Milk Exosomes Facilitate Oral Delivery of Drugs against Intestinal Bacterial Infections

Biopharmaceutics Classification System (BCS) class II and IV drugs exhibit low solubility and suffer a limitation in oral administration. Exosomes have attracted intensive attention in the efficient delivery of such compounds. However, low gastrointestinal stability and high production cost of exosomes hinder their development as drug carriers. Here, milk exosomes are functionalized with phosphatidylserine and are capable of improving the solubility of BCS class II and IV drugs, resulting in facilitating the oral delivery of the drugs. A natural flavonoid, α-mangostin, is loaded into exosomes (AExo) to enhance the antibacterial efficiency, demonstrated by clearing 99% of bacteria in macrophages. Furthermore, AExo exhibits high mucus penetrability and shows a significant therapeutic efficacy in two animal infection models. Collectively, this work expands the application of exosomes from bovine milk with simple operation and low cost, shedding light on the potential of milk exosomes in improving the solubility of drugs to enhance the efficacy of oral administration

Characteristics of included studies about the four VDR polymorphisms and coronary artery disease.

Characteristics of included studies about the four VDR polymorphisms and coronary artery disease.</p

Complex Formation between NheB and NheC Is Necessary to Induce Cytotoxic Activity by the Three-Component <i>Bacillus cereus</i> Nhe Enterotoxin

<div><p>The nonhemolytic enterotoxin (Nhe) is known as a major pathogenicity factor for the diarrheal type of food poisoning caused by <i>Bacillus cereus.</i> The Nhe complex consists of NheA, NheB and NheC, all of them required to reach maximum cytotoxicity following a specific binding order on cell membranes. Here we show that complexes, formed between NheB and NheC under natural conditions before targeting the host cells, are essential for toxicity in Vero cells. To enable detection of NheC and its interaction with NheB, monoclonal antibodies against NheC were established and characterized. The antibodies allowed detection of recombinant NheC in a sandwich immunoassay at levels below 10 ng ml⁻¹, but no or only minor amounts of NheC were detectable in natural culture supernatants of <i>B. cereus</i> strains. When NheB- and NheC-specific monoclonal antibodies were combined in a sandwich immunoassay, complexes between NheB and NheC could be demonstrated. The level of these complexes was directly correlated with the relative concentrations of NheB and NheC. Toxicity, however, showed a bell-shaped dose-response curve with a plateau at ratios of NheB and NheC between 50:1 and 5:1. Both lower and higher ratios between NheB and NheC strongly reduced cytotoxicity. When the ratio approached an equimolar ratio, complex formation reached its maximum resulting in decreased binding of NheB to Vero cells. These data indicate that a defined level of NheB-NheC complexes as well as a sufficient amount of free NheB is necessary for efficient cell binding and toxicity. Altogether, the results of this study provide evidence that the interaction of NheB and NheC is a balanced process, necessary to induce, but also able to limit the toxic action of Nhe.</p></div

The PRISMA flow diagram.

(DOCX)</p

The RNAfold structure analysis of the VDR rs1544410 polymorphism.

A: rs2228570 polymorphism; B: rs731236 polymorphism. VDR = vitamin D receptor.</p

The PRISMA 2009 checklist.

(DOCX)</p

Forest plot of CAD risk associated with the VDR polymorphism.

CAD = Coronary artery disease, A: rs2228570 polymorphism; B: rs1544410 polymorphism; C: rs731236 polymorphism; D: rs7975232 polymorphism. VDR = vitamin D receptor, OR = odd ration, CI = confidence interval.</p

Binding of NheB to Vero cells.

<p>(A) Decrease of NheB binding to Vero cells as determined by flow cytometry. (B) Histogram showing the overlay of NheB-specific fluorescence counts (FL1-H) for the isotype control (a), a 1:1 (b), 5:1 (c), and 10:1 (d) ratio between NheB and NheC.</p