Oral supplementation of solvent-free kynurenic acid/cyclodextrin nanosponges complexes increased its bioavailability.

Many nutraceuticals present problems due to their poor water solubility or stability, which prevents the final bioactivity achievement. For that reason, the oral administration of KYNA complexed with HPß-CD and ßNS-CDI nanosponges was evaluated in mice. The solvent-free technology was used to prepare the complexes in a complete comparison between kneading in ball milling and classical inclusion complex preparation. The solvent-free ones showed higher strength and efficiency with ball milling, considerably reducing time. A 50 mg KYNA/kg/day dosage was orally administered in formulations showing a higher bioavailability when the nutraceutical was complexed with ßNS-CDI compared to HPß-CD and free KYNA, respectively. Several antioxidant statuses demonstrated a higher global antioxidant level perfectly related to bioavailability. Finally, the formulation of KYNA reduced the temporal oxidative stress damage in the kidney and liver, making ßNS-CDI the best formulation. These results suggest an important future application of cyclodextrin-based nanosponges for the oral delivery of nutraceuticals and their stabilization.

Hyper-Branched Cyclodextrin-Based Polymers as Anticoagulant Agents: In Vitro and In Vivo Studies.

This study tested the anticoagulant effect of cyclodextrin (CD) hyper-branched-based polymers (HBCD-Pols). These polymers were synthesized and tested for their coagulant characteristics in vitro and in vivo. Due to their polymeric structure and anionic nature, the polymers can chelate Ca2+, reducing the free quantity in blood. HBCD-Pol increased the blood clotting time, PT, and aPTT 3.5 times over the control, showing a better effect than even ethylenediaminetetraacetic acid (EDTA), as occured with recalcification time as well. A titration of HBCD-Pol and EDTA showed exciting differences in the ability to complex Ca2+ between both materials. Before executing in vivo studies, a hemocompatibility study was carried out with less than 5% red blood cell hemolysis. The fibrinogen consumption and bleeding time were analyzed in vivo. The fibrinogen was considerably decreased in the presence of HBCD-Pol in a higher grade than EDTA, while the bleeding time was longer with HBCD-Pols. The results demonstrate that the anticoagulant effect of this HBCD-Pol opens novel therapy possibilities due to the possible transport of drugs in this carrier. This would give combinatorial effects and a potential novel anticoagulant therapy with HBCD-Pol per se.

Hyper-Branched Cationic Cyclodextrin Polymers for Improving Plasmid Transfection in 2D and 3D Spheroid Cells.

In this article, we used monolayer two dimensional (2D) and 3D multicellular spheroid models to improve our understanding of the gene delivery process of a new modified cationic hyper-branched cyclodextrin-based polymer (Ppoly)-loaded plasmid encoding Enhanced Green Fluorescent Protein (EGFP). A comparison between the cytotoxicity effect and transfection efficiency of the plasmid DNA (pDNA)-loaded Ppoly system in 2D and 3D spheroid cells determined that the transfection efficiency and cytotoxicity of Ppoly-pDNA nanocomplexes were lower in 3D spheroids than in 2D monolayer cells. Furthermore, histopathology visualization of Ppoly-pDNA complex cellular uptake in 3D spheroids demonstrated that Ppoly penetrated into the inner layers. This study indicated that the Ppoly, as a non-viral gene delivery system in complex with pDNA, is hemocompatible, non-toxic, high in encapsulation efficiency, and has good transfection efficiency in both 2D and 3D cell cultures compared to free pDNA and lipofectamine (as the control).

Circulating salivary and serum miRNA-182, 320a, 375 and 503 expression levels in type 2 diabetes.

Aim: Early-stage diagnosis of diabetes through non-invasive and diagnostic biofluid-like saliva has become a very popular approach to facilitate future preventive interventions and improve patient care. Meanwhile, the alteration of small non-coding RNA in human fluids has been suggested as a probable precedent for the early stages of diabetes. Methods: In the present study, we checked the expression of miR-320a, 182-5p, 503, and 375 by using quantitative PCR in both stimulated and unstimulated saliva and blood samples of 40 adult patients with type-2 diabetes compared to 40 healthy individuals. In addition, we have sought to understand the possibility that miRNAs could provide new information about the status of type 2 diabetes in salivary samples beyond what can now be identified from blood samples and link their expression to the presence of clinically relevant risk factors. For this purpose, we have used a set of multivariate models. Results: The results showed that three miRNAs were more highly expressed in patients with type 2 diabetes, while miR-320-a was down-regulated in those patients compared to healthy subjects. Furthermore, the data showed that miR-320a was the most reliable predictor for distinguishing diabetic patients from healthy subjects, with AUCs of 0.997, 0.97, and 0.99 (97.4% sensitivity and 100% specificity, p = 0.001) for serum, unstimulated, and stimulated saliva samples, respectively. Conclusions: Interestingly, the results of this study indicated that the amount of four miRNAs expressed in stimulated saliva was the same as in serum samples, which could conclude that specific miR-320a and 503 in stimulated saliva may introduce credible, non-invasive, and diagnostic biomarkers that can be used to monitor diabetic patients' status, while there is a need to design more research studies to confirm these findings.

Dextrin-Based Nanohydrogels for Rokitamycin Prolonged Topical Delivery.

Macrolides are widely used antibiotics with a broad spectrum of activity. The development of drug carriers to deliver this type of antibiotics has attracted much research. The present study aims at developing new swellable dextrin-based nanohydrogels for the topical delivery of rokitamycin, as model macrolide. Rokitamycin is a synthetic analogous of macrolides with advantageous characteristics as far as bacterial uptake and post-antibiotic effect are concerned. It is also indicated for the treatment of severe infections caused by Acanthamoeba and for topical infections. The nanohydrogels have been prepared from two types of cross-linked polymers obtained by using ß-cyclodextrin or Linecaps® was provided by the Roquette Italia SPA (Cassano Spinola, Al, Italy) as building blocks. The cross-linked polymers have been then formulated into aqueous nanosuspensions refined and tuned to achieve the incorporation of the drug. Cross-linked ß-cyclodextrin (ß-CD) and Linecaps® (LC) polymers formed dextrin-based nanohydrogels with high swelling degree and mucoadhesion capability. Rokitamycin was loaded into the nanohydrogels displaying an average size around 200 nm with negative surface charge. In vitro kinetic profiles of free and loaded drug in nanohydrogels were compared at two pH levels. Interestingly, a sustained and controlled release was obtained at skin pH level due to the high degree of swelling and a pH responsiveness possibly. The results collected suggest that these nanohydrogels are promising for the delivery of rokitamycin and may pave the way for the topical delivery of other macrolide antibiotics.

Salivary microRNA-126 and 135a: a potentially non-invasive diagnostic biomarkers of type- 2 diabetes.

PURPOSE: Emerging of miRNAs have illustrated the new mechanistic layer to regulate type 2 diabetes process and suggests a possible role of these RNAs in this defect. Thus, we designed this study to improve our understanding of salivary miRNA-126 and 135a expression utility as an easy of collection and non-invasive way in diabetic patients instead of blood sample. METHODS: This case-control study was done on T2D (n = 40) and healthy individuals (n = 40). The level of biochemical parameters were determined by enzymatic methods as well as glycosylated hemoglobin (HbA1c) was measured by immunoturbidimetry. We used the pooled whole stimulated saliva sample from cases and controls to assess the differentiation expression of miRNA 126 and 135-a with quantitative RT-PCR method. Unpaired Student's t test, Pearson's correlation coefficient and Receiver Operating Characteristic (ROC) analysis were used. RESULTS: A correlation was observed between the level of HbA1c, glucose and lipid profiles (TG, TC, and LDL) in serum and whole stimulated saliva samples in T2D patients compared to control (p < 0.001). miR-135a expression was considerably higher by 4.7-fold in T2D compared to the control group (1.8-fold) (p < 0.001) while the miR126 expression was significantly decreased by 3.9-fold in T2D compared to the controls (6.3-fold) (p < 0.001). CONCLUSIONS: The results of this case and control study showed that miR-135a and miR126 expression in saliva fluid as a reliable biomarkers and non-invasive approach in combination by change of lipid profiles, glucose and HbA1c may be used to monitor diabetic and non-diabetic patients, while further research is needed to investigate the relationship of these salivary miRNAs (miR135a, miR126) levels change on shifting the levels of clinical laboratory outcomes.

Cyclodextrin Monomers and Polymers for Drug Activity Enhancement.

Cyclodextrins (CDs) and cyclodextrin (CD)-based polymers are well-known complexing agents. One of their distinctive features is to increase the quantity of a drug in a solution or improve its delivery. However, in certain instances, the activity of the solutions is increased not only due to the increase of the drug dose but also due to the drug complexation. Based on numerous studies reviewed, the drug appeared more active in a complex form. This review aims to summarize the performance of CDs and CD-based polymers as activity enhancers. Accordingly, the review is divided into two parts, i.e., the effect of CDs as active drugs and as enhancers in antimicrobials, antivirals, cardiovascular diseases, cancer, neuroprotective agents, and antioxidants.

Circulating miR-135 May Serve as a Novel Co-biomarker of HbA1c in Type 2 Diabetes.

Hemoglobin A1c (HbA1c) is a reliable marker of insulin resistance in normal glucose tolerance patients; however, several physiological, environmental, and genetic factors may affect HbA1c and cause false results. Therefore, it is essential to use new biomarkers due to increasing diabetes predictive value. Recently, it has been indicated that microRNAs (miRNAs) are involved in the pathophysiology of diabetes, particularly, in insulin resistance pathways. Therefore, miRNAs have the potential to be introduced as new glycemic control biomarkers. The aim of this study was to investigate the association between plasma level of miRNA-135a and HbA1c in patients with prediabetes and type 2 diabetes. In this case-control study, 120 samples were enrolled (healthy individuals, people with type 2 diabetes, and prediabetes) and HbA1c and miR-135a expression level in their plasma samples were evaluated. Multinomial logistic regression and ROC curve analysis were conducted to assess the diagnostic accuracy of plasma miR-135a in T2D , prediabetes, and healthy control groups. Data analysis indicated that miR-135a was significantly elevated in both diabetes/prediabetes samples. Then, subjects were reclassified based on the calculated cutoff value of miRNA. Logistic Regression analysis showed that an increased level of miRNA positively correlated with HbA1c level in prediabetes (Adjusted OR = 1.14, p value = 0.033) and diabetic status (Adjusted OR = 1.27, p value = 0.024 ). miR-135 may provide an assistant marker for HbA1c to detect type 2 diabetes.