The activation of leukocytes and the subsequent immune cascade play an essential role in sterile and infectious inflammation. Dysregulation of these immune responses or excess leukocyte activation can induce tissue damage, organ dysfunction and mortality. Formyl peptide receptors (FPRs) are functionally diverse pattern recognition receptors responsible for recognizing different endogenous damage-associated molecular patterns or exogenous pathogen-associated molecular patterns. FPRs mediate leukocyte activation during inflammation. FPR1 antagonists and FPR2 agonists have demonstrated significant anti-inflammatory effects based on in vitro and in vivo studies. An increasing number of synthesized compounds targeting FPRs, especially potential FPR1 antagonists and FPR2 agonists, have been disclosed in patents.Areas covered: This article summarizes the current pharmacology patents related to FPR family modulators and their therapeutic indications based on a review of patent applications d...

Formyl peptide receptor modulators: a patent review and potential applications for inflammatory diseases (2012-2015).

Colonic inflammation was produced in rats by chemotactic peptides acting on polymorphonuclear leucocytes. Instillation during one hour of formylated tripeptide: formylmethionyl-leucyl-phenylalanine (FMLP) and a tetrapeptide: alanine-glycine-sefine-glutamine (AGSG) into rat colon caused erosions and exulcerations. Neutrophils increased secondary to instillation, predominantly with FMLP, and mucus depletion was marked in the cecum. Chloride ion secretion and mucosal permeability were significatively greater in the colonic lumen with the chemotactic peptides. Histamine and serotonin concentration were greater in the colonic fluid in animals treated with the peptides. These observations could suggest that the presence of chemotactic peptides at the colonic lumen produce changes at the mucosal wall, that would participate in generation and perpetuation of the colonic inflammation.

Stimulation of inflammatory mediators secretion by chemotactic peptides in rat colitis model.

IgA in the gastric content and in the serum of eutrophic and malnourished infants

Action of hypoglycemic drugs on the stomach

Depending on quantity and/or quality, the presence of lactic acid in the colonic lumen may be associated with metabolic damage of the colon. The influence exerted on the rat colon by the different isomers and racemic of the lactic acid, used at two extreme dilutions (20 and 100 mEq/l), has been the subject of study in this paper. The modifications on pH, water and electrolytes are associated with the absorptive/secretory action of the colonic wall. In addition, a study has been made on the influence of lactic acid on the colonic mucus and albumin permeation. Histopathologic studies of the caecum and left colon have been performed. There is a different colonic wall behaviour for each of the different isomers of the lactic and its racemic; a larger absorption of water, Na+ and Cl- for the D (-) isomer at a low concentration; its behaviour is completely opposite at high concentration. The final pH is higher when the D (-) isomer takes part; comparing the different isomers, there are small variations as far as albumin permeation is concerned. At high concentration there is a decline in Cl- absorption. The high percentage of erosions that take place especially in the caecum, where L (+) isomer can be found at high concentration, it is remarkable. The present observations suggest that the presence of lactic acid in (the) ulcerative colitis deserves great attention, especially in about the quantity and quality in which the acid can be found.

Bustos Fernandez L

Papers

Stimulation of inflammatory mediators secretion by chemotactic peptides in rat colitis model.

IgA in the gastric content and in the serum of eutrophic and malnourished infants

Action of hypoglycemic drugs on the stomach

La acción de los diferentes isómeros del acido láctico en el colón de la rata