Alpha-cyclodextrin increases glucagon-like peptide-1 secretion in multiple models and improves metabolic status in mice.

Alpha-cyclodextrin (α-CD) is a non-absorbable and soluble fiber that causes weight loss. We studied whether this is due to an effect on GLP-1 secretion. In GLUTag cells, α-CD increased GLP-1 secretion up to 170% via adenylyl cyclase, phospholipase C, and L-type calcium channels dependent processes. In rat isolated colon perfusions, luminal α-CD increased GLP-1 secretion with 20%. In lean mice, once daily α-CD versus saline caused weight loss and lowered the peak in glucose after an oral glucose tolerance test (OGTT). In obese mice, α-CD added to high-fat diet caused weight loss similar to the control group (receiving cellulose). However, compared to cellulose, the α-CD group ate less. During an OGTT, no differences were observed in glucose, insulin and GLP-1. Thus, α-CD increases GLP-1 secretion in a dose-dependent manner and could be a safe and easy addition to food products to help reduce body weight.

Thiolated α-cyclodextrin: The likely smallest drug carrier providing enhanced cellular uptake and endosomal escape.

This study aimed to evaluate the effect of thiolated α-cyclodextrin (α-CD-SH) on the cellular uptake of its payload. For this purpose, α-CD was thiolated using phosphorous pentasulfide. Thiolated α-CD was characterized by FT-IR and 1H NMR spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffractometry (PXRD). Cytotoxicity of α-CD-SH was evaluated on Caco-2, HEK 293, and MC3T3 cells. Dilauryl fluorescein (DLF) and coumarin-6 (Cou) serving as surrogates for a pharmaceutical payload were incorporated in α-CD-SH, and cellular uptake was analyzed by flow cytometry and confocal microscopy. Endosomal escape was investigated by confocal microscopy and hemolysis assay. Results showed no cytotoxic effect within 3 h, while dose-dependent cytotoxicity was observed within 24 h. The cellular uptake of DLF and Cou was up to 20- and 11-fold enhanced by α-CD-SH compared to native α-CD, respectively. Furthermore, α-CD-SH provided an endosomal escape. According to these results, α-CD-SH is a promising carrier to shuttle drugs into the cytoplasm of target cells.

Glucocorticoid-loaded pH/ROS dual-responsive nanoparticles alleviate joint destruction by downregulating the NF-κB signaling pathway.

Rheumatoid arthritis (RA) is an autoimmune disease causing severe symptoms that are difficult to treat. Nano-drug delivery system is recognized as a promising strategy for management of RA. However, how to thoroughly release payloads from nanoformulations and synergistic therapy of RA needs to be further investigated. To address this issue, a pH and reactive oxygen species (ROS) dual-responsive, methylprednisolone (MPS)-loaded and arginine-glycine-aspartic acid (RGD)-modified nanoparticles (NPs) was fabricated using phytochemical and ROS-responsive moiety co-modified α-cyclodextrin (α-CD) as a carrier. In vitro and in vivo experiments verified that the pH/ROS dual-responsive nanomedicine could be efficiently internalized by activated macrophages and synovial cells, and the released MPS could promote transformation of M1-type macrophages into M2 phenotype, thereby down-regulating pro-inflammatory cytokines. In vivo experiments demonstrated that the pH/ROS dual-responsive nanomedicine was remarkably accumulated in the inflamed joints of mice with collagen-induced arthritis (CIA). The accumulated nanomedicine could obviously relieve joint swelling and cartilage destruction without obvious adverse effects. Importantly, the expression of interleukin-6 and tumor necrosis factor-α in the joints of CIA mice were significantly inhibited by the pH/ROS dual-responsive nanomedicine in comparison with free drug and non-targeted counterparts. In addition, the expression of the NF-κB signaling pathway molecule P65 was also significantly decreased by nanomedicine-treatment. Our results reveal that MPS-loaded pH/ROS dual-responsive NPs can effectively alleviate joint destruction via down-regulation of the NF-κB signaling pathway. STATEMENT OF SIGNIFICANCE: Nanomedicine is recognized as an attractive method for the targeting treatment of rheumatoid arthritis (RA). To thorough release of payloads from nanoformulations and synergistic therapy of RA, herein, a phytochemical and ROS-responsive moiety co-modified α-cyclodextrin was used as a pH/ROS dual-responsive carrier to encapsulate methylprednisolone to manage RA. The fabricated nanomedicine can effectively release its payloads under pH and/or ROS microenvironment, and the released drugs dramatically promote transformation of M1-type macrophages into M2 phenotype to reduce the release of pro-inflammatory cytokines. The prepared nanomedicine also obviously decreased the NF-κB signaling pathway molecule P65 expression in the joints, thereby down-regulating pro-inflammatory cytokines expression to alleviate joint swelling and cartilage destruction. We provided a candidate for the targeting treatment of RA.

Positive postprandial glycaemic and appetite-related effects of wheat breads enriched with either α-cyclodextrin or hydroxytyrosol/α-cyclodextrin inclusion complex.

PURPOSE: Enrichment of wheat bread with either α-cyclodextrin (α-CD) or an inclusion complex of hydroxytyrosol (HT) and α-CD was performed to examine potential postprandial benefits. METHODS: Ten healthy normoglycaemic adults were provided with either a glucose solution (reference food, GS), white wheat bread (WB), wheat bread enriched with α-CD (α-CDB) or wheat bread enriched with HT/α-CD complex ((HT + α-CD)B), with 1-week intervals in amounts that yielded 50 g of available carbohydrates. Venous blood samples were collected before consumption and at 15, 30, 45, 60, 90, 120 and 180 min, postprandially. Glycaemic, insulinaemic and appetite hormone responses as well as glycaemic index (GI) and subjective appetite ratings were evaluated. RESULTS: Both enriched breads were characterized as low GI foods (α-CDB:49.7, (HT + α-CD)B:40.0) and presented similar reduction in glucose, insulin and GLP-1 responses. Significant differences were found in glucose values 45 min after (HT + α-CD)B consumption compared to α-CDB (P < 0.05) as well as in serum ghrelin, 120 min postprandially, between (HT + α-CD)B and WB in (- 90.55 ± 29.17 and 16.53 ± 21.78 pg/dL, respectively, P < 0.05). Neither of the enriched breads prevailed regarding the induced self-reported satiety. However, their consumption led to a lower desire for the next meal compared to WB. CONCLUSION: Enrichment of bread with α-CD resulted in positive effects on postprandial glycaemia and induced satiety. Incorporation of encapsulated HT offered similar overall acceptability, due to the bitter taste-masking effect provided by α-CD, and a slightly additional positive effect in postprandial glycaemia and satiety. The development of foods with favorable metabolic effects is of great importance for the prevention of chronic diseases. The study was prospectively registered in clinicaltrials.gov (NCT04725955, date: 27th January 2021).

In vitro and clinical studies on the efficacy of α-cyclodextrin and hydroxytyrosol against SARS-CoV-2 infection.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new coronavirus responsible for the current pandemic of coronavirus disease 2019 (COVID-19). This virus attacks cells of the airway epithelium by binding transmembrane angiotensin-converting enzyme 2 (ACE2). Hydroxytyrosol has anti-viral properties. Alpha-cyclodextrin can deplete sphingolipids and phospholipids from cell membranes. The aim of the present experimental study was to evaluate the efficacy of α-cyclodextrin and hydroxytyrosol in improving defenses against SARS-CoV-2 infection in in vitro cell models and humans. PATIENTS AND METHODS: For in vitro experiments on Vero E6 cells, RNA for RT-qPCR analysis was extracted from Caco2 and human fibroblast cell lines. For study in humans, the treatment group consisted of 149 healthy volunteers in Northern Cyprus, considered at higher risk of SARS-CoV-2 infection than the general population. The volunteers used nasal spray containing α-cyclodextrin and hydroxytyrosol for 4 weeks. The control group consisted of 76 healthy volunteers who did not use the spray. RESULTS: RT-qPCR experiments on targeted genes involved in endocytosis showed a reduction in gene expression, whereas cytotoxicity and cytoprotective tests showed that the compounds exerted a protective effect against SARS-CoV-2 infection at non-cytotoxic concentrations. None of the volunteers became positive to SARS-CoV-2 RT-qPCR assay during the 30 days of treatment. CONCLUSIONS: Treatment with α-cyclodextrin and hydroxytyrosol nasal spray improved defenses against SARS-CoV-2 infection and reduced synthesis of viral particles.

Scoping review on the role and interactions of hydroxytyrosol and alpha-cyclodextrin in lipid-raft-mediated endocytosis of SARS-CoV-2 and bioinformatic molecular docking studies.

OBJECTIVE: The aim of the study was to show the effect that two naturally occurring compounds, a cyclodextrin and hydroxytyrosol, can have on the entry of SARS-CoV-2 into human cells. MATERIALS AND METHODS: The PubMed database was searched to retrieve studies published from 2000 to 2020, satisfying the inclusion criteria. The search keywords were: SARS-CoV, SARS-CoV-2, coronavirus, lipid raft, endocytosis, hydroxytyrosol, cyclodextrin. Modeling of alpha-cyclodextrin and hydroxytyrosol were done using UCSF Chimera 1.14. RESULTS: The search results indicated that cyclodextrins can reduce the efficiency of viral endocytosis and that hydroxytyrosol has antiviral properties. Bioinformatic docking studies showed that alpha-cyclodextrin and hydroxytyrosol, alone or in combination, interact with the viral spike protein and its host cell receptor ACE2, thereby potentially influencing the endocytosis process. CONCLUSIONS: Hydroxytyrosol and alpha-cyclodextrin can be useful against the spread of SARS-CoV-2.

Lecithin Inclusion by α-Cyclodextrin Activates SREBP2 Signaling in the Gut and Ameliorates Postprandial Hyperglycemia.

BACKGROUND: α-cyclodextrin (α-CD) is one of the dietary fibers that may have a beneficial effect on cholesterol and/or glucose metabolism, but its efficacy and mode of action remain unclear. METHODS: In the present study, we examined the anti-hyperglycemic effect of α-CD after oral loading of glucose and liquid meal in mice. RESULTS: Administration of 2 g/kg α-CD suppressed hyperglycemia after glucose loading, which was associated with increased glucagon-like peptide 1 (GLP-1) secretion and enhanced hepatic glucose sequestration. By contrast, 1 g/kg α-CD similarly suppressed hyperglycemia, but without increasing secretions of GLP-1 and insulin. Furthermore, oral α-CD administration disrupts lipid micelle formation through its inclusion of lecithin in the gut luminal fluid. Importantly, prior inclusion of α-CD with lecithin in vitro nullified the anti-hyperglycemic effect of α-CD in vivo, which was associated with increased intestinal mRNA expressions of SREBP2-target genes (Ldlr, Hmgcr, Pcsk9, and Srebp2). CONCLUSIONS: α-CD elicits its anti-hyperglycemic effect after glucose loading by inducing lecithin inclusion in the gut lumen and activating SREBP2, which is known to induce cholecystokinin secretion to suppress hepatic glucose production via a gut/brain/liver axis.

Effects of alpha-cyclodextrin on water transport, cell hydration and longevity.

Among parent cyclodextrins (CDs), alpha-CD (a-CD) has been utilized in a number of nutraceutical products, and approved as a dietary fiber to affect glycemic response and reduce dietary fat absorption. To extend our current knowledge on the biology of this natural carbohydrate, here we investigated its potential effects on cellular water uptake and aging. Two independent in vivo biological test systems were used, a single cell Xenopus oocyte with expressed human aquaporin for cell hydration studies and the nematode Caenorhabditis elegans for testing life span in the treated animals. a-CD was found to enhance water uptake through aquaporins of oocytes. Furthermore, the compound promoted longevity in C. elegans. Together, these results raise a rational for assaying a-CD as a potent drug candidate in treating various age-related diseases.

Effects of α-Cyclodextrin on Cholesterol Control and Hydrolyzed Ginseng Extract on Glycemic Control in People With Prediabetes: A Randomized Clinical Trial.

Importance: Effective strategies for preventing type 2 diabetes are needed. Many people turn to complementary medicines, but there is little well-conducted scientific evidence to support their use. Objective: To assess the efficacy of α-cyclodextrin for cholesterol control and that of hydrolyzed ginseng for glycemic control in people with prediabetes and overweight or obesity. Design, Setting, and Participants: This 6-month double-blind, placebo-controlled, randomized clinical trial, with a 2 × 2 factorial design, was conducted between July 2015 and October 2018 at 2 locations in Sydney, Australia. Eligible participants were aged 18 years or older, had a body mass index (weight in kilograms divided by height in meters squared) of 25 or higher, and had prediabetes within 6 months of study entry according to the American Diabetes Association guidelines. Data analysis was performed from May to August 2019. Interventions: Participants were randomized to 1 of 4 groups to take active or placebo versions of each supplement (α-cyclodextrin plus hydrolyzed ginseng, α-cyclodextrin plus placebo, placebo plus hydrolyzed ginseng, or placebo plus placebo) for 6 months. All participants received dietetic advice for weight loss. Main Outcomes and Measures: The primary outcomes were the differences in total cholesterol and fasting plasma glucose between groups after 6 months. The primary analysis used the intention-to-treat principle. Multiple predetermined subsample analyses were conducted. Results: A total of 401 participants were eligible for the study (248 women [62%]; mean [SD] age, 53.5 [10.2] years; mean [SD] body mass index, 34.6 [6.2]). One hundred one patients were randomized to receive α-cyclodextrin plus hydrolyzed ginseng, 99 were randomized to receive α-cyclodextrin plus placebo, 101 were randomized to receive placebo plus hydrolyzed ginseng, and 100 were randomized to receive placebo plus placebo. For 200 participants taking α-cyclodextrin compared with 201 participants taking placebo, there was no difference in total cholesterol after 6 months (-1.5 mg/dL; 95% CI, -6.6 to 3.5 mg/dL; P = .51). For 202 participants taking hydrolyzed ginseng compared with 199 participants taking placebo, there was no difference in fasting plasma glucose after 6 months (0.0 mg/dL; 95% CI, -1.6 to 1.8 mg/dL; P = .95). Use of α-cyclodextrin was associated with constipation (16 participants vs 4 participants; P = .006) and cough (8 participants vs 1 participant; P = .02). Use of hydrolyzed ginseng was associated with rash and pruritus (13 participants vs 2 participants; P = .006). Only 37 of 401 participants (9.2%) experienced these adverse events. Conclusions and Relevance: Although they are safe for use, there was no benefit found for either α-cyclodextrin for cholesterol control or hydrolyzed ginseng for glycemic control in people with prediabetes and overweight or obesity. Trial Registration: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12614001302640.

A pH-responsive citric-acid/α-cyclodextrin-functionalized Fe3O4 nanoparticles as a nanocarrier for quercetin: An experimental and DFT study.

Developing new nanocarriers and understanding the interactions between the drug and host molecules in the nanocarrier at the molecular level is of importance for future of nanomedicine. In this work, we synthesized and characterized a series of iron oxide nanoparticles (IONPs) functionalized with different organic molecules (citric acid, α-cyclodextrin, and citric acid/α-cyclodextrin composite). It was found that incorporation of citric acid into the α-cyclodextrin had negligible effect on the adsorption efficiency (<5%) of citric acid/α-cyclodextrin functionalized IONPs, while the isotherm adsorption data were well described by the Langmuir isotherm model (qmax = 2.92 mg/g at T = 25 °C and pH = 7). In addition, the developed nanocarrier showed pH-responsive behavior for releasing the quercetin molecules as drug model, where the Korsmeyer-Peppas model could describe the release profile with Fickian diffusion (n < 0.45 for at all pH and temperatures). Then, Density functional theory was applied to calculate the absolute binding energies (ΔEb) of the complexation of quercetin with different host molecules in the developed nanocarriers. The calculated energies are as follow: 1) quercetin and citric acid: ΔEb = -16.58 kcal/mol, 2) quercetin and α-cyclodextrin: ΔEb = -46.98 kcal/mol, and 3) quercetin and citric acid/α-cyclodextrin composite: ΔEb = -40.15 kcal/mol. It was found that quercetin tends to interact with all hosts via formation of hydrogen bonds and van der Waals interactions. Finally, the cytotoxicity of the as-developed nanocarriers was evaluated using MTT assay and both normal NIH-3T3 and cancereous HeLa cells. The cell viability results showed that the quercetin could be delivered effectively to the HeLa cells due to the acidic environment inside the cells with minimum effect on the viability of NIH-3T3 cells. These results might open a new window to design of stimuli-responsive nanocarriers for drug delivery applications.