Zebrafish: A New Promise to Study the Impact of Metabolic Disorders on the Brain

Zebrafish has become a popular model to study many physiological and pathophysiological processes in humans. In recent years, it has rapidly emerged in the study of metabolic disorders, namely, obesity and diabetes, as the regulatory mechanisms and metabolic pathways of glucose and lipid homeostasis are highly conserved between fish and mammals. Zebrafish is also widely used in the field of neurosciences to study brain plasticity and regenerative mechanisms due to the high maintenance and activity of neural stem cells during adulthood. Recently, a large body of evidence has established that metabolic disorders can alter brain homeostasis, leading to neuro-inflammation and oxidative stress and causing decreased neurogenesis. To date, these pathological metabolic conditions are also risk factors for the development of cognitive dysfunctions and neurodegenerative diseases. In this review, we first aim to describe the main metabolic models established in zebrafish to demonstrate their similarities with their respective mammalian/human counterparts. Then, in the second part, we report the impact of metabolic disorders (obesity and diabetes) on brain homeostasis with a particular focus on the blood–brain barrier, neuro-inflammation, oxidative stress, cognitive functions and brain plasticity. Finally, we propose interesting signaling pathways and regulatory mechanisms to be explored in order to better understand how metabolic disorders can negatively impact neural stem cell activity.     

Impact of Metabolic Surgery on Gut Microbiota and Sera Metabolomic Patterns among Patients with Diabetes

Metabolic surgery is a promising treatment for obese individuals with type 2 diabetes mellitus (T2DM), but the mechanism is not completely understood. Current understanding of the underlying ameliorative mechanisms relies on alterations in parameters related to the gastrointestinal hormones, biochemistry, energy absorption, the relative composition of the gut microbiota, and sera metabolites. A total of 13 patients with obesity and T2DM undergoing metabolic surgery treatments were recruited. Systematic changes of critical parameters and the effects and markers after metabolic surgery, in a longitudinal manner (before surgery and three, twelve, and twenty-four months after surgery) were measured. The metabolomics pattern, gut microbiota composition, together with the hormonal and biochemical characterizations, were analyzed. Body weight, body mass index, total cholesterol, triglyceride, fasting glucose level, C-peptide, HbA1c, HOMA-IR, gamma-glutamyltransferase, and des-acyl ghrelin were significantly reduced two years after metabolic surgery. These were closely associated with the changes of sera metabolomics and gut microbiota. Significant negative associations were found between the Eubacterium eligens group and lacosamide glucuronide, UDP-L-arabinose, lanceotoxin A, pipercyclobutanamide B, and hordatine B. Negative associations were identified between Ruminococcaceae UCG-003 and orotidine, and glucose. A positive correlation was found between Enterococcus and glutamic acid, and vindoline. Metabolic surgery showed positive effects on the amelioration of diabetes and metabolic syndromes, which were closely associated with the change of sera metabolomics, the gut microbiota, and other disease-related parameters.     

Zein‐based micro‐ and nano‐particles for drug and nutrient delivery: A review

Zein is the major storage protein from corn with strong hydrophobicity and unique solubility and has been considered as a versatile food biopolymer. Due to the special tertiary structures, zein can self‐assemble to form micro‐ and nano‐particles through liquid–liquid dispersion or solvent evaporation approaches. Zein‐based delivery systems have been particularly investigated for hydrophobic drugs and nutrients. Recently, increasing attention has been drawn to fabricate zein‐based advanced drug delivery systems for various applications. In this review, the molecular models of zein tertiary structure and possible mechanisms involved in zein self‐assembly micro‐ and nano‐particles are briefly introduced. Then, a state‐of‐the‐art introduction and discussion are given in terms of preparation, characterization, and application of zein‐based particles as delivery systems in the fields of food science, pharmaceutics, and biomedicine. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40696.     

Solution blow spinning: A new method to produce micro‐ and nanofibers from polymer solutions

A solution blow spinning technique was developed using elements of both electrospinning and melt blowing technologies as an alternative method for making non‐woven webs of micro‐ and nanofibers with diameters comparable with those made by the electrospinning process with the advantage of having a fiber production rate (measured by the polymer injection rate) several times higher. The diameters of fibers produced ranged from 40 nm for poly(lactic acid) to several micrometers for poly(methyl methacrylate). This solution blow spinning method uses a syringe pump to deliver a polymer solution to an apparatus consisting of concentric nozzles whereby the polymer solution is pumped through the inner nozzle while a constant, high velocity gas flow is sustained through the outer nozzle. Analysis of the process showed that pressure difference and shearing at the gas/solution interface jettisoned multiple strands of polymer solution towards a collector. During flight, the solvent component of the strands rapidly evaporates forming a web of micro and nanofibers. The effect of injection rate, gas flow pressure, polymer concentration, working distance, and protrusion distance of the inner nozzle was investigated. Polymer type and concentration had a greater effect on fiber diameter than the other parameters tested. Injection rate, gas flow pressure, and working distance affected fiber production rate and/or fiber morphology. Fibers were easily formed into yarns of micro‐ and nanofibers or non‐woven films that could be applied directly onto biological tissue or collected in sheets on a rotating drum. Indeed, virtually any type of target could be used for fiber collection. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Treatment of Low HDL‐C Subjects with the CETP Modulator Dalcetrapib Increases Plasma Campesterol Only in Those Without ABCA1 and/or ApoA1 Mutations

We investigated the effect of dalcetrapib treatment on phytosterol levels in patients with familial combined hyperlipidemia (FCH) or familial hypoalphalipoproteinemia (FHA) due to mutations in apolipoprotein A1 (ApoA1) or ATP‐binding cassette transporter A1 (ABCA1). Patients (n = 40) with FCH or FHA received dalcetrapib 600 mg or placebo in this 4‐week, double‐blind, crossover study. Lipids, apolipoproteins, cholesteryl ester transfer protein (CETP) activity and mass, and phytosterols were assessed. Dalcetrapib increased high‐density lipoprotein cholesterol (HDL‐C) and ApoA1 levels to a similar extent in FHA (+22.8, +13.9 %) and FCH (+18.4, +12.1 %), both p < 0.001 vs. placebo. Changes in CETP activity and mass were comparable for FHA (?31.5, +120.9 %) and FCH (?26.6, +111.9 %), both p < 0.0001 vs. placebo. Campesterol and lathosterol were unchanged in FHA (+3.8, +3.0 %), but only campesterol was markedly increased in FCH (+25.0 %, p < 0.0001 vs. placebo). Campesterol increased with dalcetrapib treatment in FCH but not in FHA, despite comparable HDL‐C and ApoA1 increases, suggesting that ApoA1 and/or ABCA1 is essential for HDL lipidation by enterocytes in humans.     

Potent,Metabolically Stable 2‐Alkyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐adenines as Adenosine A2A Receptor Ligands

Inhibition of adenosine A_2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson’s disease (PD). We previously identified the triazolo‐9H‐purine, ST1535, as a potent A_2AR antagonist. Studies revealed that ST1535 is extensively hydroxylated at the ω‐1 position of the butyl side chain. Here, we describe the synthesis and evaluation of derivatives in which the ω‐1 position has been substituted (F, Me, OH) in order to block metabolism. The stability of the compounds was evaluated in human liver microsomes (HLM), and the affinity for A_2AR was determined. Two compounds, (2‐(3,3‐dimethylbutyl)‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐6‐amine ( 3 b ) and 4‐(6‐amino‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐2‐yl)‐2‐methylbutan‐2‐ol ( 3 c ), exhibited good affinity against A_2AR (K_i=0.4 nM and 2 nM , respectively) and high in vitro metabolic stability (89.5 % and 95.3 % recovery, respectively, after incubation with HLM for two hours).     

The versatile synthesis method for hierarchical micro‐ and mesoporous zeolite: An embedded nanocarbon cluster approach

In this work, we are reporting for the first time the synthesis of hierarchical micro‐ and mesoporous zeolite using silica–carbon (SiO₂/C) composites prepared by pyrolysis of carbonaceous gases in the presence of silica gel. The pyrolysis effectively yielded carbon deposited onto the raw silica material. The obtained SiO₂/C composites were utilised as a bifunctional material, mesoporous template and silica source, for the zeolite synthesis. Tetrapropylammonium hydroxide (TPAOH) was used as a microporous template. The combination of the obtained composites and the TPAOH for the hydrothermal synthesis resulted in the formation of hierarchical micro‐ and mesoporous ZSM‐5. The results from the SEM, TEM, and N₂ adsorption/desorption isotherms, and ²⁷Al MAS NMR characterisations of the synthesised samples obtained after the removal of the templates confirmed the successful formation of the micro‐ and mesoporous zeolites. The mesoporosity of the zeolites could be controlled by adjusting the carbon content in the SiO₂/C composites while the carbon content could be controlled by varying the deposition time and the concentration of the carbonaceous gases used. This controllable and efficient synthesis method is considered to be a promising method for creating hierarchical micro‐ and mesoporous zeolites. © 2011 Canadian Society for Chemical Engineering     

A constitutive model for non‐linear behavior of SMC accounting for linear viscoelasticity and micro‐damage

An approach for modeling sheet molding compound (SMC) composites as viscoelastic damageable material is presented. Continuum damage mechanics theory by Chow and Wang (Int. J. Fract., 33, 3 (1987)) was used in combination with linear viscoelasticity. The model was applied to a modern SMC composite material containing both hollow glass spheres for low density and toughening additive for improved impact resistance. Tensile tests and uniaxial creep test were employed to build the constitutive model. Validation was done by comparing test data with simulations of uniaxial creep on material with different degrees of damage. The model has good accuracy at moderate damage levels under controlled time‐dependent crack propagation. Tensile testing at two different fixed strain rates was simulated using quasi‐elastic method to calculate relaxation modulus. The model predicts the stress‐strain curve with good accuracy until the region is close to failure, where new mechanisms not accounted for are taking place. Finally, a simulation of a cyclic tensile test with increasing maximum strain per cycle was performed, and since both damage and viscoelasticity are included in the model, the slope change, accumulation of residual strain, and hysteresis in the stress‐strain, loading‐unloading curve are predicted. POLYM. COMPOS., 26:84–97, 2005. © 2004 Society of Plastics Engineers     

α‐Amylase Modulation: Discovery of Inhibitors Using a Multi‐Pharmacophore Approach for Virtual Screening

Better control of postprandial hyperglycemia can be achieved by delaying the absorption of glucose resulting from carbohydrate digestion. Because α‐amylase initiates the hydrolysis of polysaccharides, the design of α‐amylase inhibitors can lead to the development of new treatments for metabolic disorders such as type II diabetes and obesity. In this study, a rational computer‐aided approach was developed to identify novel α‐amylase inhibitors. Three‐dimensional pharmacophores were developed based on the binding mode analysis of six different families of compounds that bind to this enzyme. In a stepwise virtual screening workflow, seven molecules were selected from a library of 1.4 million. Five out of seven biologically tested compounds showed α‐amylase inhibition, and the two most potent compounds inhibited α‐amylase with IC₅₀ values of 17 and 27 μm . The scaffold benzylideneacetohydrazide was shared by four of the discovered inhibitors, emerging as a novel drug‐like non‐carbohydrate fragment and constituting a promising lead scaffold for α‐amylase inhibition.     

Role of Biliverdin Reductase A in the Regulation of Insulin Signaling in Metabolic and Neurodegenerative Diseases: An Update

Insulin signaling is a conserved pathway that orchestrates glucose and lipid metabolism, energy balance, and inflammation, and its dysregulation compromises the homeostasis of multiple systems. Insulin resistance is a shared hallmark of several metabolic diseases, including obesity, metabolic syndrome, and type 2 diabetes, and has been associated with cognitive decline during aging and dementia. Numerous mechanisms promoting the development of peripheral and central insulin resistance have been described, although most of them were not completely clarified. In the last decades, several studies have highlighted that biliverdin reductase-A (BVR-A), over its canonical role in the degradation of heme, acts as a regulator of insulin signaling. Evidence from human and animal studies show that BVR-A alterations are associated with the aberrant activation of insulin signaling, metabolic syndrome, liver steatosis, and visceral adipose tissue inflammation in obese and diabetic individuals. In addition, recent findings demonstrated that reduced BVR-A levels or impaired BVR-A activation contribute to the development of brain insulin resistance and metabolic alterations in Alzheimer’s disease. In this narrative review, we will provide an overview on the literature by focusing on the role of BVR-A in the regulation of insulin signaling and how BVR-A alterations impact on cell dysfunctions in both metabolic and neurodegenerative disorders.     

Accuracy of FIB-4 to Detect Elevated Liver Stiffness Measurements in Patients with Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study in Referral Centers

The identification of advanced fibrosis by applying noninvasive tests is still a key component of the diagnostic algorithm of NAFLD. The aim of this study is to assess the concordance between the FIB-4 and liver stiffness measurement (LSM) in patients referred to two liver centers for the ultrasound-based diagnosis of NAFLD. Fibrosis 4 Index for Liver Fibrosis (FIB-4) and LSM were assessed in 1338 patients. A total of 428 (32%) had an LSM ≥ 8 kPa, whereas 699 (52%) and 113 (9%) patients had an FIB-4 < 1.3 and >3.25, respectively. Among 699 patients with an FIB-4 < 1.3, 118 (17%) had an LSM ≥ 8 kPa (false-negative FIB-4). This proportion was higher in patients ≥60 years, with diabetes mellitus (DM), arterial hypertension or a body mass index (BMI) ≥ 27 kg/m². In multiple adjusted models, age ≥ 60 years (odds ratio (OR) = 1.96, 95% confidence interval (CI) 1.19–3.23)), DM (OR = 2.59, 95% CI 1.63–4.13), body mass index (BMI) ≥ 27 kg/m² (OR = 2.17, 95% CI 1.33–3.56) and gamma-glutamyltransferase ≥ 25 UI/L (OR = 2.68, 95% CI 1.49–4.84) were associated with false-negative FIB-4. The proportion of false-negative FIB-4 was 6% in patients with none or one of these risk factors and increased to 16, 31 and 46% among those with two, three and four concomitant risk factors, respectively. FIB-4 is suboptimal to identify patients to refer to liver centers, because about one-fifth may be false negative at FIB-4, having instead an LSM ≥ 8 KPa.     

Kinetics and mechanism of styrene‐acrylonitrile copolymerization in micro‐emulsion

Stable and transparent poly(styrene‐acrylonitrile) latexes were produced by the polymerization of styrene‐acrylonitrile in ternary o/w micro‐emulsions containing sodium dodecyl sulfate as an anionic surfactant. Kinetics of copolymerization was studied at different temperatures using different concentrations of potassium persulfate and hydrogen peroxide/ascorbic acid. The suitability of existing model for homopolymerization was examined for styrene‐acrylonitrile copolymerization after appropriate modification. The latexes were characterized for particle size and number of particles by dynamic light scattering and TEM. The isolated products were characterized by ¹H and ¹³C NMR as well as by thermal analysis. The overall size of particles was found to be between 15 and 20 nm. © 2000 Society of Chemical Industry     

Distinct Fatty Acid Compositions of HDL Phospholipids Are Characteristic of Metabolic Syndrome and Premature Coronary Heart Disease—Family Study

HDL particles can be structurally modified in atherosclerotic disorders associated with low HDL cholesterol level (HDL-C). We studied whether the lipidome of the main phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and sphingomyelin (SM) species of HDL2 and HDL3 subfractions is associated with premature coronary heart disease (CHD) or metabolic syndrome (MetS) in families where common low HDL-C predisposes to premature CHD. The lipidome was analyzed by LC-MS. Lysophosphatidylcholines were depleted of linoleic acid relative to more saturated and shorter-chained acids containing species in MetS compared with non-affected subjects: the ratio of palmitic to linoleic acid was elevated by more than 30%. A minor PC (16:0/16:1) was elevated (28–40%) in MetS. The contents of oleic acid containing PCs were elevated relative to linoleic acid containing PCs in MetS; the ratio of PC (16:0/18:1) to PC (16:0/18:2) was elevated by 11–16%. Certain PC and SM ratios, e.g., PC (18:0/20:3) to PC (16:0/18:2) and a minor SM 36:2 to an abundant SM 34:1, were higher (11–36%) in MetS and CHD. The fatty acid composition of certain LPCs and PCs displayed a characteristic pattern in MetS, enriched with palmitic, palmitoleic or oleic acids relative to linoleic acid. Certain PC and SM ratios related consistently to CHD and MetS.     

UV‐initiated copolymerization route for facile fabrication of epoxy‐functionalized micro‐zone plates

Bisphenol A‐based epoxy acrylate (BABEA), a commercial ultraviolet (UV)‐curable material, was introduced as a new manufacturing material for facile fabrication of epoxy‐functionalized micro‐zone plates through UV‐initiated copolymerization using glycidyl methacrylate (GMA) as the functional monomer. The poly (BABEA‐co‐GMA) was highly transparent in visible range while highly opaque when the wavelength is less than 295 nm, and of high replication fidelity. X‐ray photoelectron spectroscope (XPS) results indicated the existence of epoxy groups on the surface of the poly (BABEA‐co‐GMA), which allowed for binding protein through an epoxy‐amino group reaction. A fabrication procedure was proposed for manufacturing BABEA based epoxy‐functionalized micro‐zone plates. The fabrication procedure was very simple; obviating the need of micromachining equipments, wet etching or imprinting techniques. To evaluate the BABEA‐based epoxy‐functionalized micro‐zone plates, α‐fetoprotein (AFP) was immobilized onto the capture zone for chemiluminescent (CL) detection in a noncompetitive immune response format. The proposed AFP immunoaffinity micro‐zone plate was demonstrated as a low cost, flexible, homogeneous, and stable assay for α‐fetoprotein (AFP). © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 39787.     

Early Signs of Atherogenic Features in the HDL Lipidomes of Normolipidemic Patients Newly Diagnosed with Type 2 Diabetes

Cardiovascular disease (CVD) is the major cause of death in patients with type-2 diabetes mellitus (T2DM), although the factors that accelerate atherosclerosis in these patients are poorly understood. The identification of the altered quantity and quality of lipoproteins, closely related to atherogenesis, is limited in routine to a pattern of high triglycerides and low HDL-cholesterol (HDL-C) and in research as dysfunctional HDLs. We used the emerging NMR-based lipidomic technology to investigate compositional features of the HDLs of healthy individuals with normal coronary arteries, drug-naïve; recently diagnosed T2DM patients with normal coronary arteries; and patients with recent acute coronary syndrome. Patients with T2DM and normal serum lipid profiles even at diagnosis presented significant lipid alterations in HDL, characterized by higher triglycerides, lysophosphatidylcholine and saturated fatty acids; and lower cholesterol, phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, plasmalogens and polyunsaturated fatty acids, an atherogenic pattern that may be involved in the pathogenesis of atherosclerosis. These changes are qualitatively similar to those found, more profoundly, in normolipidemic patients with established Coronary Heart Disease (CHD). We also conclude that NMR-based lipidomics offer a novel holistic exploratory approach for identifying and quantifying lipid species in biological matrixes in physiological processes and disease states or in disease biomarker discovery.     

Pathophysiological Molecular Mechanisms of Obesity: A Link between MAFLD and NASH with Cardiovascular Diseases

Obesity is now a worldwide epidemic ensuing an increase in comorbidities’ prevalence, such as insulin resistance, type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular disease (CVD), autoimmune diseases, and some cancers, CVD being one of the main causes of death in the world. Several studies provide evidence for an association between MAFLD and atherosclerosis and cardio-metabolic disorders, including CVDs such as coronary heart disease and stroke. Therefore, the combination of MAFLD/NASH is associated with vascular risk and CVD progression, but the underlying mechanisms linking MAFLD/NASH and CVD are still under investigation. Several underlying mechanisms may probably be involved, including hepatic/systemic insulin resistance, atherogenic dyslipidemia, hypertension, as well as pro-atherogenic, pro-coagulant, and pro-inflammatory mediators released from the steatotic/inflamed liver. MAFLD is strongly associated with insulin resistance, which is involved in its pathogenesis and progression to NASH. Insulin resistance is a major cardiovascular risk factor in subjects without diabetes. However, T2D has been considered the most common link between MAFLD/NASH and CVD. This review summarizes the evidence linking obesity with MAFLD, NASH, and CVD, considering the pathophysiological molecular mechanisms involved in these diseases. We also discuss the association of MAFLD and NASH with the development and progression of CVD, including structural and functional cardiac alterations, and pharmacological strategies to treat MAFLD/NASH and cardiovascular prevention.     

Prolyl Carboxypeptidase Activity Is Present in Human Adipose Tissue and Is Elevated in Serum of Obese Men with Type 2 Diabetes

Prolyl carboxypeptidase (PRCP) is involved in metabolic disorders by hydrolyzing anorexigenic peptides. A link between serum PRCP activity and obesity has been reported, but its origin/source is still unclear. Previously proven correlations between human serum PRCP activity and the amount of adipose tissue may suggest that adipose tissue is an important source of circulating PRCP. We investigated PRCP activity in visceral, subcutaneous adipose tissue (VAT and SCAT), skeletal muscle tissue and serum of lean and obese men with or without type 2 diabetes (T2D). Correlations between PRCP activity, metabolic and biochemical parameters and immune cell populations were assessed. PRCP activity was the highest in VAT, compared to SCAT, and was very low in skeletal muscle tissue in the overall group. Serum PRCP activity was significantly higher in T2-diabetic obese men, compared to lean and obese non-diabetic men, and was positively correlated with glycemic control. A positive correlation was observed between serum PRCP activity and VAT immune cell populations, which might indicate that circulating PRCP activity is deriving rather from the immune fraction than from adipocytes. In conclusion, PRCP activity was observed in human adipose tissue for the first time and serum PRCP activity is correlated with T2D in obese men.     

Changes in sialylation of low‐density lipoprotein in coronary artery disease

Reduction of LDL sialylation may correlate with coronary artery disease (CAD), but the details of this modification and its effect on CAD are not well studied. This study was aimed to show desialylation of LDL and to reveal more details of this modification. Blood samples were collected from 16 patients with CAD and 25 healthy individuals. Serum sialic acid was determined. LDL was extracted from all samples, and the interaction of the extracted materials with lectins (MAA, SNA, and DSA) was studied using the lectin blotting method. Serum total sialic acid (TSA) concentrations in CAD patients and healthy individuals were 71.9 ± 2.66 and 60.76 ± 2.34 mg/dL, respectively, and the difference between the two groups was statistically significant (p <0.001). The intensity of interaction of extracted LDL with SNA and MAA lectins was lower in CAD patients compared to that in normal subjects (p <0.001). The intensity of interaction of LDL with DSA was higher in CAD (p <0.001). There was a reverse correlation between TSA and intensity of LDL interaction with SNA and MAA in both groups, but in the case of DSA this correlation was direct and positive. These findings indicated an increase in desialylation of LDL in CAD. It was concluded that LDL was subjected to glycosylation changes in CAD and that there was a positive correlation between TSA and the desialylated form of LDL. This modification may contribute to the pathogenesis of CAD.     

Simulation of dry powder inhalers: Combining micro‐scale,meso‐scale and macro‐scale modeling

The flow of carrier particles, coated with active drug particles, is studied in a prototype dry powder inhaler. A novel, multiscale approach consisting of a discrete element model (DEM) to describe the particles coupled with a dynamic large eddy simulation (LES) model to describe the dynamic nature of the flow is applied. The model consists of three different scales: the micro‐scale, the meso‐scale, and the macro‐scale. At the micro‐scale, the interactions of the small active drug particles with larger carrier particles, with the wall, with the air flow, and with each other is thoroughly studied using discrete element modeling and detailed computational fluid dynamics (CFD), i.e., resolving the flow structures around the particles. This has led to the development of coarse‐grained models, describing the interaction of the small active drug particles at the larger scales. At the meso‐scale the larger carrier particles, and all of their interactions are modeled individually using DEM and CFD‐LES. Collisions are modeled using a visco‐elastic model to describe the local deformation at each point of particle‐particle contact in conjunction with a model to account for cohesion. At the macro‐scale, simulations of a complete prototype inhaler are carried out. By combining the relevant information of each of the scales, simulations of the inhalation of one dose from a prototype inhaler using a patient relevant air flow profile show that fines leave the inhaler faster than the carrier particles. The results also show that collisions are not important for particle‐particle momentum exchange initially but become more important as the particles accelerate. It is shown that for the studied prototype inhaler the total release efficiency of the fine particles is between 10 and 30%, depending on the Hamaker constant, using typical settings for the properties of both particles. The results are also used to study regions of recirculation, where carrier particles can become trapped, and regions where fines adhere to the wall of the device. © 2016 American Institute of Chemical Engineers AIChE J, 63: 501–516, 2017