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33 pages, 1782 KiB  
Review
Synthalin, Buformin, Phenformin, and Metformin: A Century of Intestinal “Glucose Excretion” as Oral Antidiabetic Strategy in Overweight/Obese Patients
by Giuliano Pasquale Ramadori
Livers 2025, 5(3), 35; https://doi.org/10.3390/livers5030035 - 31 Jul 2025
Viewed by 87
Abstract
After the first release of synthalin B (dodecamethylenbiguanide) in 1928 and its later retraction in the 1940s in Germany, the retraction of phenformin (N-Phenethylbiguanide) and of Buformin in the USA (but not outside) because of the lethal complication of acidosis seemed to have [...] Read more.
After the first release of synthalin B (dodecamethylenbiguanide) in 1928 and its later retraction in the 1940s in Germany, the retraction of phenformin (N-Phenethylbiguanide) and of Buformin in the USA (but not outside) because of the lethal complication of acidosis seemed to have put an end to the era of the biguanides as oral antidiabetics. The strongly hygroscopic metformin (1-1-dimethylbiguanide), first synthesized 1922 and resuscitated as an oral antidiabetic (type 2 of the elderly) compound first released in 1959 in France and in other European countries, was used in the first large multicenter prospective long-term trial in England in the UKPDS (1977–1997). It was then released in the USA after a short-term prospective trial in healthy overweight “young” type 2 diabetics (mean age 53 years) in 1995 for oral treatment of type 2 diabetes. It was, however, prescribed to mostly multimorbid older patients (above 60–65 years of age). Metformin is now the most used oral drug for type 2 diabetes worldwide. While intravenous administration of biguanides does not have any glucose-lowering effect, their oral administration leads to enormous increase in their intestinal concentration (up to 300-fold compared to that measured in the blood), to reduced absorption of glucose from the diet, to increased excretion of glucose through the stool, and to decrease in insulin serum level through increased hepatic uptake and decreased production. Intravenously injected F18-labeled glucose in metformin-treated type 2 diabetics accumulates in the small and even more in the large intestine. The densitometry picture observed in metformin-treated overweight diabetics is like that observed in patients after bowel-cleansing or chronically taking different types of laxatives, where the accumulated radioactivity can even reach values observed in colon cancer. The glucose-lowering mechanism of action of metformin is therefore not only due to inhibition of glucose uptake in the small intestine but also to “attraction” of glucose from the hepatocyte into the intestine, possibly through the insulin-mediated uptake in the hepatocyte and its secretion into the bile. Furthermore, these compounds have also a diuretic effect (loss of sodium and water in the urine) Acute gastrointestinal side effects accompanied by fluid loss often lead to the drugs’ dose reduction and strongly limit adherence to therapy. Main long-term consequences are “chronic” dehydration, deficiency of vitamin B12 and of iron, and, as observed for all the biguanides, to “chronic” increase in fasting and postprandial lactate plasma level as a laboratory marker of a clinical condition characterized by hypotension, oliguria, adynamia, and evident lactic acidosis. Metformin is not different from the other biguanides: synthalin B, buformin, and phenformin. The mechanism of action of the biguanides as antihyperglycemic substances and their side effects are comparable if not even stronger (abdominal pain, nausea, vomiting, diarrhea, fluid loss) to those of laxatives. Full article
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12 pages, 4529 KiB  
Article
Somatostatin Receptor Expression of Gastroenteropancreatic Neuroendocrine Tumors: A Comprehensive Analysis in the Era of Somatostatin Receptor PET Imaging
by Maria Grazia Maratta, Taymeyah Al-Toubah, Jaime Montilla-Soler, Eleonora Pelle, Mintallah Haider, Ghassan El-Haddad and Jonathan Strosberg
Cancers 2025, 17(12), 1937; https://doi.org/10.3390/cancers17121937 - 11 Jun 2025
Cited by 1 | Viewed by 602
Abstract
Background: There is limited data on somatostatin receptor (SSTR) expression of metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) using modern imaging techniques and stratifying by primary site and tumor grade (G). Understanding patterns of SSTR expression and tumor heterogeneity is essential when determining the [...] Read more.
Background: There is limited data on somatostatin receptor (SSTR) expression of metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) using modern imaging techniques and stratifying by primary site and tumor grade (G). Understanding patterns of SSTR expression and tumor heterogeneity is essential when determining the relevance of cold and radiolabeled somatostatin analog treatments. Methods: A single-institutional retrospective analysis of metastatic well-differentiated G1-3 GEP-NET patients who underwent Gallium-68 ([68Ga])-DOTATATE or Copper-64 ([64Cu])-DOTATATE positron emission tomography (PET) imaging from September 2016 to June 2024 was performed. Results: A total of 1192 patients were considered eligible for this study. Among them, 26 (2.2%) were completely negative on SSTR PET/computed tomography (CT), and 27 (2.3%) had weak uptake (less or equal to the normal liver). Up to 40 (3.4%) had heterogeneous SSTR expression on PET/CT: 26 (2.2%) displayed the coexistence of strongly avid lesions with the absence or near absence of SSTR uptake in measurable tumors (heterogeneous strong), while 14 (1.2%) had a combination of absent and weakly expressing SSTR tumors (heterogeneous low). An additional nine cases with prior homogeneous expression (0.8%) developed new SSTR-negative tumors along with disease progression, potentially indicating dedifferentiation. The absent or heterogeneous SSTR expression rates were greater in NET G3 than G1/G2 and in tumors originating outside the small bowel (midgut). Most NETs with absent or heterogeneous SSTR expression were fluorodeoxyglucose-F-18 ([18F]FDG)-avid. Conclusions: The large majority of metastatic GEP-NETs demonstrate strong and relatively uniform SSTR expression, but approximately 8% are SSTR-negative, weak or heterogeneous on PET/CT. Higher than average rates of absent/heterogeneous/weak SSTR expression occur in G3 NETs and lower rates among small intestine primaries. Full article
(This article belongs to the Special Issue Updates in Neuroendocrine Neoplasms)
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20 pages, 2006 KiB  
Article
99mTc-Labeled Diarylpyrazoles for Single-Emission Computer Tomography Imaging of Neurotensin Receptor-Positive Tumors: A Comparative Preclinical Study
by Roman Potemkin, Simone Maschauer, Harald Hübner, Torsten Kuwert, Tobias Bäuerle, Peter Gmeiner and Olaf Prante
Pharmaceutics 2025, 17(6), 700; https://doi.org/10.3390/pharmaceutics17060700 - 27 May 2025
Viewed by 615
Abstract
Background/Objectives: Neurotensin receptors (NTSRs), members of the G protein-coupled receptor (GPCR) family, have been found to be overexpressed in several types of human cancers, including breast, colon, lung, liver, prostate, and pancreatic cancer. In particular, NTSR1 is overexpressed in at least 75% of [...] Read more.
Background/Objectives: Neurotensin receptors (NTSRs), members of the G protein-coupled receptor (GPCR) family, have been found to be overexpressed in several types of human cancers, including breast, colon, lung, liver, prostate, and pancreatic cancer. In particular, NTSR1 is overexpressed in at least 75% of pancreatic ductal adenocarcinomas. The aim of the present study was the development and evaluation of new 99mTc-labeled nonpeptide NTSR1-antagonists for SPECT imaging of NTSR-positive tumors. Methods: Multistep syntheses of NTSR1 antagonist derivatives were performed following our previously described procedure. Two different chelating strategies were applied for 99mTc radiolabeling to provide the [99mTc]Tc-HYNIC complex [99mTc]1 and the [99mTc]Tc-tricarbonyl complex [99mTc]2. Receptor binding assays were performed using hNTSR1-expressing CHO cells. Radiochemical yields (RCYs) were determined by radio-HPLC. For [99mTc]1 and [99mTc]2, log D7.4, plasma protein binding, stability in human plasma and serum, and cellular uptake in HT-29 cells were determined. Biodistribution studies and small animal SPECT studies were performed in HT-29 tumor-bearing nude mice. Results: The radiosynthesis of [99mTc]1 (log D7.4 = −0.27) and [99mTc]2 (log D7.4 = 1.00) was successfully performed with RCYs of 94–96% (decay-corrected). Both radioligands were stable in human serum and plasma, showed plasma protein binding of 72% ([99mTc]1) and 82% ([99mTc]2), and exhibited high and specific uptake in HT-29 cells. Biodistribution studies in HT-29 tumor-bearing mice showed a higher tumor accumulation of [99mTc]1 compared to [99mTc]2 (8.8 ± 3.4 %ID/g vs. 2.7 ± 0.2 %ID/g at 2 h p.i.). [99mTc]2 showed exceptionally high intestinal accumulation (49 ± 22 %ID/g at 1 h p.i.) and was therefore considered unfavorable. In the SPECT/CT imaging of HT-29 tumor xenografts, [99mTc]1 showed a higher NTSR1-specific tumor uptake than [99mTc]2 at all time points after tracer injection, with 12 ± 2.8 %ID/g for [99mTc]1 vs. 3.1 ± 1.1 %ID/g for [99mTc]2 at 4 h p.i. and adequate tumor-to-background ratios. Conclusions: In particular, the [99mTc]Tc-HYNIC ligand ([99mTc]1) showed promising preclinical results, being a potential candidate for SPECT imaging and, therefore, appropriate for translation into the clinic. Full article
(This article belongs to the Special Issue Pharmaceutical Applications of Metal Complexes and Derived Materials)
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12 pages, 1831 KiB  
Article
Intestinal Epithelial-Derived Exosomes Under Cold Stimulation Promote Adipose Thermogenesis
by Xue Han, Tiange Feng, Yaxu Yang, Ziming Zhu, Fangyu Shao, Lijun Sun, Yue Yin and Weizhen Zhang
Metabolites 2025, 15(5), 324; https://doi.org/10.3390/metabo15050324 - 14 May 2025
Viewed by 550
Abstract
Background: Whether intestinal epithelial cells can regulate distant adipose tissue remains a mystery. Methods: Cold-stimulated intestinal epithelial cell-derived exosomes (Cold IEC-Exo) play a pivotal role in enhancing adipose thermogenesis and metabolic homeostasis, as demonstrated in this study. Results: IEC-Exo can [...] Read more.
Background: Whether intestinal epithelial cells can regulate distant adipose tissue remains a mystery. Methods: Cold-stimulated intestinal epithelial cell-derived exosomes (Cold IEC-Exo) play a pivotal role in enhancing adipose thermogenesis and metabolic homeostasis, as demonstrated in this study. Results: IEC-Exo can accumulate in adipose tissue. Compared with IEC-Exo derived from room temperature mice (RT IEC-Exo), Cold IEC-Exo significantly enhanced the thermogenesis of adipose. In vitro, Cold IEC-Exo directly stimulated thermogenesis in primary adipocytes by elevating oxygen consumption rate, proton leak, and fatty acid uptake, with no effect on glucose uptake. Small RNA sequencing identified miR-674-3p as a key mediator enriched in Cold IEC-Exo. miR-674-3p mimicry replicated Cold IEC-Exo effects, augmenting Ucp1 expression, mitochondrial uncoupling, and fatty acid utilization in adipocytes. Local overexpression of miR-674-3p in BAT and sWAT via AAV in vivo enhanced thermogenesis and attenuated diet-induced glucose intolerance. Conclusions: These findings establish that Cold IEC-Exo, via miR-674-3p transfer, drive adipose thermogenic activation and mitigate metabolic dysfunction, highlighting their therapeutic potential in obesity-related disorders. Full article
(This article belongs to the Special Issue Energy Metabolism in Brown Adipose Tissue)
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20 pages, 1744 KiB  
Article
Glutathione Contributes to Caloric Restriction-Triggered Shift in Taurine Homeostasis
by András Gregor, Manuel Malleier, Arturo Auñon-Lopez, Sandra Auernigg-Haselmaier, Jurgen König, Marc Pignitter and Kalina Duszka
Nutrients 2025, 17(5), 777; https://doi.org/10.3390/nu17050777 - 23 Feb 2025
Cited by 1 | Viewed by 1246
Abstract
Background/Objectives: Previously, we found that caloric restriction (CR) in mice increases taurine levels by stimulating hepatic synthesis, secretion into the intestine and deconjugation of taurine-conjugated bile acids (BA). Subsequently, in the intestine, taurine conjugates various molecules, including glutathione (GSH). The current study explores [...] Read more.
Background/Objectives: Previously, we found that caloric restriction (CR) in mice increases taurine levels by stimulating hepatic synthesis, secretion into the intestine and deconjugation of taurine-conjugated bile acids (BA). Subsequently, in the intestine, taurine conjugates various molecules, including glutathione (GSH). The current study explores the mechanisms behind forming taurine-GSH conjugate and its consequences for taurine, other taurine conjugates, and BA in order to improve understanding of their role in CR. Methods: The non-enzymatic conjugation of taurine and GSH was assessed and the uptake of taurine, GSH, and taurine-GSH was verified in five sections of the small intestine. Levels of taurine, gavaged 13C labeled taurine, taurine conjugates, taurine-GSH, and GSH were measured in various tissues of ad libitum and CR mice. Next, the taurine-related CR phenotype was challenged by applying the inhibitors of taurine transporter (SLC6A6) and GSH-S transferases (GST). Results: The CR-related increase in taurine in intestinal mucosa was accompanied by the uptake and distribution of taurine towards selected organs. A unique composition of taurine conjugates characterized each tissue. Although taurine-GSH conjugate could be formed in non-enzymatic reactions, GST activity contributed to taurine-related CR outcomes. Upon SLC6A6 and GST inhibition, the taurine-related parameters were affected mainly in the ileum rather than the liver. Meanwhile, BA levels were somewhat affected by GST inhibition in the ileum and in the liver by SLC6A6 inhibitor. Conclusions: The discovered CR phenotype involves a regulatory network that adjusts taurine and BA homeostasis. GSH supports these processes by conjugating taurine, impacting taurine uptake from the intestine and its availability to form other types of conjugates. Full article
(This article belongs to the Section Nutrition and Metabolism)
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21 pages, 3293 KiB  
Article
X-Ray Irradiation Induces Oxidative Stress and Upregulates Intestinal Nrf2-Mrp2 Pathway, Leading to Decreased Intestinal Absorption of Valsartan
by Yunhua Teng, Jiaojiao Ma, Junxia Zhang, Bohan Liang, Aijie Zhang, Yanjie Li, Shiqi Dong and Huirong Fan
Pharmaceutics 2025, 17(2), 268; https://doi.org/10.3390/pharmaceutics17020268 - 17 Feb 2025
Viewed by 822
Abstract
Background: It has been documented that radiation can influence the pharmacokinetics of chemotherapy drugs, yet the underlying mechanisms remain poorly understood. In clinical practice, a considerable number of cancer patients undergo radiotherapy, and those with comorbid hypertension required antihypertensive drugs, including valsartan, an [...] Read more.
Background: It has been documented that radiation can influence the pharmacokinetics of chemotherapy drugs, yet the underlying mechanisms remain poorly understood. In clinical practice, a considerable number of cancer patients undergo radiotherapy, and those with comorbid hypertension required antihypertensive drugs, including valsartan, an angiotensin II receptor blocker. However, there is no research investigating whether radiotherapy poses a risk of altering the pharmacokinetics. Objective: The objective of this study is to investigate the impact of X-ray abdominal irradiation on the pharmacokinetics of valsartan and to preliminarily elucidate the underlying mechanism. Methods: The pharmacokinetics of valsartan after X-ray irradiation was investigated in rats and in vitro by detecting the concentration of valsartan in biological samples by LC-MS/MS. The oxidative stress in the intestine and the mRNA expression of partial transporters and Nrf2 in the liver and small intestine were detected by biochemical reagent kit or RT-qPCR. Results: In vivo studies showed that X-ray irradiation resulted in a significant decrease in the AUC and Cmax of valsartan, and the cumulative fractional excretion of valsartan in bile and urine, although there was no significant change in fecal excretion. In vitro studies showed that the uptake of valsartan by both intestine and Caco-2 cells decreased after irradiation, and the cellular uptake could be restored by Mrp2 inhibitor MK571. The levels of GSH, SOD, and CAT in the intestine decreased after irradiation. The mRNA expressions of Mrp2 and P-gp in the intestine or Caco-2 cells were significantly upregulated after irradiation while there was a downregulation of Mrp2 and oatp1b2 in liver. Nrf2 and HO-1 in the intestine were also significantly upregulated, which clarified the involvement of Mrp2 and the possible molecular mechanism. Conclusions: Abdominal X-ray irradiation can cause oxidative stress and upregulate intestinal Mrp2, which may be related to oxidative stress and upregulation of Nrf2, reducing intestinal absorption of valsartan and leading to a significant decrease in the blood concentration of valsartan. Full article
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12 pages, 1110 KiB  
Article
Cholesin mRNA Expression in Human Intestinal, Liver, and Adipose Tissues
by Hannah Gilliam-Vigh, Malte P. Suppli, Sebastian M. N. Heimbürger, Asger B. Lund, Filip K. Knop and Anne-Marie Ellegaard
Nutrients 2025, 17(4), 619; https://doi.org/10.3390/nu17040619 - 8 Feb 2025
Viewed by 1417
Abstract
Objective: Cholesin is a recently discovered gut-derived hormone secreted by enterocytes upon dietary cholesterol uptake via the transmembrane sterol transporter Niemann–Pick disease C1-like intracellular cholesterol transporter 1 (NPC1L1). In the liver, cholesin activates G protein-coupled receptor 146 (GPR146), causing reduced cholesterol synthesis. In [...] Read more.
Objective: Cholesin is a recently discovered gut-derived hormone secreted by enterocytes upon dietary cholesterol uptake via the transmembrane sterol transporter Niemann–Pick disease C1-like intracellular cholesterol transporter 1 (NPC1L1). In the liver, cholesin activates G protein-coupled receptor 146 (GPR146), causing reduced cholesterol synthesis. In this exploratory, hypothesis-generating study based on post hoc analysis, human data on the cholesin system are presented. Methods: Mucosal biopsies were collected throughout the intestinal tract from 12 individuals with type 2 diabetes (T2D) and 12 healthy, matched controls. Upper small intestinal mucosal biopsies were collected from 20 individuals before and after Roux-en-Y gastric bypass (RYGB) surgery. Liver biopsies were collected from 12 men with obesity and 15 matched controls without obesity. Subcutaneous abdominal adipose tissue biopsies were collected from 20 men with type 1 diabetes (T1D). All biopsies underwent full mRNA sequencing. Results: Cholesin mRNA expression was observed throughout the intestinal tracts of the individuals with T2D and the controls, in the livers of men with and without obesity, and in adipose tissue of men with T1D. NPC1L1 mRNA expression was robust throughout the small intestines but negligible in the large intestines of both individuals with and without T2D. RYGB surgery induced the expression of NPC1L1 mRNA in the upper small intestine. GPR146 mRNA was expressed in the livers of men, both with and without obesity, and in the adipose tissue of men with T1D, but not in the intestines. Conclusions: Our results suggest a role of the cholesin system in human physiology, but whether it is perturbed in metabolic diseases remains unknown. Clinical trial registration numbers: NCT03044860, NCT03093298, NCT02337660, NCT03734718. Full article
(This article belongs to the Special Issue Bioactive Lipids and Metabolic Disease)
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11 pages, 2023 KiB  
Article
Utilisation of the Innovative [18F]-Labelled Radiotracer [18F]-BIBD-071 Within HR+ Breast Cancer Xenograft Mouse Models
by Di Fan, Xin Wang, Xueyuan Ling, Hongbin Li, Lu Zhang, Wei Zheng, Zehui Wu and Lin Ai
Pharmaceuticals 2025, 18(1), 66; https://doi.org/10.3390/ph18010066 - 9 Jan 2025
Viewed by 1031
Abstract
Background/Objectives: Aromatase plays a crucial role in the conversion of androgens to oestrogens and is often overexpressed in hormone-dependent tumours, particularly breast cancer. [18F]BIBD-071, which has excellent binding affinity for aromatase and good pharmacokinetics, has potential for the diagnosis and treatment of aromatase-related [...] Read more.
Background/Objectives: Aromatase plays a crucial role in the conversion of androgens to oestrogens and is often overexpressed in hormone-dependent tumours, particularly breast cancer. [18F]BIBD-071, which has excellent binding affinity for aromatase and good pharmacokinetics, has potential for the diagnosis and treatment of aromatase-related diseases. The MCF-7 cell line, which is hormone receptor-positive (HR+), was used in the assessment of the novel [18F]-labelled radiotracer [18F]BIBD-071 via positron emission tomography (PET) imaging of an HR+ breast cancer xenograft model. Methods: [18F]BIBD-071 was synthesised, radiolabelled, and then subjected to in vitro stability testing. MCF-7 cells were cultured and implanted into BALB/c nude mice to establish subcutaneous tumour models. MicroPET/CT imaging was conducted after injection of the tracer at 1 and 2 h, and a blocking study was also conducted using the aromatase inhibitor letrozole. A block experiment was used to prove the specificity of the probe. Biodistribution studies were performed at 0.5, 1, and 2 h post injection (p.i.). Immunofluorescence was used to assess aromatase expression in MCF-7 cells. Results: [18F]BIBD-071 showed excellent in vitro stability and specific uptake in an MCF-7 xenograft tumour model. MicroPET/CT imaging at 1 and 2 h p.i. revealed excellent tumour visualisation with a favourable tumour-to-background ratio. Biodistribution data revealed high tracer uptake in the liver, small intestine, and stomach, with significant washout from the bloodstream and tumour over time. The tumour uptakes at 0.5 h, 1 h, and 2 h were 3.84 ± 0.13, 2.5 ± 0.17, and 2.54 ± 0.32, respectively. The tumour uptake significantly decreased between 0.5 h and 1 h (p < 0.0001), whereas there was no significant difference between 1 and 2 h. The tumour/background ratios at 0.5 h, 1 h, and 2 h were 1.19 ± 0.03, 1.12 ± 0.17, and 1.42 ± 0.11, respectively. Immunofluorescence confirmed robust aromatase expression in MCF-7 cells, which was correlated with [18F]BIBD-071 tumour uptake. Conclusions: [18F]BIBD-071 is a promising PET tracer for diagnosing and monitoring HR+ breast cancer, warranting further research into hormone-dependent cancers. Full article
(This article belongs to the Special Issue PET and SPECT Molecular Imaging in Drug Development)
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22 pages, 2697 KiB  
Article
Ingested Polystyrene Micro-Nanoplastics Increase the Absorption of Co-Ingested Arsenic and Boscalid in an In Vitro Triculture Small Intestinal Epithelium Model
by Davood Kharaghani, Glen M. DeLoid, Trung Huu Bui, Nubia Zuverza-Mena, Carlos Tamez, Craig Musante, Jason C. White and Philip Demokritou
Microplastics 2025, 4(1), 4; https://doi.org/10.3390/microplastics4010004 - 7 Jan 2025
Cited by 2 | Viewed by 2925
Abstract
Micro-nano plastics (MNPs) are emerging environmental and food contaminants that are raising serious health concerns. Due to the polycontamination of the food web with environmental pollutants (EPs), and now MNPs, the co-ingestion of EPs and MNPs is likely to occur, and the potential [...] Read more.
Micro-nano plastics (MNPs) are emerging environmental and food contaminants that are raising serious health concerns. Due to the polycontamination of the food web with environmental pollutants (EPs), and now MNPs, the co-ingestion of EPs and MNPs is likely to occur, and the potential synergistic effects of such co-ingestions are completely unstudied. In this study, we therefore sought to determine the effects of the two model EPs, arsenic and boscalid, on the uptake and toxicity of two model MNPs, 25 and 1000 nm polystyrene (PS-25 and PS-1000), and vice versa, employing a triculture small intestinal epithelium model combined with simulated digestion. In 24 h triculture exposures, neither MNPs, EPs, nor MNPs + EPs caused significant toxicity. The presence of PS-25 significantly increased arsenic uptake (from 0.0 to 5.8%, p < 0.001) and translocation (from 5.2 to 9.8%, p < 0.05) but had no effect on boscalid uptake or translocation, whereas PS-1000 had no effect on the uptake or translocation of either EP. The uptake of both PS MNPs was also increased by EPs, rising from 10.6 to 19.5% (p < 0.01) for PS-25 and from 4.8 to 8.5% (p < 0.01) for PS-1000. These findings highlight the need for further studies to assess MNP-EP interactions and possible synergistic adverse health impacts. Full article
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16 pages, 1633 KiB  
Article
The Expression of Proteases and the Oligopeptide Transporter PepT1 in the Yolk Sac Membrane, Proventriculus, and Small Intestine During the Development of Anas platyrhynchos domestica Embryo
by Seba Jamal Shbailat and Ibtisam Omar Aslan
Biology 2024, 13(12), 989; https://doi.org/10.3390/biology13120989 - 29 Nov 2024
Viewed by 1097
Abstract
The role of the yolk sac membrane (YSM) and digestive tract in the processing of egg yolk proteins during embryogenesis is unexplored in the duck Anas platyrhynchos domestica. Here, we investigated in the duck embryo the function of the YSM, proventriculus, and [...] Read more.
The role of the yolk sac membrane (YSM) and digestive tract in the processing of egg yolk proteins during embryogenesis is unexplored in the duck Anas platyrhynchos domestica. Here, we investigated in the duck embryo the function of the YSM, proventriculus, and small intestine in protein digestion and uptake. We tested the expression of aminopeptidase N (APN) and the oligopeptide transporter PepT1 as well as the expression of cathepsin B (CTSB) and cathepsin D (CTSD) lysosomal genes in the YSM during incubation days 12, 14, 16–18, 20, 22, 24, 26, and 28 (the day of hatch). Also, we examined embryonic duck pepsinogen (EDPg) expression in the proventriculus and APN and PepT1 expression in the small intestine. In the YSM, CTSD expression was weak compared to that of CTSB, and the expression of CTSB, APN, and PepT1 reached its maximum on day 24 and decreased afterwards. In the proventriculus, EDPg expression peaked on days 17 to 20 and decreased thereafter. The APN and PepT1 expression levels were highest in the jejunum and ileum and reached their maximum on day 28. Our results suggest that the YSM plays a role in the degradation and uptake of the peptides that are digested by the activated yolk proteases, and it also functions in the lysosomal digestion of yolk lipoproteins. Furthermore, the proventriculus is possibly involved in the digestion of yolk proteins. Finally, the jejunum and ileum appear to be the primary sites for peptide digestion and absorption at the end of the incubation. Full article
(This article belongs to the Section Biochemistry and Molecular Biology)
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11 pages, 1496 KiB  
Article
Novel Expression of Apical Bile Acid Transport (ASBT) More Proximally Than Distal Ileum Contributing to Enhanced Intestinal Bile Acid Absorption in Obesity
by Shanmuga Sundaram, Arunkumar Jagadeesan, Raja Singh Paulraj, Uma Sundaram and Subha Arthur
Int. J. Mol. Sci. 2024, 25(21), 11452; https://doi.org/10.3390/ijms252111452 - 25 Oct 2024
Viewed by 1725
Abstract
Dietary lipid absorption is facilitated by bile acids. In the Zucker rat (ZR) model of obesity, bile acid absorption, mediated by the apical sodium bile acid transporter (ASBT), was increased in villus cells from the distal ileum. However, whether ASBT may be de [...] Read more.
Dietary lipid absorption is facilitated by bile acids. In the Zucker rat (ZR) model of obesity, bile acid absorption, mediated by the apical sodium bile acid transporter (ASBT), was increased in villus cells from the distal ileum. However, whether ASBT may be de novo expressed more proximally in the small intestine during obesity to facilitate additional bile acid absorption is not known. For this, starting from the end of the ileum to the mid jejunum, caudal-orally, five intestinal segments of equal length (S1–S5) were separated from lean and obese ZRs (LZR and OZR). Intestinal mucosa obtained from these segments were used for total RNA extraction, RT-qPCR and 3H-TCA uptake. The results showed that bile acid absorption along with the mRNA expression of ASBT and FXR progressively decreased caudal-orally in both LZRs and OZRs but was significantly higher in all small intestinal segments in OZRs. The expression of GATA4 was absent in the distal ileum (S1) in both LZRs and OZRs, but steadily increased along the proximal length in both. However, this steady increase was significantly reduced in the comparative obese proximal intestinal segments S2, S3, S4 and S5. The expressions of bile acid-activated G-protein-coupled bile acid receptor TGR5 and S1PR2 were unaltered in segments S1–S4 but were significantly increased in OZR S5. The paradigm changing observation of this study is that ASBT is expressed more proximally in the small intestine in obesity. This likely increases overall bile acid absorption and thereby lipid absorption in the proximal small intestine in obesity. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Obesity and Metabolic Diseases)
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19 pages, 2459 KiB  
Article
Regular Exercise Training Induces More Changes on Intestinal Glucose Uptake from Blood and Microbiota Composition in Leaner Compared to Heavier Individuals in Monozygotic Twins Discordant for BMI
by Martin S. Lietzén, Maria Angela Guzzardi, Ronja Ojala, Jaakko Hentilä, Marja A. Heiskanen, Sanna M. Honkala, Riikka Lautamäki, Eliisa Löyttyniemi, Anna K. Kirjavainen, Johan Rajander, Tarja Malm, Leo Lahti, Juha O. Rinne, Kirsi H. Pietiläinen, Patricia Iozzo and Jarna C. Hannukainen
Nutrients 2024, 16(20), 3554; https://doi.org/10.3390/nu16203554 - 20 Oct 2024
Cited by 1 | Viewed by 1720
Abstract
Background/Objectives: Obesity impairs intestinal glucose uptake (GU) (intestinal uptake of circulating glucose from blood) and alters gut microbiome. Exercise improves intestinal insulin-stimulated GU and alters microbiome. Genetics influence the risk of obesity and gut microbiome. However, the role of genetics on the effects [...] Read more.
Background/Objectives: Obesity impairs intestinal glucose uptake (GU) (intestinal uptake of circulating glucose from blood) and alters gut microbiome. Exercise improves intestinal insulin-stimulated GU and alters microbiome. Genetics influence the risk of obesity and gut microbiome. However, the role of genetics on the effects of exercise on intestinal GU and microbiome is unclear. Methods: Twelve monozygotic twin pairs discordant for BMI (age 40.4 ± 4.5 years, BMI heavier 36.7 ± 6.0, leaner 29.1 ± 5.7, 8 female pairs) performed a six-month-long training intervention. Small intestine and colonic insulin-stimulated GU was studied using [18F]FDG-PET and microbiota from fecal samples with 16s rRNA. Results: Ten pairs completed the intervention. At baseline, heavier twins had lower small intestine and colonic GU (p < 0.05). Response to exercise differed between twins (p = 0.05), with leaner twins increasing colonic GU. Alpha and beta diversity did not differ at baseline. During the intervention, beta diversity changed significantly, most prominently at the mid-point (p < 0.01). Beta diversity changes were only significant in the leaner twins when the twin groups were analyzed separately. Exercise was associated with changes at the phylum level, mainly at the mid-point (pFDR < 0.05); at the genus level, several microbes increased, such as Lactobacillus and Sellimonas (pFDR < 0.05). In type 1 analyses, many genera changes were associated with exercise, and fewer, such as Lactobacillus, were also associated with dietary sugar consumption (p < 0.05). Conclusions: Obesity impairs insulin-stimulated intestinal GU independent of genetics. Though both twin groups exhibited some microbiota changes, most changes in insulin-stimulated colon GU and microbiota were significant in the leaner twins. Full article
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22 pages, 10272 KiB  
Article
Transport of Neutral Amino Acids in the Jejunum of Pigs with Special Consideration of L-Methionine
by Isabel I. Schermuly, Stella Romanet, Amlan K. Patra, Lucia Mastrototaro, Andreas Lemme, Robert Pieper, Jürgen Zentek and Jörg R. Aschenbach
Nutrients 2024, 16(19), 3418; https://doi.org/10.3390/nu16193418 - 9 Oct 2024
Cited by 1 | Viewed by 1574
Abstract
Background: Methionine (Met) is a popular nutritional supplement in humans and animals. It is routinely supplemented to pigs as L-Met, DL-Met, or DL-2-hydroxy-4-(methylthio) butanoic acid (DL-HMTBA). Methods: We investigated the effect of these Met supplements on jejunal amino acid (AA) transport in male [...] Read more.
Background: Methionine (Met) is a popular nutritional supplement in humans and animals. It is routinely supplemented to pigs as L-Met, DL-Met, or DL-2-hydroxy-4-(methylthio) butanoic acid (DL-HMTBA). Methods: We investigated the effect of these Met supplements on jejunal amino acid (AA) transport in male castrated Piétrain × Danbred pigs, also including a non-supplemented group. The mucosal-to-serosal flux of ten [14C]-labeled AAs (L-glutamine, glycine, L-leucine, L-lysine, L-Met, L-serine, L-threonine, L-tryptophan, L-tyrosine and L-valine) was investigated at two concentrations (50 µM and 5 mM). Inhibition of apical uptake by mucosal L-Met was also measured for these AAs. The intestinal expression of apical AA transporters, angiotensin-converting enzyme II and inflammation-related genes were compared with those of a previous study. Results: Except for tryptophan and lysine at 5 mM, all AA fluxes were Na+-dependent (p ≤ 0.05), and the uptake of most AAs, except glycine and lysine, was inhibited by L-Met (p < 0.001). A correlation network existed between Na+-dependent fluxes of most AAs (except tryptophan and partly glycine). We observed the upregulation of B0AT1 (SLC6A19) (p < 0.001), the downregulation of ATB0,+ (SLC6A14) (p < 0.001) and a lower expression of CASP1, IL1β, IL8, TGFβ and TNFα in the present vs. the previous study (p < 0.001). Conclusions: The correlating AAs likely share the same Na+-dependent transporter(s). A varying effect of the Met supplement type on AA transport in the two studies might be related to a different level of supplementation or a different inflammatory status of the small intestine. Full article
(This article belongs to the Section Proteins and Amino Acids)
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14 pages, 3110 KiB  
Communication
Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers
by Jennifer Haynes, Balasubramanian Palaniappan, John M. Crutchley and Uma Sundaram
Cells 2024, 13(19), 1623; https://doi.org/10.3390/cells13191623 - 28 Sep 2024
Cited by 1 | Viewed by 1902
Abstract
In the small intestine, sodium (Na) absorption occurs primarily via two apical transporters, Na-hydrogen exchanger 3 (NHE3) and Na-glucose cotransporter 1 (SGLT1). The two primary Na-absorptive pathways were previously shown to compensatorily regulate each other in rabbit and rat intestinal epithelial cells. However, [...] Read more.
In the small intestine, sodium (Na) absorption occurs primarily via two apical transporters, Na-hydrogen exchanger 3 (NHE3) and Na-glucose cotransporter 1 (SGLT1). The two primary Na-absorptive pathways were previously shown to compensatorily regulate each other in rabbit and rat intestinal epithelial cells. However, whether NHE3 and SGLT1 regulate one another in normal human enterocytes is unknown, mainly due to a lack of appropriate experimental models. To investigate this, we generated 2D enterocyte monolayers from human jejunal 3D organoids and used small interfering RNAs (siRNAs) to knock down NHE3 or SGLT1. Molecular and uptake studies were performed to determine the effects on NHE3 and SGLT1 expression and activity. Knockdown of NHE3 by siRNA in enterocyte monolayers was verified by qPCR and Western blot analysis and resulted in reduced NHE3 activity. However, in NHE3 siRNA-transfected cells, SGLT1 activity was significantly increased. siRNA knockdown of SGLT1 was confirmed by qPCR and Western blot analysis and resulted in reduced SGLT1 activity. However, in SGLT1 siRNA-transfected cells, NHE3 activity was significantly increased. These results demonstrate for the first time the functionality of siRNA in patient-derived organoid monolayers. Furthermore, they show that the two primary Na absorptive pathways in human enterocytes reciprocally regulate one another. Full article
(This article belongs to the Special Issue Organoids as an Experimental Tool)
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19 pages, 6638 KiB  
Article
Extracellular Vesicles of the Probiotic Escherichia coli Nissle 1917 Reduce PepT1 Levels in IL-1β-Treated Caco-2 Cells via Upregulation of miR-193a-3p
by Yenifer Olivo-Martínez, Sergio Martínez-Ruiz, Cecilia Cordero, Josefa Badia and Laura Baldoma
Nutrients 2024, 16(16), 2719; https://doi.org/10.3390/nu16162719 - 15 Aug 2024
Cited by 6 | Viewed by 2604
Abstract
PepT1, a proton-coupled oligopeptide transporter, is crucial for intestinal homeostasis. It is mainly expressed in small intestine enterocytes, facilitating the absorption of di/tri-peptides from dietary proteins. In the colon, PepT1 expression is minimal to prevent excessive responses to proinflammatory peptides from the gut [...] Read more.
PepT1, a proton-coupled oligopeptide transporter, is crucial for intestinal homeostasis. It is mainly expressed in small intestine enterocytes, facilitating the absorption of di/tri-peptides from dietary proteins. In the colon, PepT1 expression is minimal to prevent excessive responses to proinflammatory peptides from the gut microbiota. However, increased colonic PepT1 is linked to chronic inflammatory diseases and colitis-associated cancer. Despite promising results from animal studies on the benefits of extracellular vesicles (EVs) from beneficial gut commensals in treating IBD, applying probiotic EVs as a postbiotic strategy in humans requires a thorough understanding of their mechanisms. Here, we investigate the potential of EVs of the probiotic Nissle 1917 (EcN) and the commensal EcoR12 in preventing altered PepT1 expression under inflammatory conditions, using an interleukin (IL)-1-induced inflammation model in Caco-2 cells. The effects are evaluated by analyzing the expression of PepT1 (mRNA and protein) and miR-193a-3p and miR-92b, which regulate, respectively, PepT1 mRNA translation and degradation. The influence of microbiota EVs on PepT1 expression is also analyzed in the presence of bacterial peptides that are natural substrates of colonic PepT1 to clarify how the regulatory mechanisms function under both physiological and pathological conditions. The main finding is that EcN EVs significantly decreases PepT1 protein via upregulation of miR-193a-3p. Importantly, this regulatory effect is strain-specific and only activates in cells exposed to IL-1β, suggesting that EcN EVs does not control PepT1 expression under basal conditions but can play a pivotal role in response to inflammation as a stressor. By this mechanism, EcN EVs may reduce inflammation in response to microbiota in chronic intestinal disorders by limiting the uptake of bacterial proinflammatory peptides. Full article
(This article belongs to the Special Issue Probiotics and Their Metabolites in Human Health)
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