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15 pages, 27241 KiB  
Article
Compact Quantum Cascade Laser-Based Noninvasive Glucose Sensor Upgraded with Direct Comb Data-Mining
by Liying Song, Zhiqiang Han, Hengyong Nie and Woon-Ming Lau
Sensors 2025, 25(2), 587; https://doi.org/10.3390/s25020587 - 20 Jan 2025
Viewed by 376
Abstract
Mid-infrared spectral analysis has long been recognized as the most accurate noninvasive blood glucose measurement method, yet no practical compact mid-infrared blood glucose sensor has ever passed the accuracy benchmark set by the USA Food and Drug Administration (FDA): to substitute for the [...] Read more.
Mid-infrared spectral analysis has long been recognized as the most accurate noninvasive blood glucose measurement method, yet no practical compact mid-infrared blood glucose sensor has ever passed the accuracy benchmark set by the USA Food and Drug Administration (FDA): to substitute for the finger-pricking glucometers in the market, a new sensor must first show that 95% of their glucose measurements have errors below 15% of these glucometers. Although recent innovative exploitations of the well-established Fourier-transform infrared (FTIR) spectroscopy have reached such FDA accuracy benchmarks, an FTIR spectrometer is too bulky. The advancements of quantum cascade lasers (QCLs) can lead to FTIR spectrometers of reduced size, but compact QCL-based noninvasive blood glucose sensors are not yet available. This work reports on two compact sensor system designs, both reaching the FDA accuracy benchmark. Each design commonly comprises a mid-infrared QCL for emission, a multiple attenuation total reflection prism (MATR) for data acquisition, and a computer-controlled infrared detector for data analysis. The first design translates the comb-like signals into conventional spectra, and then data-mines the resultant spectra to yield blood glucose concentrations. When a pressure actuator is employed to press the patient’s hypothenar against the MATR, the sensor accuracy is considered to reach the FDA accuracy benchmark. The second design abandons the data processing step of translating combs-to-spectra and directly data-mines the “first-hand” comb signal. Beyond increasing the measurement accuracy to the FDA accuracy benchmark, even without a pressure actuator, direct comb data-mining upgrades the sensor system with speed and data integrity, which can impact the healthcare of diabetic patients. Specifically, the sensor performance is validated with 492 glucose absorption scans in the time domain, each with 20 million datapoints measured from four subjects with glucose concentrations of 3.9–7.9 mM. The sensor data-mines 164 sets of critical singularity strengths, each comprising 4 critical singularity strengths directly from the 9840 million raw signal datapoints, and the 656 critical singularity strengths are subjected to a machine-learning regression model analysis, which yields 164 glucose concentrations. These concentrations are correlated with those measured with a standard finger-pricking glucometer. An accuracy of 99.6% is confirmed from the 164 measurements with errors not more than 15% from the reference of the standard glucometer. Full article
(This article belongs to the Section Biomedical Sensors)
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Figure 1

Figure 1
<p>(<b>a</b>) Schematic of an FTIR-based sensor equipped with a single-pass ATR plus a pressure actuator [<a href="#B17-sensors-25-00587" class="html-bibr">17</a>]. (<b>b</b>) The Clarke error grid plot for such a sensor with spectral analysis of the region of 1000 to 1040 cm<sup>−1</sup> for reducing spectral interference, with data collection from the hypothenar replacing that from the finger [<a href="#B18-sensors-25-00587" class="html-bibr">18</a>] (the blue circles are the data of the training set, and the orange crosses are the data of the testing set).</p>
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<p>Schematic diagram of a QCL-based noninvasive blood glucose sensor.</p>
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<p>Schematics of the operation of QCL-Sensor-System #1: (<b>a</b>) Interface between the patient’s hypothenar and the sensor; (<b>b</b>) the route from raw comb signal, to comb-to-spectrum translation, and finally to statistical analysis of glucose concentration.</p>
Full article ">Figure 4
<p>Schematics of the operation of QCL-Sensor-System #2: (<b>a</b>) Simplified interface hardware between the patient’s hypothenar and the sensor; (<b>b</b>) the simplified software route from generation of raw comb signal, to direct MFDFA data-mining of the four critical singularity strengths associated with MFDFA singularity plots, and finally to statistical analysis of glucose concentration.</p>
Full article ">Figure 5
<p>Conversion of raw data to continuous line spectrum (envelope). (<b>a</b>) Raw time signals of 36 full cycles. (<b>b</b>) An example showing 1 (in the red box) of these 36 full cycles. (<b>c</b>) Overlapping result for 36 full cycles. (<b>d</b>) A continuous emission spectrum from merging these two axisymmetric spectra of (<b>c</b>).</p>
Full article ">Figure 5 Cont.
<p>Conversion of raw data to continuous line spectrum (envelope). (<b>a</b>) Raw time signals of 36 full cycles. (<b>b</b>) An example showing 1 (in the red box) of these 36 full cycles. (<b>c</b>) Overlapping result for 36 full cycles. (<b>d</b>) A continuous emission spectrum from merging these two axisymmetric spectra of (<b>c</b>).</p>
Full article ">Figure 6
<p>The comb-to-spectrum-translation results of 41 photoabsorption spectra (painted in color) from Patient-Subject #1, with a photoabsorption spectrum (painted in blue) collected by an FTIR spectrometer as a reference.</p>
Full article ">Figure 7
<p>The singularity spectra generated by MFDFA of the same 41 comb trains the comb-to-spectrum translation of which give the 41 photoabsorption spectra shown in <a href="#sensors-25-00587-f006" class="html-fig">Figure 6</a>.</p>
Full article ">Figure 8
<p>Clarke error grid plots corresponding to (<b>a</b>) Sensor-System #1 without a pressure actuator; (<b>b</b>) Sensor-System #1 with a pressure actuator; (<b>c</b>) Sensor-System #2 without a pressure actuator. (The blue circles are the data of the training set, and the orange crosses are the data of the testing set.)</p>
Full article ">
16 pages, 1477 KiB  
Article
Effect of Drying Temperature on Sensory Quality, Flavor Components, and Bioactivity of Lichuan Black Tea Processed by Echa No. 10
by Dan Su, Junyu Zhu, Yuchuan Li, Muxue Qin, Zhendong Lei, Jingtao Zhou, Zhi Yu, Yuqiong Chen, De Zhang and Dejiang Ni
Molecules 2025, 30(2), 361; https://doi.org/10.3390/molecules30020361 - 17 Jan 2025
Viewed by 352
Abstract
Lichuan black tea (LBT) is a well-known congou black tea in China, but there is relatively little research on its processing technology. Echa No. 10 is the main tea tree variety for producing LBT. This study investigated the sensory quality, flavor components, and [...] Read more.
Lichuan black tea (LBT) is a well-known congou black tea in China, but there is relatively little research on its processing technology. Echa No. 10 is the main tea tree variety for producing LBT. This study investigated the sensory quality, flavor components, and bioactivity of Echa No. 10 Lichuan black tea (LBT) at different drying temperatures (70, 80, 90, 100, 110, 120, and 130 °C). During 80–120 °C, increasing the drying temperature enabled a higher sweet aroma concentration and enhanced the sweetness in the taste, in contrast to reducing the floral, fruity, and sweet aromas, and increasing the bitterness and astringency, at >120 °C. Additionally, with an increasing drying temperature, the contents of tea polyphenols and total catechins significantly decreased, with the theaflavins decreasing first and then increasing, and the alcohols, aldehydes, esters, and hydrocarbons increasing first and then decreasing. Meanwhile, compounds (including linalool, (Z)-linalool oxide (furanoid), (E)-linalool oxide (furanoid), cis-β-Ocimene, and methyl salicylate) contribute more to the floral and fruity aromas at <110 °C. Furthermore, low-temperature drying favors the antioxidant and inhibitory effects of the α-amylase, α-glucosidase, and glucose absorption activity. Both the tea quality and bioactivity results revealed 80–110 °C as the optimal drying temperature range for LBT. Full article
(This article belongs to the Special Issue Effects of Functional Foods and Dietary Bioactives on Human Health)
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Figure 1
<p>QDA radar chart of the aroma (<b>A</b>) and taste (<b>B</b>) of LBT at different drying temperatures.</p>
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<p>OPLS-DA score plot (<b>A</b>) and heat map (<b>B</b>) of the differential volatile components of the LBT at different drying temperatures.</p>
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<p>The process and experimental flowchart of Lichuan black tea.</p>
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16 pages, 3864 KiB  
Article
Effects of the Interactions Between Food Additive Titanium Dioxide and Matrices on Genotoxicity
by Su-Min Jeong, Han-Na Nam and Soo-Jin Choi
Int. J. Mol. Sci. 2025, 26(2), 617; https://doi.org/10.3390/ijms26020617 - 13 Jan 2025
Viewed by 334
Abstract
Titanium dioxide (TiO2), a white color food additive, is widely used in bakery products, candies, chewing gums, soups, and creamers. Concerns about its potential genotoxicity have recently emerged, particularly following the European Union’s ban on its usage as a food additive [...] Read more.
Titanium dioxide (TiO2), a white color food additive, is widely used in bakery products, candies, chewing gums, soups, and creamers. Concerns about its potential genotoxicity have recently emerged, particularly following the European Union’s ban on its usage as a food additive due to its genotoxicity potential. Conflicting in vitro and in vivo results regarding its genotoxicity highlight the need for further in-depth investigation. Moreover, food additives can interact with food components or biological matrices, potentially altering their biological responses and genotoxicity. In this study, we evaluated the interactions between two different sizes of additive TiO2 particles and food or biological matrices, including albumin, fetal bovine serum (FBS), and glucose. The results showed that the hydrodynamic diameters of TiO2 increased upon interaction with albumin or FBS, but not with glucose. The presence of albumin or FBS reduced TiO2-induced cytotoxicity, oxidative stress, in vitro intestinal transport, and ex vivo intestinal absorption to untreated control levels, regardless of particle size. While TiO2 caused DNA damage in intestinal Caco-2 cells, the interactions with albumin or FBS significantly reduced the DNA damage to levels comparable to untreated controls. The DNA damage was closely related to oxidative stress caused by TiO2. These findings suggest that the interaction of TiO2 with albumin or FBS, resulting in increased hydrodynamic diameters, mitigates its cytotoxicity, oxidative stress, intestinal transport, and genotoxicity. Further investigation is required to fully understand the potential genotoxicity of TiO2 in food contexts. Full article
(This article belongs to the Collection New Advances in Molecular Toxicology)
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Figure 1
<p>(<b>A</b>) Scanning electron microscopy (SEM) images and (<b>B</b>) size distribution of two differently sized TiO<sub>2</sub> particles (T3 and T4). Particle size distribution was determined by randomly selecting 100 particles from SEM images.</p>
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<p>(<b>A</b>) Cell proliferation inhibition, (<b>B</b>) lactate dehydrogenase (LDH) release, and (<b>C</b>) reactive oxygen species (ROS) production caused in Caco-2 cells exposed to TiO<sub>2</sub> particles (T3 and T4) interacted with food or biological matrices. Different lowercase letters (a, b) above bars denote significant differences among different matrices interacted (untreated control, MEM, FBS, albumin, and glucose) (<span class="html-italic">p</span> &lt; 0.05). * denotes significant difference compared to untreated control cells (<span class="html-italic">p</span> &lt; 0.05). Abbreviation: DCF, dichlorofluorescein fluorescence.</p>
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<p>(<b>A</b>) Catalase (CAT) and (<b>B</b>) superoxide dismutase (SOD) activities in Caco-2 cells exposed to TiO<sub>2</sub> particles (T3 and T4) interacted with food or biological matrices. Control represents the basal antioxidant enzyme activities in Caco-2 cells without particles. Different lowercase letters (a, b, c) above bars denote significant differences among different matrices interacted (untreated control, MEM, FBS, albumin, and glucose) (<span class="html-italic">p</span> &lt; 0.05).</p>
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<p>In vitro intestinal transports of TiO<sub>2</sub> particles (T3 and T4) interacted with food or biological matrices through (<b>A</b>) Caco-2 monolayers and (<b>B</b>) follicle-associated epithelial (FAE) models. Control represents the basal Ti levels in the two models without particles. Different lowercase letters (a, b) above bars denote significant differences among different matrices interacted (untreated control, MEM, FBS, albumin, and glucose) (<span class="html-italic">p</span> &lt; 0.05).</p>
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<p>Ex vivo intestinal absorption of TiO<sub>2</sub> particles ((<b>A</b>) T3; (<b>B</b>) T4) interacted with food or biological matrices at two different doses using an everted gut sac model. Control represents basal Ti levels in everted gut sac without particles. Different lowercase letters (a, b) above bars denote significant differences among different matrices interacted (untreated control, MEM, FBS, albumin, and glucose) (<span class="html-italic">p</span> &lt; 0.05).</p>
Full article ">Figure 6
<p>DNA damage caused by TiO<sub>2</sub> particles (T3 and T4) interacted with food or biological matrices assessed with comet assay in Caco-2 cells. (<b>A</b>) Representative images of Caco-2 cells treated with TiO<sub>2</sub>. Images were magnified at 20×. Percentage DNA values in tails exposed to (<b>B</b>) T3 and (<b>C</b>) T4. Control represents DNA (%) in tails of untreated cells without particles. Different lowercase letters (a, b, c) above bars denote significant differences among different matrices interacted (untreated control, MEM, FBS, albumin, and glucose) (<span class="html-italic">p</span> &lt; 0.05).</p>
Full article ">Figure 7
<p>8-hydroxyl-2′-deoxyguanosine (8-OHdg) generated by TiO<sub>2</sub> particles (T3 and T4) interacted with food or biological matrices in Caco-2 cells. Control represent basal 8-OHdg levels of untreated cells without particles. Different lowercase letters (a, b, c, d) above bars denote significant differences among different matrices interacted (untreated control, MEM, FBS, albumin, and glucose) (<span class="html-italic">p</span> &lt; 0.05).</p>
Full article ">
23 pages, 1323 KiB  
Article
Construction of a Library of Fatty Acid Esters of Hydroxy Fatty Acids
by Olga G. Mountanea, Charikleia S. Batsika, Christiana Mantzourani, Christoforos G. Kokotos and George Kokotos
Molecules 2025, 30(2), 286; https://doi.org/10.3390/molecules30020286 - 13 Jan 2025
Viewed by 759
Abstract
Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) have emerged as extraordinary bioactive lipids, exhibiting diverse bioactivities, from the enhancement of insulin secretion and the optimization of blood glucose absorption to anti-inflammatory effects. The intricate nature of FAHFAs’ structure reflects a synthetic challenge [...] Read more.
Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) have emerged as extraordinary bioactive lipids, exhibiting diverse bioactivities, from the enhancement of insulin secretion and the optimization of blood glucose absorption to anti-inflammatory effects. The intricate nature of FAHFAs’ structure reflects a synthetic challenge that requires the strategic introduction of ester bonds along the hydroxy fatty acid chain. Our research seeks to create an effective methodology for generating varied FAHFA derivatives. Our primary approach centers on a photochemical hydroacylation reaction, merging terminal alkenes, either ω-alkenoic acids or ω-alkenyl alcohols, with commercially available aldehydes. This transformative, environmentally friendly process, orchestrated by phenylglyoxylic acid as the photoinitiator, serves as the linchpin in establishing a practical and relatively simple method for constructing a library of racemic FAHFAs. The ketones produced by the photochemical reactions are easily converted to hydroxy derivatives, which are coupled with caproic, palmitic, or oleic acid, providing a large set of FAHFAs, which broaden our ability for future structure–activity relationship studies. Full article
(This article belongs to the Section Organic Chemistry)
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Figure 1
<p>General structure of Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) and schematic overview of the basic strategies for the synthesis of FAHFAs.</p>
Full article ">Scheme 1
<p>General synthetic route for the construction of FAHFAs from <span class="html-italic">ω</span>-alkenoic acids and aldehydes, using a photocatalytic hydroacylation protocol as the key step. (a) Phenylglyoxylic acid (20 mol%), H<sub>2</sub>O, hv (2 × 85 W CFL household bulbs); (b) CH<sub>3</sub>OH, conc. H<sub>2</sub>SO<sub>4</sub>; (c) NaBH<sub>4</sub>, CH<sub>3</sub>OH; (d) CH<sub>3</sub>(CH<sub>2</sub>)<sub>4</sub>COOH or CH<sub>3</sub>(CH<sub>2</sub>)<sub>14</sub>COOH or CH<sub>3</sub>(CH<sub>2</sub>)<sub>7</sub>CH=CH(CH<sub>2</sub>)<sub>7</sub>COOH, EDCI<sub>·</sub>HCl, Et<sub>3</sub>N, 4-dimethylaminopyridine, dry CH<sub>2</sub>Cl<sub>2</sub>; (e) LiOH<sub>·</sub>H<sub>2</sub>O, THF:H<sub>2</sub>O.</p>
Full article ">Scheme 2
<p>Synthetic pathway for the conversion of <span class="html-italic">α</span>,<span class="html-italic">ω</span>-commercially available diols to <span class="html-italic">ω</span>-alkenyl alcohols. (a) <span class="html-italic">tert</span>-Butyldimethylsilyl chloride, imidazole, 4-dimethylaminopyridine, dry <span class="html-italic">N</span>,<span class="html-italic">N</span>-dimethylformamide; (b) Pyridinium chlorochromate, dry CH<sub>2</sub>Cl<sub>2</sub>; (c) MePPh<sub>3</sub>Br, <span class="html-italic">n</span>-BuLi (1.6 M in hexanes), dry THF.</p>
Full article ">Scheme 3
<p>General synthetic route for the construction of FAHFAs from <span class="html-italic">ω</span>-alkenyl alcohols and aldehydes through photocatalytic hydroacylation. (a) Phenylglyoxylic acid (20 mol%), H<sub>2</sub>O, hv (2 × 85 W CFL household bulbs); (b) NaBH<sub>4</sub>, CH<sub>3</sub>OH; (c) CH<sub>3</sub>(CH<sub>2</sub>)<sub>4</sub>COOH or CH<sub>3</sub>(CH<sub>2</sub>)<sub>14</sub>COOH or CH<sub>3</sub>(CH<sub>2</sub>)<sub>7</sub>CH=CH(CH<sub>2</sub>)<sub>7</sub>COOH, EDCI<sub>·</sub>HCl, Et<sub>3</sub>N, 4-dimethylaminopyridine, dry CH<sub>2</sub>Cl<sub>2</sub>; (d) TBAF, dry THF; (e) Jones reagent, acetone.</p>
Full article ">
21 pages, 3729 KiB  
Article
Submicron Dispersions of Phytosterols Reverse Liver Steatosis with Higher Efficacy than Phytosterol Esters in a Diet Induced-Fatty Liver Murine Model
by Raimundo Gillet, Tomás G. Cerda-Drago, María C. Brañes and Rodrigo Valenzuela
Int. J. Mol. Sci. 2025, 26(2), 564; https://doi.org/10.3390/ijms26020564 - 10 Jan 2025
Viewed by 427
Abstract
Consumption of phytosterols is a nutritional strategy employed to reduce cholesterol absorption, but recent research shows that their biological activity might go beyond cholesterol reduction for the treatment of metabolic dysfunction-associated fatty liver disease (MAFLD), and novel phytosterol formulations, such as submicron dispersions, [...] Read more.
Consumption of phytosterols is a nutritional strategy employed to reduce cholesterol absorption, but recent research shows that their biological activity might go beyond cholesterol reduction for the treatment of metabolic dysfunction-associated fatty liver disease (MAFLD), and novel phytosterol formulations, such as submicron dispersions, could improve these effects. We explored the therapeutic activity of phytosterols, either formulated as submicron dispersions of phytosterols (SDPs) or conventional phytosterol esters (PEs), in a mouse model of MAFLD. MAFLD was induced in mice by atherogenic diet (AD) feeding. The reversion of distorted serum and liver parameter values after a period of AD feeding was investigated after supplementation of the AD with SDPs, PEs, or a placebo (PT). Additionally, the metabolic parameters of fatty acid synthesis, fatty acid oxidation, and inflammation were studied to understand the mechanism of action of phytosterols. AD supplementation with SDPs was shown to reduce liver fat, along with showing a significant improvement in liver triglycerides (TGs), free fatty acids (FFAs), and liver cholesterol levels. These results were reinforced by the analyses of the liver steatosis scores, and liver histologies, where SDP intervention showed a consistent improvement. Treatment with PEs showed slighter effects in the same analyses, and no effects were observed with the PT treatment. Additionally, SDP intervention reversed, with a higher efficacy than PEs, the effect of AD on the serum levels of TGs, total- and LDL-cholesterol levels, and glucose levels. And, exceptionally, while SDP improved HDL-cholesterol serum levels, PEs did not show any effect on this parameter. We provide evidence for the therapeutical activity of phytosterols in MAFLD beyond the regulation of cholesterol levels, which is increased when the phytosterols are formulated as submicron dispersions compared to ester formulations. Full article
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Figure 1
<p>Effect of different treatments in the reduction of lipid liver parameters normalized to the values obtained in the AD group. Values for liver fat, triglycerides (TGs), free fatty acids (FFAs), and cholesterol, obtained in the experimental groups of the animals treated with CD, AD supplemented with SDPs, phytosterol esters (PEs), PT, are normalized with respect to the levels obtained in the AD experimental group (AD = 0%). Results correspond to the average ± SD of three independent experiments that were carried out using <span class="html-italic">n</span> = 5 in each experimental group. In this figure, a: <span class="html-italic">p</span> &lt; 0.05 versus the CD group; b: <span class="html-italic">p</span> &lt; 0.05 versus the PT group; and c: <span class="html-italic">p</span> &lt; 0.05 when comparing SDP group to PE group.</p>
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<p>Effect of phytosterol treatments on liver steatosis. Representative images of liver histologies 10× with hematoxylin and eosin staining for the experimental groups of animals treated with atherogenic diet (AD), AD supplemented with submicron dispersion of phytosterols (SDPs), or phytosterol esters (PEs), and control diet (CD). In the image, arrows indicate fat droplets: thick arrow = macrovesicular; thin arrow = microvesicular; n = 5 in each experimental group. Fat globules are depicted with arrows. The graph below shows the quantitative liver steatosis score analysis, where one liver section was considered per mouse. Each bar corresponds to the average ± SD of three independent experiments that were carried out using n = 5 in each experimental group. Liver steatosis scores were evaluated according to Brunt et al., 1999, as a percent of hepatocytes showing macrovesicular steatosis (0 is none, 1 is up to 33%, 2 is 33–66%, and 3 is &gt;66%) [<a href="#B33-ijms-26-00564" class="html-bibr">33</a>]. In the figure, a: <span class="html-italic">p</span> &lt; 0.05 versus the AD group; b: <span class="html-italic">p</span> &lt; 0.05 versus the CD group; and c: <span class="html-italic">p</span> &lt; 0.05 when comparing SDP group to PE group.</p>
Full article ">Figure 3
<p>Effect of different treatments in the reduction of liver oxidative stress parameters normalized to the values obtained in the AD group. Values in Liver F8 isoprostanes, hepatic oxidized proteins, liver thiobarbituric acid reactive substances (TBARSs), reduced glutathione (GSH), glutathione disulfide (GSSG), total GSH equivalents, and the ratio of GSH/GSSG, obtained in the experimental groups of animals treated with CD, or AD supplemented with SDPs, are normalized with respect to levels obtained in the AD experimental group (AD = 0%). Each bar represents the average ± SD of three independent experiments that were carried out using <span class="html-italic">n</span> = 5 in each experimental group. In the figure, a: <span class="html-italic">p</span> &lt; 0.05 versus the CD group.</p>
Full article ">Figure 4
<p>Effect of different treatments on serum lipid and carbohydrate metabolism parameters normalized to the values obtained in the AD group. Values in serum parameters related to lipid and carbohydrate metabolism obtained in the experimental groups of animals treated with CD, AD supplemented with SDPs, or PEs, or PT, are normalized with respect to the levels obtained in the AD experimental group. Each bar represents the average ± SD of three independent experiments that were carried out using <span class="html-italic">n</span> = 5 in each experimental group. In the figure, a: <span class="html-italic">p</span> &lt; 0.05 versus the CD group; b: <span class="html-italic">p</span> &lt; 0.05 versus the PT group; and c: <span class="html-italic">p</span> &lt; 0.05 when comparing SDP group to PE group.</p>
Full article ">Figure 5
<p>Effect of different treatments on serum transaminases, inflammation parameters, and insulin, normalized to the values obtained in the AD group. Serum transaminases, inflammation parameters, and insulin values obtained in the experimental groups of animals treated with CD, AD supplemented with SDPs, or PT, normalized with respect to the levels obtained in the AD experimental group. Each bar represents the average ± SD of three independent experiments that were carried out using <span class="html-italic">n</span> = 5 in each experimental group. In the figure, a: <span class="html-italic">p</span> &lt; 0.05 versus the CD group and b: <span class="html-italic">p</span> &lt; 0.05 versus the PT group.</p>
Full article ">Figure 6
<p>Effect of different treatments on transcript levels of fatty acid oxidation markers normalized to the values obtained in the AD group. Transcript levels of genes linked to the oxidation of fatty acids and obtaining energy (PPAR-α, CPT-1, ACOX) observed in the experimental groups of animals treated with AD supplemented with SDPs, or PT, and CD, normalized with respect to the levels obtained in the AD experimental group. Each bar represents the average ± SD of three experimental replicas that were carried out using <span class="html-italic">n</span> = 5 in each experimental group. In the figure, a: <span class="html-italic">p</span> &lt; 0.05 versus the AD group and b: <span class="html-italic">p</span> &lt; 0.05 versus the CD group.</p>
Full article ">Figure 7
<p>Effect of different treatments on transcript levels of fatty acids synthesis markers normalized to the values obtained in the AD group. Transcript levels of genes linked to the synthesis of fatty acids (SREBP-1c, ACC, FAS) observed in the experimental groups of animals treated with AD supplemented with SDPs, or PT, and CD, normalized with respect to the levels obtained in the AD experimental group. Each bar represents the average ± SD of three experimental replicas that were carried out using <span class="html-italic">n</span> = 5 in each experimental group. In the figure, a: <span class="html-italic">p</span> &lt; 0.05 versus the AD group and b: <span class="html-italic">p</span> &lt; 0.05 versus the CD group.</p>
Full article ">Figure 8
<p>Effect of different treatments on transcript levels of pro-inflammatory markers normalized to the values obtained in the AD group. Transcript levels of genes linked to inflammatory responses (NF-κB, TNF-α, IL-6, IL-1β) observed in the experimental groups of animals treated with AD supplemented with SDPs, or PT, and CD, normalized with respect to the levels obtained in the AD experimental group. Each bar represents the average ± SD of three experimental replicas that were carried out using <span class="html-italic">n</span> = 5 in each experimental group. In the figure, a: <span class="html-italic">p</span> &lt; 0.05 versus the AD group and b: <span class="html-italic">p</span> &lt; 0.05 versus the CD group.</p>
Full article ">Figure 9
<p>Effect of different treatments on hepatic activities of CPT-1, linked to fatty acid oxidation and obtaining energy, and ACC and FAS, linked to fatty acid synthesis, normalized to the values obtained in the AD group. Liver enzymatic activities of CPT-1, ACC, and FAS observed in the experimental groups of animals treated with AD supplemented with SDPs, or PT, and CD, normalized with respect to the levels obtained in the AD experimental group. Each bar represents the average ± SD of three experimental replicas that were carried out using <span class="html-italic">n</span> = 5 in each experimental group. In the figure, a: <span class="html-italic">p</span> &lt; 0.05 versus the AD group and b: <span class="html-italic">p</span> &lt; 0.05 versus the CD group.</p>
Full article ">Figure 10
<p>Summary of the results obtained in this study. Mice fed an AD during a 4-week protocol period developed MAFLD. Then, 4-week co-supplementation of AD with phytosterols in the form of SDPs, or PEs, was able to significantly improve Liver Fat, Liver TGs, Liver FFA, and Liver Cholesterol levels. The effectiveness of SDPs was observed to be significantly higher than that of PEs in regard to the aforementioned parameters. Additionally, to understand the action of SDPs, the metabolic parameters related to MAFLD were studied. It was observed that SDPs improved oxidative stress parameters (namely F8 Isoprostanes, TBARS, GSH, GSH equivalents, and the ratio of GSH/GSSG), inflammation parameters (namely NF-κB, TNF-α, IL-6, and IL-1β), fatty acid synthesis parameters (namely SREBP-1c, AAC, and FAS), and fatty acids oxidation parameters (PPAR-α, ACOX, and CPT-1). In the figure, arrows up and down indicate significant increase and decrease, respectively, of each set of parameters.</p>
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<p>Experimental design used in this study. Five experimental groups were considered following the protocol of fatty liver generation with atherogenic diet (AD) for four weeks, and then another four weeks with AD alone or supplementation with a submicron dispersion of phytosterols (SDPs), or phytosterol esters (PEs) or placebo (PT). Another group was fed for eight weeks with control diet.</p>
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18 pages, 2566 KiB  
Article
Early Weaning Impairs the Growth Performance of Hu Lambs Through Damaging Intestinal Morphology and Disrupting Serum Metabolite Homeostasis
by Haoyun Jiang, Haibo Wang, Haobin Jia, Yuhang Liu, Yue Pan, Xiaojun Zhong, Junhong Huo and Jinshun Zhan
Animals 2025, 15(1), 113; https://doi.org/10.3390/ani15010113 - 6 Jan 2025
Viewed by 461
Abstract
This study aimed to evaluate the effect of early weaning (EW) on the growth performance, gastrointestinal development, serum parameters, and metabolomics of Hu sheep lambs. Twenty-four male Hu lambs were initially ewe-reared. A total of 12 lambs were weaned at 30 d of [...] Read more.
This study aimed to evaluate the effect of early weaning (EW) on the growth performance, gastrointestinal development, serum parameters, and metabolomics of Hu sheep lambs. Twenty-four male Hu lambs were initially ewe-reared. A total of 12 lambs were weaned at 30 d of age (D30) as the EW group, and the remaining 12 lambs were weaned at 45 d of age (D45) as the control (CON) group. Serum samples were collected from six lambs per treatment on D30, D33, D36, and D45, and the lambs were slaughtered on D45 to collect the rumen and small intestine. The results showed that, compared with the CON group, the average daily gain (ADG), final body weight (p < 0.001), as well as average daily feed intake (ADFI) of lambs in the EW group significantly decreased in the first (p = 0.004) and second (p = 0.013) 5 days of treatment. Additionally, EW increased the ruminal weight and papillae length but reduced the duodenal villus height on D45 (p < 0.05). As for the serum parameters, the concentrations of glucose on D33, D36, and D45 (p < 0.001), and the IL-6 content on D45 (p = 0.018) were observed to be lower, while the levels of immunoglobulin A (IgA) (p = 0.027), IgG (p = 0.035), and IgM (p = 0.002) on the four ages were all higher in the EW group than those in CON group. Additionally, both treatment and age interactively affected the levels of GLU (p = 0.001), TP (p = 0.041), and IL-6 (p = 0.016). Additionally, the serum metabolomics analysis on D45 showed that the contents of 5-HT and arachidonic acid were increased, while L-phenylalanine, L-tyrosine, and L-glutamic acid were reduced in the EW group (p < 0.05). These differential metabolites were enriched in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including inflammatory mediator regulation, protein digestion and absorption, and phenylalanine and tyrosine biosynthesis. The current results identify that EW at D30 decreased the growth performance (ADG and ADFI) of Hu lambs within two weeks post-weaning, which might be associated with impaired duodenal morphology and glucose metabolism. The serum metabolomics analysis revealed that EW altered the concentrations of 5-HT, phenylalanine, tyrosine, and arachidonic acid, which could serve as potential regulatory targets for modulating the health of EW Hu lambs. Full article
(This article belongs to the Section Small Ruminants)
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<p>The orthogonal projections to latent structures discriminant analyses (OPLS-DA), and permutation score plots based on LC-MS between CON and EW groups. OPLS-DA score derived from the untargeted LC-MS profiles in the CON (blue dots) and EW (red dots) groups in the positive (<b>A</b>) and negative ion modes (<b>B</b>). Permutation score plot in the positive (<b>C</b>) and negative (<b>D</b>) ion modes. CON = control group, lambs were weaned at 45 d of age; EW = early-weaning group, lambs were weaned at 30 d of age.</p>
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<p>Differentially accumulating metabolites between CON and EW groups. Volcano maps of serum metabolites in positive (<b>A</b>) and negative (<b>B</b>) ion modes. Heatmap of 59 differential metabolites in positive (<b>C</b>) and 50 differential metabolites in negative (<b>D</b>) ion modes. CON = control group, lambs were weaned at 45 d of age; EW = early-weaning group, lambs were weaned at 30 d of age.</p>
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<p>Differentially pathway enrichment analysis between CON and EW groups. Key metabolic pathways analysis of differential metabolites in positive (<b>A</b>) and negative (<b>B</b>) ion modes. The top 20 KEGG pathways displayed enrichment in differential metabolites between CON and EW group (<b>C</b>). CON = control group, lambs were weaned at 45 d of age; EW = early-weaning group, lambs were weaned at 30 d of age.</p>
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<p>The study design and schematic diagram of the effect of early weaning (EW) on the growth performance, gastrointestinal development, serum parameters, and metabolomics of Hu sheep lambs.</p>
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33 pages, 2821 KiB  
Review
The Gut Microbiota-Related Antihyperglycemic Effect of Metformin
by Izabela Szymczak-Pajor, Józef Drzewoski, Małgorzata Kozłowska, Jan Krekora and Agnieszka Śliwińska
Pharmaceuticals 2025, 18(1), 55; https://doi.org/10.3390/ph18010055 - 6 Jan 2025
Viewed by 626
Abstract
It is critical to sustain the diversity of the microbiota to maintain host homeostasis and health. Growing evidence indicates that changes in gut microbial biodiversity may be associated with the development of several pathologies, including type 2 diabetes mellitus (T2DM). Metformin is still [...] Read more.
It is critical to sustain the diversity of the microbiota to maintain host homeostasis and health. Growing evidence indicates that changes in gut microbial biodiversity may be associated with the development of several pathologies, including type 2 diabetes mellitus (T2DM). Metformin is still the first-line drug for treatment of T2DM unless there are contra-indications. The drug primarily inhibits hepatic gluconeogenesis and increases the sensitivity of target cells (hepatocytes, adipocytes and myocytes) to insulin; however, increasing evidence suggests that it may also influence the gut. As T2DM patients exhibit gut dysbiosis, the intestinal microbiome has gained interest as a key target for metabolic diseases. Interestingly, changes in the gut microbiome were also observed in T2DM patients treated with metformin compared to those who were not. Therefore, the aim of this review is to present the current state of knowledge regarding the association of the gut microbiome with the antihyperglycemic effect of metformin. Numerous studies indicate that the reduction in glucose concentration observed in T2DM patients treated with metformin is due in part to changes in the biodiversity of the gut microbiota. These changes contribute to improved intestinal barrier integrity, increased production of short-chain fatty acids (SCFAs), regulation of bile acid metabolism, and enhanced glucose absorption. Therefore, in addition to the well-recognized reduction of gluconeogenesis, metformin also appears to exert its glucose-lowering effect by influencing gut microbiome biodiversity. However, we are only beginning to understand how metformin acts on specific microorganisms in the intestine, and further research is needed to understand its role in regulating glucose metabolism, including the impact of this remarkable drug on specific microorganisms in the gut. Full article
(This article belongs to the Section Pharmacology)
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<p>Microbiota functions.</p>
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<p>Microbial-derived metabolites and their impact on pathways associated with insulin resistance. Stimulatory interactions are expressed by arrows, and suppression by T-bars. Interactions that promote insulin resistance are expressed in red, while interactions that prevent insulin resistance are expressed in green.</p>
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<p>Metformin exerts its antihyperglycemic effects not only by the inhibition of gluconeogenesis in the liver and intestine, but also through partial restoration of the physiological function of gut microbiota. ↓—decrease.</p>
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14 pages, 11937 KiB  
Article
A Refractive Index-Based Dual-Band Metamaterial Sensor Design and Analysis for Biomedical Sensing Applications
by Lakshmi Darsi and Goutam Rana
Sensors 2025, 25(1), 232; https://doi.org/10.3390/s25010232 - 3 Jan 2025
Viewed by 450
Abstract
We propose herein a metamaterial (MM) dual-band THz sensor for various biomedical sensing applications. An MM is a material engineered to have a particular property that is rarely observed in naturally occurring materials with an aperiodic subwavelength arrangement. MM properties across a wide [...] Read more.
We propose herein a metamaterial (MM) dual-band THz sensor for various biomedical sensing applications. An MM is a material engineered to have a particular property that is rarely observed in naturally occurring materials with an aperiodic subwavelength arrangement. MM properties across a wide range of frequencies, like high sensitivity and quality factors, remain challenging to obtain. MM-based sensors are useful for the in vitro, non-destructive testing (NDT) of samples. The challenge lies in designing a narrow band resonator such that higher sensitivities can be achieved, which in turn allow for the sensing of ultra-low quantities. We propose a compact structure, consisting of a basic single-square split ring resonator (SRR) with an integrated inverted Z-shaped unit cell. The projected structure provides dual-band frequencies resonating at 0.75 THz and 1.01 THz with unity absorption at resonant peaks. The proposed structure exhibits a narrow bandwidth of 0.022 THz and 0.036 THz at resonances. The resonant frequency exhibits a shift in response to variations in the refractive index of the surrounding medium. This enables the detection of various biomolecules, including cancer cells, glucose, HIV-1, and M13 viruses. The refractive index varies between 1.35 and 1.40. Furthermore, the sensor is characterized by its performance, with an average sensitivity of 2.075 THz and a quality factor of 24.35, making it suitable for various biomedical sensing applications. Full article
(This article belongs to the Section Optical Sensors)
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<p>Different outlooks of the sensor structure: (<b>a</b>) front view, (<b>b</b>) 3D perspective view, (<b>c</b>) periodic arrangement, and (<b>d</b>) cross-sectional view.</p>
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<p>The suggested absorber’s evolution: (<b>a</b>) a basic single-square SRR, (<b>b</b>) an inverted “Z”-shape, and (<b>c</b>) a combination of a basic single-square SRR and inverted Z-shape.</p>
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<p>Distribution of electric and magnetic fields, as well as surface currents, at the resonant frequencies of 0.75 THz and 1.01 THz: (<b>a</b>,<b>b</b>) E-fields, (<b>c</b>,<b>d</b>) H-fields, and (<b>e</b>,<b>f</b>) surface current.</p>
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<p>Absorption spectrum analysis by adjusting various design structure parameters: (<b>a</b>) slit width (g) of the basic single-square SRR, (<b>b</b>) width (w) of the basic single-square SRR, (<b>c</b>) interaction (i) between the inverted Z arms and the basic single-square SRR, and (<b>d</b>) substrate height <math display="inline"><semantics> <mrow> <mo>(</mo> <msub> <mi>h</mi> <mn>2</mn> </msub> <mo>)</mo> </mrow> </semantics></math>.</p>
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<p>The sensing performance of the sensor for (<b>a</b>) analyte n = 1.35 to 1.40 and (<b>b</b>) water and glucose detection.</p>
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<p>Relationship between the refractive index and (<b>a</b>) change in resonant frequency, (<b>b</b>) quality factor, (<b>c</b>) sensitivity, and (<b>d</b>) figure of merit.</p>
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<p>Relationship between the refractive index and (<b>a</b>) change in resonant frequency, (<b>b</b>) quality factor, (<b>c</b>) sensitivity, and (<b>d</b>) figure of merit.</p>
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<p>The sensing performance of the sensor for (<b>a</b>) HIV virus detection and (<b>b</b>) M13 virus detection.</p>
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<p>The sensing performance of the design: (<b>a</b>) breast cancer detection, (<b>b</b>) skin cancer detection, (<b>c</b>) MCF-7 detection, and (<b>d</b>) PC12 detection.</p>
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<p>Proposed working setup for the recommended sensor.</p>
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24 pages, 5516 KiB  
Article
DAG-MAG-ΒHB: A Novel Ketone Diester Modulates NLRP3 Inflammasome Activation in Microglial Cells in Response to Beta-Amyloid and Low Glucose AD-like Conditions
by Valentina Gentili, Giovanna Schiuma, Latha Nagamani Dilliraj, Silvia Beltrami, Sabrina Rizzo, Djidjell Lara, Pier Paolo Giovannini, Matteo Marti, Daria Bortolotti, Claudio Trapella, Marco Narducci and Roberta Rizzo
Nutrients 2025, 17(1), 149; https://doi.org/10.3390/nu17010149 - 31 Dec 2024
Viewed by 879
Abstract
Background: A neuroinflammatory disease such as Alzheimer’s disease, presents a significant challenge in neurotherapeutics, particularly due to the complex etiology and allostatic factors, referred to as CNS stressors, that accelerate the development and progression of the disease. These CNS stressors include cerebral hypo-glucose [...] Read more.
Background: A neuroinflammatory disease such as Alzheimer’s disease, presents a significant challenge in neurotherapeutics, particularly due to the complex etiology and allostatic factors, referred to as CNS stressors, that accelerate the development and progression of the disease. These CNS stressors include cerebral hypo-glucose metabolism, hyperinsulinemia, mitochondrial dysfunction, oxidative stress, impairment of neuronal autophagy, hypoxic insults and neuroinflammation. This study aims to explore the efficacy and safety of DAG-MAG-ΒHB, a novel ketone diester, in mitigating these risk factors by sustaining therapeutic ketosis, independent of conventional metabolic pathways. Methods: We evaluated the intestinal absorption of DAG-MAG-ΒHB and the metabolic impact in human microglial cells. Utilizing the HMC3 human microglia cell line, we examined the compound’s effect on cellular viability, Acetyl-CoA and ATP levels, and key metabolic enzymes under hypoglycemia. Additionally, we assessed the impact of DAG-AG-ΒHB on inflammasome activation, mitochondrial activity, ROS levels, inflammation and phagocytic rates. Results: DAG-MAG-ΒHB showed a high rate of intestinal absorption and no cytotoxic effect. In vitro, DAG-MAG-ΒHB enhanced cell viability, preserved morphological integrity, and maintained elevated Acetyl-CoA and ATP levels under hypoglycemic conditions. DAG-MAG-ΒHB increased the activity of BDH1 and SCOT, indicating ATP production via a ketolytic pathway. DAG-MAG-ΒHB showed remarkable resilience against low glucose condition by inhibiting NLRP3 inflammasome activation. Conclusions: In summary, DAG-MAG-ΒHB emerges as a promising treatment for neuroinflammatory conditions. It enhances cellular health under varying metabolic states and exhibits neuroprotective properties against low glucose conditions. These attributes indicate its potential as an effective component in managing neuroinflammatory diseases, addressing their complex progression. Full article
(This article belongs to the Section Nutrition and Neuro Sciences)
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<p>ESI-MS spectrum of (<b>a</b>) DAG-ΒHB and (<b>b</b>) MAG-ΒHB.</p>
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<p>(<b>a</b>) Evaluation of cytotoxicity by MTT assay after 24 h treatment with different concentrations of DAG/MAG-ΒHB of Caco-2cells (12.5, 25, 50, 100, 150, 200 mM). (<b>b</b>) Intestinal absorption of DAG/MAG-ΒHB determined using an in vitro human intestinal model based on human Caco-2 intestinal adenocarcinoma cells. The bioavailability was expressed as a percentage of uptake (%), calculated on the mass balance of the active ingredient (amount of active ingredient in apical + amount of active ingredient in basolateral). (<b>c</b>) Pharmacokinetics evaluation was performed in blood samples collected at the intervals of 30, 60, 90, and 120 min post-supplementation with 0.9% NaCl saline solution as the vehicle or DAG/MAG-ΒHB at the concentrations of 500 mg/kg, 1000 mg/kg, and 2000 mg/kg. Gas chromatography was used to measure blood DAG-MAG/ΒHB. (<b>d</b>) Paraffin-embedded tissue specimens were sectioned at 5 μm, and then haematoxylin and eosin stain were performed. For histological investigations, the sections were stained with haematoxylin and eosin and then observed under optical microscope.</p>
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<p>(<b>a</b>) Assessment of BBB passage of DAG/MAG-BHB (10 mM) and TMS (10 mM) through BBB in vitro system (Transwell endothelial cells (hBMECs) system) during 240 min observation. Gas chromatography was used to measure blood DAG-MAG/ΒHB and TMS. (<b>b</b>) Morphological evaluation of HMC3 cell line treated with different concentrations of glucose in the presence/absence of DAG/MAG-BHB. (<b>c</b>) Viability evaluation by MTT assay of HMC3 cell line treated with different concentrations of glucose in the presence/absence of DAG/MAG-BHB. (<b>d</b>) Levels of pyruvate, lactate, AcAc and acetylCoA in the presence of 5 mM glucose for 18 h in HMC3 cells. (<b>e</b>) BDH1, (<b>f</b>) SCOT, (<b>g</b>) ATP. Mean ± SEM for each group is reported. <span class="html-italic">p</span> values were obtained by statistical analysis with the Student’s <span class="html-italic">t</span>-test.</p>
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<p>(<b>a</b>) Evaluation of IL-1beta secretion in inflammasomes-primed HCM3 cells. Evaluation of IL-1beta secretion in Aβ1-42-primed HCM3 cells in (<b>b</b>) normal (25 mM) glucose medium and in (<b>c</b>) low (5.5 mM) glucose medium. (<b>d</b>) Evaluation of IL-1beta secretion in Aβ1-42-primed HCM3 cells in low glucose medium with pharmacological inhibition of TLR4 by CLI-095. (<b>e</b>) Evaluation of IL-1beta secretion in Aβ1-42-primed HCM3 cells in low glucose medium with 10 mM DAG/MAG-ΒHB (DAG/MAG-ΒHB). (<b>f</b>) Caspase-1 activation in Aβ1-42-primed HCM3 cells in low glucose medium with or without 10 mM DAG/MAG-ΒHB (DAG/MAG-ΒHB). (<b>g</b>) Caspase-1 and (<b>h</b>) IL-1beta cleavage in Aβ42-primed HCM3 in low glucose medium in the absence (Aβ1-42) or presence of 10 mM DAG/MAG-ΒHB (DAG/MAG-BHB). (<b>i</b>) NLRP3 mRNA expression of in Aβ42-primed HCM3 in low glucose medium in the absence (Aβ1-42) or presence of 10 mM DAG/MAG-ΒHB (DAG/MAG-BHB). (<b>j</b>) Immunofluorescence staining for ASC (red) speck and nuclei (DAPI) in Aβ42-primed HCM3 in low glucose medium in the absence (Aβ1-42) or presence of 10 mM DAG/MAG-ΒHB (DAG/MAG-BHB). Scale bar: 20 μm. (<b>k</b>) Percentages of microglia containing ASC foci were quantified. (<b>l</b>) Relative phagocytic activity of microglia measured by bead uptake assay in Aβ42-primed HCM3 in the absence (Aβ1-42) or presence of 10 mM DAG/MAG-ΒHB (DAG/MAG-BHB). Mean ± SEM for each group is reported. <span class="html-italic">p</span> values were obtained by statistical analysis with the Student’s <span class="html-italic">t</span>-test and Fisher’s exact test.</p>
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<p>(<b>a</b>) Mitochondrial membrane potential with Jc-1 staining method in Aβ1-42-primed HCM3 in low glucose medium. (<b>b</b>) Quantitative analysis of the ratio of red/green fluorescent intensity. (<b>c</b>) ATP content in in Aβ1-42-primed HCM3 in low glucose medium. (<b>d</b>) ROS levels in Aβ1-42-primed HCM3 in low glucose medium evaluated by the probe CM-H2DCFDA. (<b>e</b>) Quantitative analysis of fold intensity of CM-H2DCFDA intensity. Mean ± SEM for each group is reported. <span class="html-italic">p</span> values were obtained by statistical analysis with the Student’s <span class="html-italic">t</span>-test.</p>
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<p>Overall reaction scheme.</p>
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<p>Mechanisms of (<b>A</b>) MAG- and (<b>B</b>) BAG-ΒHB formation.</p>
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15 pages, 2977 KiB  
Article
Jeju Citrus (Citrus unshiu) Leaf Extract and Hesperidin Inhibit Small Intestinal α-Glucosidase Activities In Vitro and Postprandial Hyperglycemia in Animal Model
by Gi-Jung Kim, Yelim Jang, Kyoung-Tae Kwon, Jae-Won Kim, Seong-IL Kang, Hee-Chul Ko, Jung-Yun Lee, Emmanouil Apostolidis and Young-In Kwon
Int. J. Mol. Sci. 2024, 25(24), 13721; https://doi.org/10.3390/ijms252413721 - 23 Dec 2024
Viewed by 482
Abstract
Citrus fruits are widely distributed in East Asia, and tea made from citrus peels has demonstrated health benefits, such as a reduction in fever, inflammation, and high blood pressure. However, citrus leaves have not been evaluated extensively for their possible health benefits. In [...] Read more.
Citrus fruits are widely distributed in East Asia, and tea made from citrus peels has demonstrated health benefits, such as a reduction in fever, inflammation, and high blood pressure. However, citrus leaves have not been evaluated extensively for their possible health benefits. In this study, the α-glucosidase-inhibitory activity of Jeju citrus hot-water (CW) and ethyl alcohol (CE) extracts, along with hesperidin (HP) (a bioactive compound in citrus leaf extracts), was investigated, and furthermore, their effect on postprandial blood glucose reduction in an animal model was determined. The hesperidin contents of CW and CE were 15.80 ± 0.18 and 39.17 ± 0.07 mg/g-extract, respectively. Hesperidin inhibited α-glucosidase (IC50, 4.39), sucrase (0.50), and CE (2.62) and demonstrated higher α-glucosidase inhibitory activity when compared to CW (4.99 mg/mL). When using an SD rat model, during sucrose and starch loading tests with CE (p < 0.01) and HP (p < 0.01), a significant postprandial blood glucose reduction effect was observed when compared to the control. The maximum blood glucose levels (Cmax) of the CE administration group decreased by about 15% (from 229.3 ± 14.5 to 194.0 ± 7.4, p < 0.01) and 11% (from 225.1 ± 13.8 to 201.1 ± 7.2 hr·mg/dL, p < 0.05) in the sucrose and starch loading tests, respectively. Our findings suggest that citrus leaf extracts standardized to hesperidin may reduce postprandial blood glucose levels through the observed inhibitory effect against sucrase, which results in delayed carbohydrate absorption. Our findings provide a biochemical rationale for further evaluating the benefits of citrus leaves. Full article
(This article belongs to the Special Issue Bioactive Phenolics and Polyphenols 2024)
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<p>Chemical structure of hesperidin.</p>
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<p>HPLC profiles of citrus leaf extracts (standard solution (<b>a</b>), hot-water extract (<b>b</b>), and ethyl alcohol extract (<b>c</b>)). 1. Rutin; 2. Neoeriocitrin; 3. Narirutin; 4. Rhoifolin; 5. Naringin; 6. Hesperidin; 7. Neohesperidin; 8. Neoponcirin; 9. Poncirin; 10. Naringenin; 11. Hesperetin; 12. Isosinensetin; 13. Sinensetin; 14. 4,5,7-Trimethoxy flavon; 15. Nobiletin; 16. 4,5,6,7-Tetramethoxy flavon; 17. Tangeretin; 18. 5-Demethyl nobiletin; and 19. Gardenin B.</p>
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<p>HPLC profiles of citrus leaf extracts (standard solution (<b>a</b>), hot-water extract (<b>b</b>), and ethyl alcohol extract (<b>c</b>)). 1. Rutin; 2. Neoeriocitrin; 3. Narirutin; 4. Rhoifolin; 5. Naringin; 6. Hesperidin; 7. Neohesperidin; 8. Neoponcirin; 9. Poncirin; 10. Naringenin; 11. Hesperetin; 12. Isosinensetin; 13. Sinensetin; 14. 4,5,7-Trimethoxy flavon; 15. Nobiletin; 16. 4,5,6,7-Tetramethoxy flavon; 17. Tangeretin; 18. 5-Demethyl nobiletin; and 19. Gardenin B.</p>
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<p>Dose-dependent changes in SD rat small intestinal α-glucosidase-inhibitory activity (% inhibition) of GO2KA1 (GO), Jeju citrus leaf hot-water extract (CW), Jeju citrus leaf ethyl alcohol extract (CE), and hesperidin (HP). Different corresponding letters indicate significant differences at <span class="html-italic">p</span> &lt; 0.05 by Duncan’s test. <sup>a–d</sup> First letter indicates differences among different samples, and <sup>A–C</sup> second one indicates differences among different concentrations of same samples.</p>
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<p>Dose-dependent changes in SD rat small intestinal sucrase-inhibitory activity (% inhibition) of GO2KA1 (GO), Jeju citrus leaf hot-water extract (CW), Jeju citrus leaf ethyl alcohol extract (CE), and hesperidin (HP). Different corresponding letters indicate significant differences at <span class="html-italic">p</span> &lt; 0.05 by Duncan’s test. <sup>a–c</sup> First letter indicates differences among different samples, and <sup>A–C</sup> second one indicates differences among different concentrations of same samples.</p>
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<p>Dose-dependent changes in SD rat small intestinal maltase-inhibitory activity (% inhibition) of GO2KA1 (GO), Jeju citrus leaf hot-water extract (CW), Jeju citrus leaf ethyl alcohol extract (CE), and hesperidin (HP). Different corresponding letters indicate significant differences at <span class="html-italic">p</span> &lt; 0.05 by Duncan’s test. <sup>a–c</sup> First letter indicates differences among different samples, and <sup>A–D</sup> second one indicates differences among different concentrations of same samples.</p>
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<p>Dose-dependent changes in SD rat small intestinal glucoamylase-inhibitory activity (% inhibition) of GO2KA1 (GO), Jeju citrus leaf hot-water extract (CW), Jeju citrus leaf ethyl alcohol extract (CE), and hesperidin (HP). Different corresponding letters indicate significant differences at <span class="html-italic">p</span> &lt; 0.05 by Duncan’s test. <sup>a–c</sup> First letter indicates differences among different samples, and <sup>A–D</sup> second one indicates differences among different concentrations of same samples.</p>
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<p>Dose-dependent anti-hyperglycemic effect of ethyl alcohol extracts of citrus leaves (CE) in sucrose loading test. After fasting for 24 h, 5-week-old male SD rats were orally administered sucrose solution (2.0 g/kg-body weight (b.w.)) with or without samples (CE 0.1 g/kg-b.w., CE 0.5 g/kg-b.w., and positive control: GO2KA1 0.5 g/kg-b.w.). Each point represents mean ± standard deviation (<span class="html-italic">n</span> = 10). ** <span class="html-italic">p</span> &lt; 0.01 and *** <span class="html-italic">p</span> &lt; 0.001 compared to different samples at the same concentration by unpaired Student’s <span class="html-italic">t</span>-test.</p>
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<p>The dose-dependent anti-hyperglycemic effect of hesperidin (HP) on sucrose loading test results. After fasting for 24 h, 5-week-old male SD rats were orally administered a sucrose solution (2.0 g/kg-body weight (b.w.)) with or without the test samples (HP 0.1 g/kg-b.w. and HP 0.5 g/kg-b.w.). Each point represents mean ± standard deviation (<span class="html-italic">n</span> = 10). <span class="html-italic">*** p</span> &lt; 0.001 compared to different samples at the same concentration by unpaired Student’s <span class="html-italic">t</span>-test.</p>
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<p>The dose-dependent anti-hyperglycemic effect of ethyl alcohol extracts of citrus leaves (CE) on starch loading test results. After fasting for 24 h, 5-week-old male SD rats were orally administered a starch solution (2.0 g/kg-body weight (b.w.)) with or without samples (CE 0.1 g/kg-b.w., CE 0.5 g/kg-b.w., and positive control: GO2KA1 0.5 g/kg-b.w.). Each point represents mean ± standard deviation (<span class="html-italic">n</span> = 10). <span class="html-italic">* p</span> &lt; 0.05 and <span class="html-italic">*** p</span> &lt; 0.001 compared to different samples at the same concentration by unpaired Student’s <span class="html-italic">t</span>-test.</p>
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<p>The dose-dependent anti-hyperglycemic effect of hesperidin (HP) on starch loading test results. After fasting for 24 h, 5-week-old male SD rats were orally administered a starch solution (2.0 g/kg-body weight (b.w.)) with or without samples (HP 0.1 g/kg-b.w. and HP 0.5 g/kg-b.w.). Each point represents mean ± standard deviation (<span class="html-italic">n</span> = 10). <span class="html-italic">*** p</span> &lt; 0.001 compared to different samples at the same concentration by unpaired Student’s <span class="html-italic">t</span>-test.</p>
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19 pages, 3847 KiB  
Article
The Effect of Ingesting Alginate-Encapsulated Carbohydrates and Branched-Chain Amino Acids During Exercise on Performance, Gastrointestinal Symptoms, and Dental Health in Athletes
by Lotte L. K. Nielsen, Max Norman Tandrup Lambert, Jørgen Jensen and Per Bendix Jeppesen
Nutrients 2024, 16(24), 4412; https://doi.org/10.3390/nu16244412 - 23 Dec 2024
Viewed by 906
Abstract
Background: This study aimed to compare the effects of a carbohydrate (CHO) hydrogel with (ALG-CP) or without (ALG-C) branched-chain amino acids, and a CHO-only non-hydrogel (CON), on cycling performance. The hydrogels, encapsulated in an alginate matrix, are designed to control CHO release, potentially [...] Read more.
Background: This study aimed to compare the effects of a carbohydrate (CHO) hydrogel with (ALG-CP) or without (ALG-C) branched-chain amino acids, and a CHO-only non-hydrogel (CON), on cycling performance. The hydrogels, encapsulated in an alginate matrix, are designed to control CHO release, potentially optimising absorption, increasing substrate utilisation, and reducing gastrointestinal distress as well as carious lesions. Methods: In a randomised, double-blinded, crossover trial, 10 trained male cyclists/triathletes completed three experimental days separated by ~6 days. During the experimental days, participants completed a standardised 2 h cycling bout (EX1), followed by a time-to-exhaustion (TTE) performance test at W75%. Supplements were ingested during EX1. Results: Participants cycled ~8.8 (29.6%) and ~5.4 (29.1%) minutes longer during TTE with ALG-CP compared to ALG-C and CON, respectively. TTE was 65.28 ± 2.8 min with ALG-CP, 56.46 ± 10.92 min with ALG-C, and 59.89 ± 11.89 min with CON. Heart rate (HR) was lower during EX1 with ALG-CP (p = 0.03), and insulin levels increased more significantly during the first 45 min with ALG-CP. Plasma glucose and glucagon levels remained consistent across supplements, although glucagon was higher with ALG-CP before TTE. Post-exercise myoglobin levels were lower with ALG-CP compared to ALG-C (p = 0.02), indicating reduced muscle damage. Conclusions: While ALG-CP improved performance duration compared to ALG-C and CON, the difference did not reach statistical significance. Additionally, there was a lower HR during the cycling session, alongside a significantly lower level of myoglobin with ALG-CP. These findings suggest that ALG-CP may offer advantages in cycling performance and recovery. Full article
(This article belongs to the Special Issue Nutrition and Supplements for Athletic Training and Racing)
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<p>Overview of experimental clinical trial.</p>
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<p>Presenting (<b>A</b>) time-to-exhaustion performance test in minutes, and (<b>B</b>) Heart rate (HR, beat per min.) throughout the exercise session. Data are mean ± SEM. N = 10 participants. Int: Interval; sp: sprint; TTE: time-to-exhaustion. *: significant differences between ALG-CP vs. ALG-C. #: significant differences between ALG-C vs. CON. O: significant differences between ALG-CP vs. CON.</p>
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<p>Plasma glucose during the clinical trial (<b>A</b>). Comparing ALG-CP, ALG-C, and CON. AUC during exercise is provided from t = −15 min to pre-TTE (<b>B</b>). During recovery AUC is given from t = post-TTE to 120 min. Data are mean ± SEM. * <span class="html-italic">p</span> ≤ 0.05.</p>
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<p>Plasma insulin during the clinical trial (<b>A</b>). Comparing ALG-CP, ALG-C, and CON. AUC during exercise is provided from t = −15 min to pre-TTE (<b>B</b>). During recovery, AUC is given from t = post-TTE to 120 min. Data are mean ± SEM. (¤). * <span class="html-italic">p</span> ≤ 0.05.</p>
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<p>Plasma glucagon during the clinical trial (<b>A</b>). Comparing ALG-CP, ALG-C, and CON. AUC during exercise is provided from t = −15 min to pre-TTE (<b>B</b>). Data are mean ± SEM. (¤).</p>
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<p>Plasma FFA during the clinical trial (<b>A</b>). Comparing ALG-CP, ALG-C, and CON. AUC during exercise is provided from t = −15 min to pre-TTE (<b>B</b>). During recovery, AUC is given from t = post-TTE to 120 min. Data are mean ± SEM. (¤).</p>
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<p>Time-dependent concentrations of (<b>A</b>) LDH, (<b>B</b>) CK (¤), (<b>C</b>) Myoglobin (¤), and (<b>D</b>) P-Carbamide during the clinical trials. Data are mean ± SEM.</p>
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<p>Levels of (<b>A</b>) U-Carbamide and (<b>B</b>) U-Creatinine (¤) at baseline and post-TTE. Data are mean ± SEM.</p>
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<p>pH values of saliva during the clinical trial. Data are mean ± SEM.</p>
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<p>Radar chart of perceived gastrointestinal symptoms. Data are mean ± SEM.</p>
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19 pages, 1965 KiB  
Article
Purple Yampee Derivatives and Byproduct Characterization for Food Applications
by Sandra V. Medina-López, Cristian Molina García, Maria Cristina Lizarazo-Aparicio, Maria Soledad Hernández-Gómez and Juan Pablo Fernández-Trujillo
Foods 2024, 13(24), 4148; https://doi.org/10.3390/foods13244148 - 21 Dec 2024
Viewed by 736
Abstract
This study assessed the technological potential and bioactive compounds present in purple yampee (Dioscorea trifida L.f.) lyophilized powder, peeled and whole flour, as well as the tuber peel, starch residual fiber, and wastewater mucilage. Although most values approached neutrality, flour showed a [...] Read more.
This study assessed the technological potential and bioactive compounds present in purple yampee (Dioscorea trifida L.f.) lyophilized powder, peeled and whole flour, as well as the tuber peel, starch residual fiber, and wastewater mucilage. Although most values approached neutrality, flour showed a lower pH and high density, while greater acidity was observed in the mucilage. Color differed statistically and perceptibly between all samples, with similar values of °hue to purple flours from other sources, and the maximum chroma was found in lyophilized pulp and lightness in fiber. Average moisture levels around 7.2% and water activity levels of 0.303 (0.194 for whole flour) in fractions suggested favorable storability, while the interaction of the powders with water was similar to other root and tuber powdered derivatives. Yampee periderm had the highest swelling power, oil absorption capacity, water holding capacity, and absorption index and capacity. Mucilage had a higher solubility index and outstanding emulsion activity, greater than 90%. Twelve anthocyanins, with new reports of petunidin derivatives for the species, and more than 30 phytochemicals were identified through advanced liquid chromatography techniques. The greatest amounts of pinitol and myo-inositol were found in the mucilage, and sucrose, glucose, and fructose prevailed in the other powders. Successfully characterized yampee fractions showed high potential as functional food ingredients. Full article
(This article belongs to the Section Food Security and Sustainability)
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<p>Photos of powdered fractions and simulated colors of (<b>a</b>) YSF, (<b>b</b>) YSM, (<b>c</b>) LYP, (<b>d</b>) YPF, (<b>e</b>) WTP, and (<b>f</b>) YPP.</p>
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<p>Amino acids in <span class="html-italic">D. trifida</span> mucilage (<b>upper</b> chromatogram) and lyophilized pulp (<b>under</b>) observed through HPLC-FLD.</p>
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<p>Amino acids in <span class="html-italic">D. trifida</span> mucilage (<b>upper</b> chromatogram) and lyophilized pulp (<b>under</b>) observed through HPLC-FLD.</p>
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<p>Main anthocyanin compounds identified at 520 nm through HPLC-DAD in <span class="html-italic">D. trifida</span> fractions after 20 days from their manufacture.</p>
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<p>Main anthocyanins quantified in <span class="html-italic">D. trifida</span> fractions mucilage YSM, lyophilized pulp LYP, starch fiber, flour, periderm, and whole flour from left to right, after 20-day storage. Main peonidin derivatives are depicted as follows: Peonidin 3-<span class="html-italic">O</span>-glucoside-5-<span class="html-italic">O</span>glucoside (Peonidin 1), Peonidin 3-O-feruloylglucoside-5-O-glucoside (Peonidin 2), and Peonidin 3-O-<span class="html-italic">p</span>-cumaroylglucoside-5-O-glucoside (Peonidin 3). The average concentration of the molecules (<span class="html-italic">n</span> = 3) is presented in milligrams per 100 g of sample, letters correspond to significant statistical differences among fractions (<span class="html-italic">p</span> &lt; 0.05).</p>
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<p>The evolution of sugars in time (day 43 -darker color- and 180 of storage) for each fraction depicted by individually quantified sugars (<b>a</b>) Myo-inositol, (<b>b</b>) Pinitol, (<b>c</b>) Glucose, (<b>d</b>) Fructose, (<b>e</b>) Sucrose. Concentrations of each measure are depicted as mean values with standard deviation error bars (<span class="html-italic">n</span> = 3). Means in a column followed by different lowercase letters (a–f) are significantly different at the 5% level at the initial time of measure. Means in the columns followed by different capital letters (A–E) are significantly different at the 5% level.</p>
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18 pages, 3897 KiB  
Review
Pharmacological Mechanisms of Bile Acids Targeting the Farnesoid X Receptor
by Youchao Qi, Yonggui Ma and Guozhen Duan
Int. J. Mol. Sci. 2024, 25(24), 13656; https://doi.org/10.3390/ijms252413656 - 20 Dec 2024
Viewed by 610
Abstract
Bile acids (BAs), a category of amphiphilic metabolites synthesized by liver cells and released into the intestine via the bile duct, serve a vital role in the emulsification of ingested fats during the digestive process. Beyond their conventional emulsifying function, BAs, with their [...] Read more.
Bile acids (BAs), a category of amphiphilic metabolites synthesized by liver cells and released into the intestine via the bile duct, serve a vital role in the emulsification of ingested fats during the digestive process. Beyond their conventional emulsifying function, BAs, with their diverse structures, also act as significant hormones within the body. They are pivotal in facilitating nutrient absorption by interacting with the farnesoid X receptor (FXR), and they serve as key regulators of lipid and glucose metabolism, as well as immune system balance. Consequently, BAs contribute to the metabolism of glucose and lipids, enhance the digestion and absorption of lipids, and maintain the equilibrium of the bile pool. Their actions are instrumental in addressing obesity, managing cholestasis, and treating diabetes, and are involved in the onset and progression of cancer. This paper presents an updated systematic review of the pharmacological mechanisms by which BAs target the FXR, incorporating recent findings and discussing their signaling pathways in the context of novel research, including their distinct roles in various disease states and populations. The aim is to provide a theoretical foundation for the continued research and clinical application of BAs. Full article
(This article belongs to the Special Issue Latest Review Papers in Molecular Pharmacology 2024)
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<p>Bile acid (BA) synthesis. In the human liver, BAs are synthesized via the enzymatic catalysis of three cholesterol hydroxylases: cholesterol 7α-hydroxylase (CYP7A1), human sterol 12a-hydroxylase (CYP8B1), and the human sterol 27-hydroxylase gene (CYP27A1), giving rise to cholic acid (CA) and chenodeoxycholic acid (CDCA) (black arrows). They subsequently undergo dehydroxylation at the C7 position of CA and CDCA, resulting in the formation of secondary BAs, such as deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) (black arrows). These BAs predominantly modulate physiological and pathological processes within the body through hepatointestinal circulation (purple arrow). Abbreviations: BAs, bile acids; CYP7A1, cholesterol 7α-hydroxylase; CYP8B1, human sterol 12a-hydroxylase; CYP27A1, human sterol 27-hydroxylase gene; CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; LCA, lithocholic acid; UDCA, ursodeoxycholic acid.</p>
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<p>Bile acids (BAs) play a crucial role in various physiological and pathological processes by targeting and mediating diverse receptors. In humans, cholic acid (CA) and chenodeoxycholic acid (CDCA) are predominantly expressed. In contrast, α-muricholic acid (αMCA), β-muricholic acid (βMCA), and ω-muricholic acid (ωMCA) are primarily expressed in mice and rats. Additionally, deoxycholic acid (DCA), lithocholic acid (LCA), and hyocholic acid (HCA) are predominantly expressed in pigs (red curved arrows). These BAs are involved in regulating anti-inflammatory immunity, sugar and lipid metabolism, liver regeneration, type 2 diabetes mellitus (T2DM), non-alcoholic steatohepatitis (NASH), weight loss, and cholestasis, primarily through targeted binding to receptors such as the pregnane X receptor (PXR), the steroid and X-enobiotic receptor (SXR), the constitutive androstane receptor (CAR), the vitamin D receptor (VDR), and the takeda G protein-coupled receptor 5 (TGR5) (black rays arrows and solid black arrows). Moreover, when these BAs target the farnesoid X receptor (FXR), they predominantly contribute to the regulation of liver regeneration, type 2 diabetes mellitus (T2DM), non-alcoholic steatohepatitis (NASH), weight loss, and cholestasis (red rays arrows). The green arrows represents the hepatoenteric circulation. Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; CAR, constitutive androstane receptor; DCA, deoxycholic acid; farnesoid X receptor (FXR); HCA, hyocholic acid; LCA, lithocholic acid; NASH, non-alcoholic steatohepatitis; PXR, pregnane X receptor; SXR, steroid and X-enobiotic receptor; T2DM, type 2 diabetes mellitus; TGR5, takeda G protein-coupled receptor 5; VDR, vitamin D receptor; αMCA, α-muricholic acid; βMCA, β-muricholic acid; ωMCA, ω-muricholic acid.</p>
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<p>Bile acids (BAs) regulate cholestasis via the farnesoid X receptor (FXR). In Kupffer cells, GS-9674 and obeticholic acid (OCA) exert their effects by activating the cellular FXR receptor, which results in its direct translocation to the nucleus. This process significantly enhances the expression of the platelet-derived growth factor β receptor (PDGFRβ), the transforming growth factor-β (TGFβ), and the connective tissue growth factor (CTGF), while concurrently reducing the levels of the monocyte chem-attractant protein-1 (MCP-1). Consequently, this dual mechanism markedly diminishes the expression of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), thereby contributing to the inhibition of biliary tract obstruction. Additionally, GS-9674 and OCA stimulate the cytoplasmic FXR receptor, which in turn triggers the nuclear translocation of the nuclear factor kappa-B (NF-κB) (red rays arrows). Once within the nucleus, NF-κB activates the FXR receptor, further potentiating the expression of the platelet-derived growth factor receptor (PDGFR), the transforming growth factor (TGF), and the CTGF (up-solid red arrows), and concurrently reducing MCP-1 expression (down-solid red arrows). This cascade effectively reduces the expression of PBC and PSC, playing a pivotal role in alleviating biliary tract obstruction (down-solid red arrows). Abbreviations: CTGF, connective tissue growth factor; FXR, farnesoid X receptor; MCP-1, monocyte chem-attractant protein-1; NF-κB, nuclear factor kappa-B; OCA, obeticholic acid; PDGFRβ, platelet-derived growth factor β receptor; PDGFR, platelet-derived growth factor receptor; TGFβ, transforming growth factor-β; TGF, transforming growth factor; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.</p>
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<p>Bile acids (BAs) regulate nonalcoholic fatty liver disease (NAFLD) via the farnesoid X receptor (FXR). In the nucleus of liver cells, obeticholic acid (OA) initially demonstrates a notable reduction in the solubility of cholesterol, a marked enhancement in cholesterol saturation levels, and a significant decrease in the hydrophobicity of BAs (black rays arrows). This is predominantly achieved through the up-regulation of the human cytochrome P450 (CYP) 3A4 (CYP3A4), the sulfotransferase family 2A member 1 (SULT2A1), the UDP glucuronosyl transferase family 2 member B4 (UGT2B4), and multidrug resistance protein 3 (MDR3) expression (solid-black arrows), which is facilitated by the targeted activation of the farnesoid X receptor (FXR), thereby alleviating the formation of gallstones (down-red rays arrows). Subsequently, BAs stimulate mitogen-activated protein kinases (MAPKs) activation significantly, which markedly inhibits expression of the hepatocyte nuclear factor 4 (HNF-4), the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and the forkhead transcription factor 1 (Foxo1) by reducing FXR expression (solid-black arrows). This continued down-regulation affects the expression of glucose-6-phosphatase (G6Pase), phosphoenol pyruvate carboxy kinase (PEPCK), and DNA-binding protein phosphatase 1 (DBP1) (solid-black arrows), ultimately leading to a decrease in fatty acid synthesis, insulin resistance, and gluconeogenesis (red rays arrows). Furthermore, GSK2324, a specific agonist for the FXR receptor, enhances the expression of the small heterodimer partner (SHP) by activating the FXR receptor (down-red rays arrows), subsequently blocking liver X receptor (LXR) expression (red terminating line and X). This cascade inhibits the sterol-regulatory element binding protein 1c (SREBP1c) (down-solid black arrows), reducing the expression of diacylglycerol acyltransferase 2 (Dgat2), stearoyl-CoA desaturase 1 (Scd1), and phosphatidic acid phosphohydrolase 1 (Lpin1), and ultimately results in a significant reduction in fatty acid synthesis by down-regulating the expression of monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA) (solid black arrows). Collectively, these actions significantly impede the progression of NAFLD (down-solid red arrow). Abbreviations: BAs, bile acids; CYP3A4, human cytochrome P450 (CYP) 3A4; DBP1, DNA-binding protein phosphatase 1; Dgat2, diacylglycerol acyltransferase 2; FXR, farnesoid X receptor; Foxo1, forkhead transcription factor 1; G6Pase, glucose-6-phosphatase; HNF-4, hepatocyte nuclear factor 4; LXR, liver X receptor; lpin1, phosphatidic acid phosphohydrolase 1; MDR3, multidrug resistance protein 3; MAPK, mitogen-activated protein kinase; MUFA, monounsaturated fatty acid; NAFLD, non-alcoholic fatty liver disease; OA, obeticholic acid; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator-1α; PEPCK, phosphoenol pyruvate carboxy kinase; PUFA, polyunsaturated fatty acid; SULT2A1, sulfotransferase family 2A member 1; Scd1, stearoyl-CoA desaturase 1; UGT2B4, UDP glucuronosyl transferase family 2 member B4; SHP, small heterodimer partner. Note: The symbol ⊕ represents upregulation, whereas the symbol ㊀ signifies downregulation.</p>
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<p>Bile acids (BAs) regulate Type 2 diabetes mellitus (T2DM) via the farnesoid X receptor (FXR). Hence, hyocholic acids (HCAs) and metformin potently activate the takeda G protein-coupled receptor 5 (TGR5), facilitating the production of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP) under the catalytic action of adenylate cyclase. The elevated cAMP levels subsequently lead to the phosphorylation of both protein kinase A (PKA) and the cAMP response element-binding protein (CREB) (solid black arrows). This results in the phosphorylated CREB translocating into the nucleus, thereby initiating the nuclear import of CREB. Additionally, cAMP serves to activate the expression of MAP kinase (MAPK) (solid black arrow). The conjunction of phosphorylated CREB and MAPK targets the activation of FXR within the cellular nucleus (solid black arrow and black ray arrow). The FXR, in turn, enhances the expression of proglucogen and suppresses that of bile salt export pump (BSEP) genes (solid black arrows), which collectively contribute to a significant up-regulation of glucagon-like peptide 1 (GLP-1) expression (black dotted arrows). Ultimately, this cascade effectively reduces the progression of T2DM by decreasing blood glucose levels (down-solid red arrow). Abbreviations: ATP, adenosine triphosphate; BAs, bile acids; BSEP, bile salt export pump; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; FXR, farnesoid X receptor; HCAs; hyocholic acids; GLP-1, glucagon-like peptide 1; MAPK, MAP kinase; PKA, protein kinase A; T2DM, type 2 diabetes mellitus; TGR5; takeda G protein-coupled receptor 5. Note: the symbol ⊕ indicates an increase, whereas ㊀ signifies a decrease.</p>
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<p>Bile acids (BAs) regulate cancers via the farnesoid X receptor (FXR). In breast cancer research, chenodeoxycholic acid (CDCA) has potently augmented runt-related transcription factor 2 (RUNX2) levels by triggering farnesoid X receptor (FXR) activation (down-solid black arrow), subsequently enhancing the synthesis of both bone sialoprotein (BSP) and osteopontin (OPN) (down-solid black arrow), thereby promoting the progression of the disease (up-solid red arrow). In colon cancer, CDCA markedly enhanced the expression levels of both matrix metalloproteinase 7 (MMP7) and the epidermal growth factor receptor (EGFR) (down-solid black arrow). Initially, the activated EGFR was found to promote the progression of colon cancer by engaging the Ras-Raf1-MAPK kinase 1/2 (MEK1/2)–extracellular signal-regulated kinase 1/2 (ERK1/2) signaling cascade (down-solid black arrow). Thereafter, it was revealed to contribute to the disease’s advancement through the phosphatidylinositol 3-kinase (PI3K)–protein kinase B (AKT)–mammalian target of rapamycin (mTOR) pathway (down-solid black arrow). Additionally, the activation of the EGFR was observed to facilitate the progression of colon cancer by modulating the c-Jun N-terminal kinase (JNK)–signal transducer and activator of the transcription (STATs) signaling pathway (down-solid black arrow). In liver cancer research, obeticholic acid (OCA) has been found to reduce interleukin-1β (IL-1β) and interleukin-6 (IL-6) secretion, thereby decelerating cancer progression (down-solid black arrow), which is attributed to the inhibition of the Janus kinase 2 (JAK2)–signal transducer and activator of transcription 3 (STAT3)–suppressor of cytokine signaling 3 (SOCS3) signaling pathway induced by FXR activation (down-solid black arrow). In pancreatic cancer, both deoxycholic acid (DCA) and CDCA markedly activated the FXR, orchestrating the Src-focal adhesion kinase (FAK)–c-JUN-mucin 4 (MUC4) signaling pathway (down-solid black arrow), and thereby contributing to the progression of pancreatic cancer (up-solid red arrow). Abbreviations: AKT, protein kinase B; BAs, bile acids; BSP, bone sialoprotein; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; ERK1/2, extracellular signal-regulated kinase 1/2; EGFR, epidermal growth factor receptor; FXR, farnesoid X receptor; FAK, focal adhesion kinase; IL-1β, interleukin-1β; IL-6, interleukin-6; JAK2, janus kinase 2; JNK, c-Jun N-terminal kinase; MMP7, matrix metallo proteinase-7; MEK1/2, MAPK kinase 1/2; MUC4, membrane mucin-4; mTOR, mammalian target of rapamycin; OCA, obeticholic acid; PI3K, phosphatidylinositol 3-kinase; RUNX2, transcription factor runt-related protein 2; SOCS3, suppressor of cytokine signaling-3; STATs, signal transducer and activator of transcriptions; STAT3, signal transducer and activator of transcription 3. Note: the symbol ⊕ denotes an upregulation, while the symbol ㊀ indicates a downregulation.</p>
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13 pages, 1050 KiB  
Article
Efficacy of the Once-Daily Tacrolimus Formulation LCPT Compared to the Immediate-Release Formulation in Preventing Early Post-Transplant Diabetes in High-Risk Kidney Transplant Patients: A Randomized, Controlled, Open-Label Pilot Study (EUDRACT: 2017-000718-52)
by Armando Torres, Concepción Rodríguez-Adanero, Constantino Fernández-Rivera, Domingo Marrero-Miranda, Eduardo de Bonis-Redondo, Aurelio P. Rodríguez-Hernández, Lourdes Pérez-Tamajón, Ana González-Rinne, Diego Álvarez-Sosa, Alejandra Álvarez-González, Nuria Sanchez-Dorta, Estefanía Pérez-Carreño, Laura Díaz-Martín, Sergio Luis-Lima, Ana E. Rodríguez-Rodríguez, Antonia María de Vera González, Cristina Romero-Delgado, María Calvo-Rodríguez, Rocío Seijo-Bestilleiro, Consuelo Rodríguez-Jiménez, Manuel Arturo Prieto López, Antonio Manuel Rivero-González, Domingo Hernández-Marrero and Esteban Porriniadd Show full author list remove Hide full author list
J. Clin. Med. 2024, 13(24), 7802; https://doi.org/10.3390/jcm13247802 - 20 Dec 2024
Viewed by 714
Abstract
Background/Objectives: Post-transplant diabetes mellitus (PTDM) and prediabetes (PreDM) are common after renal transplantation and increase the risk of cardiovascular events and mortality. Compared to immediate-release tacrolimus (IR-Tac), the LCPT formulation, with delayed absorption, offers higher bioavailability and a smoother time–concentration curve, potentially [...] Read more.
Background/Objectives: Post-transplant diabetes mellitus (PTDM) and prediabetes (PreDM) are common after renal transplantation and increase the risk of cardiovascular events and mortality. Compared to immediate-release tacrolimus (IR-Tac), the LCPT formulation, with delayed absorption, offers higher bioavailability and a smoother time–concentration curve, potentially reducing beta-cell stress. Methods: This randomized pilot trial compared de novo immunosuppression with IR-Tac (twice daily) and LCPT (once daily). At-risk recipients (age ≥ 60 years or 18–59 years with metabolic syndrome) were enrolled and followed for 3 months. The primary and secondary outcomes were the incidence of PTDM and PreDM, respectively. Results: 27 patients were randomized to IR-Tac and 25 to LCPT. The incidence of PTDM was comparable between groups [IR Tac: 18.5% (95% CI: 8.2–36.7%) vs. LCPT: 24% (95% CI: 11.5–43.4%); p = 0.7]. Although not statistically significant, the LCPT group exhibited a trend toward a reduction in PreDM incidence [IR-Tac: 40.7% (95% CI: 25–59%) vs. LCPT: 20% (95% CI: 9–39%); p = 0.1]. A sensitivity analysis showed similar results, with no significant differences in cumulative corticosteroid doses or baseline body mass index (BMI) between groups. The LCPT group showed a trend toward higher tacrolimus exposure at the end of the study [trough levels: IR-Tac group 8.3 (6.9–9.2) vs. LCPT group 9.4 (7.4–11.4) ng/mL; p = 0.05)], as well as fewer acute rejection episodes (none vs. three). Delayed graft function was more common in the IR-Tac group (37% vs. 8%; p = 0.01), and the eGFR was lower. Adverse events were comparable between groups. Conclusions: The potential biological activity of LCPT in preventing glucose metabolic alterations in at-risk patients warrants further investigation. Full article
(This article belongs to the Special Issue Advances in Kidney Transplantation)
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<p>Patients’ disposition. IS: Immunosuppression; OGT: Oral glucose tolerance test. PKD-1: Autosomal Dominant Polycystic Kidney Disease type I; GN: Glomerulonephritis.</p>
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<p>Distribution of glucose metabolism abnormalities at the end of the study in each group. Prediabetes: Impaired Fasting Glucose and Impaired Glucose Tolerance, isolated or combined. (<b>A</b>): All patients; (<b>B</b>): Excluding patients with acute rejection or a baseline BMI &lt; 22 Kg/m<sup>2</sup>. IR-Tac: Immediate-release tacrolimus; LCPT: LCP Tacrolimus.</p>
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11 pages, 3561 KiB  
Article
Enhanced Visible Light Controlled Glucose Photo-Reforming Using a Composite WO3/Ag/TiO2 Photoanode: Effect of Incorporated Plasmonic Ag Nanoparticles
by Katarzyna Jakubow-Piotrowska, Bartlomiej Witkowski, Piotr Wrobel, Krzysztof Miecznikowski and Jan Augustynski
Nanomaterials 2024, 14(24), 2001; https://doi.org/10.3390/nano14242001 - 13 Dec 2024
Viewed by 523
Abstract
WO3/Ag/TiO2 composite photoelectrodes were formed via the high-temperature calcination of a WO3 film, followed by the sputtering of a very thin silver film and deposition of an overlayer of commercial TiO2 nanoparticles. These synthetic photoanodes were characterized in [...] Read more.
WO3/Ag/TiO2 composite photoelectrodes were formed via the high-temperature calcination of a WO3 film, followed by the sputtering of a very thin silver film and deposition of an overlayer of commercial TiO2 nanoparticles. These synthetic photoanodes were characterized in view of the oxidation of a model organic compound glucose combined with the generation of hydrogen at a platinum cathode. During prolonged photoelectrolysis under simulated solar light, these photoanodes demonstrated high and stable photocurrents of ca. 4 mA cm−2 due, on one hand, to the occurrence of the so-called photocurrent doubling and, on the other hand, to the plasmonic effect of Ag nanoparticles. The post-photoelectrolysis analyses of the electrolyte demonstrated the formation of high-value final glucose photo-reforming products, principally gluconic acid, erythrose and formic acid. Full article
(This article belongs to the Special Issue Hydrogen Production and Evolution Based on Nanocatalysts)
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<p>(<b>a</b>) A cross-sectional SEM image of the WO<sub>3</sub>/Ag/TiO<sub>2</sub> film electrode. (<b>b</b>) The X-ray diffraction pattern of a WO<sub>3</sub> film annealed at 550 °C with a perfect monoclinic crystalline structure. (<b>c</b>) A top-view SEM image of the WO<sub>3</sub> film covered with silver nanoparticles. (<b>d</b>) A particle size distribution histogram of Ag NPs. (<b>e</b>) A top-view SEM image of the WO<sub>3</sub>/Ag/TiO film.</p>
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<p>(<b>a</b>) Absorbance spectra of FTO substrates: bare (black), with a TiO<sub>2</sub> layer (violet), with a WO<sub>3</sub> layer (red), with a TiO<sub>2</sub> and WO<sub>3</sub> bilayer (green), and with Ag nanoparticles placed between the WO<sub>3</sub> and TiO<sub>2</sub> layers. (<b>b</b>) Relative absorbance spectra of the Ag-enhanced photoanode related to the reference FTO/WO<sub>3</sub>/TiO<sub>2</sub> sample.</p>
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<p>IPCE spectra for WO<sub>3</sub>, TiO<sub>2</sub>, WO<sub>3</sub>/Ag/TiO<sub>2</sub>, and WO<sub>3</sub>/TiO<sub>2</sub> photoanodes measured at 0.6 V vs. Ag/AgCl in a 0.01 M NaCl/Na<sub>2</sub>SO<sub>4</sub> electrolyte of pH 7 containing 0.01 M glucose.</p>
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<p>The photo-currents of glucose oxidation measured during 5 h long electrolysis conducted at 0.6 V vs. Ag/AgCl in a 0.01 M NaCl/Na<sub>2</sub>SO<sub>4</sub> electrolyte of pH 7, using WO<sub>3</sub>/Ag/TiO<sub>2</sub> and WO<sub>3</sub>/TiO<sub>2</sub> photoanodes irradiated with simulated AM 1.5 G solar light.</p>
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<p>Photocurrent densities vs. imposed potential (j-E) plots in a 0.01 M NaCl/Na<sub>2</sub>SO<sub>4</sub> electrolyte of pH 7 containing 0.01 M glucose using WO<sub>3</sub>, TiO<sub>2</sub>, WO<sub>3</sub>/TiO<sub>2</sub> and WO<sub>3</sub>/Ag/TiO<sub>2</sub> recorded under simulated AM 1.5G irradiation.</p>
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<p>Photocurrent-potential plots for the WO<sub>3</sub>/Ag/TiO<sub>2</sub> electrode recorded in a 0.01 M NaCl/Na<sub>2</sub>SO<sub>4</sub> electrolyte of pH 7 with 0.01 M glucose under 3 sun illumination from the front side (black curve) and from the back side (red curve).</p>
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<p>Concentrations (<b>a</b>) and Faradaic yields (<b>b</b>) of glucose photo-reforming products collected after electrolysis performed following the conditions depicted in the legend of <a href="#nanomaterials-14-02001-f003" class="html-fig">Figure 3</a>.</p>
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<p>The proposed reaction pathway of glucose reforming over the WO<sub>3</sub>/Ag/TiO<sub>2</sub> photoanode; products quantified in this work are shown in blue. (<b>A</b>) main pathway; (<b>B</b>) parallel pathway.</p>
Full article ">Scheme 1
<p>The preparation process of WO<sub>3</sub>/Ag/TiO<sub>2</sub> film electrodes used in glucose photo-reforming experiments.</p>
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