LIFE SCIENCES
·
2021
·
IF 5.037
Zhenjie Sun,Qian Chai,Ziying Zhang,Dexue Lu,Ziang Meng,Weihua Wu
Aims Glycemic variability has been shown to be more harmful in the development of diabetic complication than sustained chronic hyperglycemia. In this present study, we tried to reveal the effects of glycemic variability on cardiac damage in diabetic mice and investigate whether sodium-glucose cotransporter 1 (SGLT1), an important cardiac glucose transporter, functions as an important mediator in the process. Materials and methods Type 2 diabetes mellitus (DM) mice were induced by a high-fat diet and intraperitoneal injection of streptozotocin (STZ), and then glycemic variability in type 2 diabetes mellitus (GVDM) was induced by alternately injecting insulin and glucose to DM mice. In order to determine the roles of SGLT1 in GVDM mice, SGLT1 inhibition was performed using shRNA against SGLT1. The blood glucose level, the cardiac function and myocardial injury were assessed. And the expressions of SGLT1 and the activations of NLRP3/caspase-1 pathway and NF-κB in left ventricular tissues were measured. Key findings The results showed that SGLT1 was highly expressed in heart of GVDM mice compared to control and DM groups, and knockdown of SGLT1 reduced glycemic variability in GVDM mice. Moreover, glycemic variability impaired cardiac function, aggravated cardiac injury and induced NLRP3/caspase-1-mediated inflammatory response and pyroptosis. And knockdown of SGLT1 significantly attenuated the cardiac damages that induced by glycemic variability. Significance The results indicated that glycemic variability could cause cardiac damage and induce inflammatory response and pyroptosis of cardiomyocytes in diabetic mice, which could be partially blocked by SGLT1 silence.
研究领域:
内分泌学
·
心脏病学
·
糖尿病
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2021
·
IF 4.013
Weihua Wu,Qian Chai,Ziying Zhang
Recent studies have shown that blood glucose fluctuation is associated with complications of diabetes mellitus (DM). SGLT1 (sodium-dependent glucose cotransporter 1), is highly expressed in pathological conditions of heart, and is expressed in cardiomyocytes induced by high glucose. Herein, we constructed a diabetic mouse model with glucose fluctuation to investigate whether SGLT1 is involved in glucose fluctuation-induced cardiac injury. Echocardiography, histology examination, and TUNEL staining were performed to evaluate cardiac dysfunction and damage. To assess glucose fluctuation-induced oxidative stress , reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels were measured. To assess mitochondrial dysfunction, mitochondrial membrane potential (MMP), ATP content, mitochondrial respiratory chain complex activity, and expression of mitochondrial fusion and fission proteins were determined. The results indicated that diabetic mice with glucose fluctuation showed elevation of cardiac SGLT1 expression, left ventricular dysfunction , oxidative stress and mitochondrial dysfunction. Knockdown of SGLT1 could abrogate the effects of glucose fluctuation on cardiac injury. Thus, our study highlighted that SGLT1 plays an important role in glucose fluctuation induced cardiac injury through oxidative stress and mitochondrial dysfunction.
研究领域:
糖尿病
·
心脏病学
·
分子生物学
·
病理生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR BIOLOGY
·
2019
·Vol. 65
·期 7
·
IF 1.463
Lijuan Wang,Liji Huang,Nan Li,Junjun Miao,Wei Liu,Jiangyi Yu
To investigate the effect of polydatin on glucose transporter, blood glucose homeostasis and renal injury in streptozotocin (STZ)-induced diabetic rats. The in vitro inhibitory effect of polydatin on sodium-glucose cotransporter-1 (SGLT1) and 2 (SGLT2) was determined using HEK293 cells. The inhibitory effect of polydatin on GLUT1 and GLUT4 was evaluated using 3T3-L1 adipocytes. Streptozotocin-induced diabetic rats were used for this study. Fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), urea nitrogen, serum creatinine and urinary protein were determined using biochemical analyzer. Histopathological examination was performed on renal tissue. Serum levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1) and C-reactive protein (CRP) were also determined. Polydatin significantly inhibited SGLT1/2 and exhibited high selectivity for both GLUT1 and GLUT4. It significantly and dose-dependently decreased hyperglycemia, enhanced urine glucose excretion in the diabetic rats. The polydatin treatment significantly ameliorated symptoms of DN such as polyuria, polydipsia and hyperphagia. The hypoglycemic effect of polydatin was maintained throughout the treatment period. In addition,the levels of IL-1β, TNF-α, MCP-1 and CRP were significantly reduced in treated group. Treatment with polydatin significantly ameliorated most of the structural and morphological changes induced by STZ. Moreover, the levels of urinary protein, serum creatinine and urea nitrogen were significantly reduced after treatment with polydatin. As a potential dual inhibitor of SGLT1/2, polydatin has high selectivity for GLUT1 and GLUT4. Its long-term administration delays the development of DN, protects renal function and ameliorates renal tissue injury.
研究领域:
药理学
·
内分泌学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2021
·
IF 4.384
Kunkun Guo,Xin Wang,Baolin Huang,Xiaoyun Wu,Shuimei Shen,Zimin Lin,Jie Zhao,Zheng Cai
Gastrodin is the main active constituent of Tianma, a famous traditional Chinese herbal medicine. Our previous research has found that gastrodin is absorbed rapidly in the intestine by the sodium-dependent glucose transporter 1 (SGLT1). In the current report, gastrodin is the best glycoside compound absorbed via the glucose transport pathway. This study aimed to investigate the effect of the slight difference in chemical structure on the drug intestinal absorption via the glucose transport pathway. Traditional biopharmaceutical and computer-aided molecular docking methods were used to evaluate the intestinal absorption characteristics of three gastrodin analogues, namely, salicin , arbutin and 4-methoxyphenyl-β-D-glucoside (4-MG). The oil–water partition coefficient (log P ) experiments showed that the log P values of the gastrodin analogues followed the order: 4-MG > salicin > arbutin. In vitro Caco-2 cell transport experiments demonstrated that the apparent permeability coefficient ( P app ) value of arbutin was higher than those of salicin and 4-MG. In situ single-pass intestinal perfusion experiments showed that the absorption of arbutin and 4-MG was better than that of salicin and that the absorption of the three compounds in the colon was lower than that in the small intestine. Quantitative real-time polymerase chain reaction results confirmed that the SGLT1 mRNA expression in the small intestine of rats was obviously higher than that in the colon of rats. In vivo pharmacokinetic experiments demonstrated that the oral bioavailability of salicin was lower than those of arbutin and 4-MG. In vitro and in vivo experiments showed that glucose or phlorizin (SGLT1 inhibitor) could decrease the intestinal absorption of the three compounds. Contrary to the above biopharmaceutical experiments, the computer-aided molecular docking test showed that the affinity of salicin to the v SGLT receptor was stronger than those of arbutin and 4-MG. In conclusion, the SGLT1 can facilitate the intestinal absorption of salicin, arbutin and 4-MG, and the slight difference in chemical structure can affect absorption.
研究领域:
药理学
·
生物医学工程
·
中药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOLOGY
·
2023
·
IF 5.3
Weihua Wu,Qian Chai,Ziying Zhang
Glycemic variability has been considered one of the predictors of diabetes complications in patients with diabetes mellitus (DM). In this work, we evaluated whether glycemic variability induces cardiac fibrosis through regulating cardiac fibroblast activation and macrophage polarization. Moreover, we determined whether glucose transporter sodium-glucose cotransporter 1 (SGLT1) plays an important role in this process. Glycemic variability-induced mice were established using DM mice (GVDM mice), and intermittent high-glucose (IHG) treatment was used to simulate glycemic variability in RAW264.7 macrophages and cardiac fibroblasts. The short hairpin RNA for SGLT1 was used to knock down SGLT1. The results showed that glycemic variability aggravated the cardiac fibrosis in GVDM mice. Additionally, glycemic variability promoted the expression of fibrogenic cytokine and the extracellular matrix proteins in left ventricular tissues and cardiac fibroblasts. GVDM mice showed a higher incidence of macrophage infiltration and M1 polarization in left ventricular tissues. Moreover, IHG-promoted RAW264.7 macrophages tended to differentiate to M1 phenotype. SGLT1 knockdown alleviated cardiac fibrosis in GVDM mice and inhibited activations of cardiac fibroblast and macrophage M1 polarization. Our results indicated that glycemic variability aggravates cardiac fibrosis through activating cardiac fibroblast and macrophage M1 polarization, which could be partially inhibited by SGLT1 knockdown.
研究领域:
内分泌学
·
心脏病学
·
糖尿病研究
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Foods
·
2022
·Vol. 11
·期 23
·3793
·
IF 5.561
Yang Liu,Jiali Lin,Tiantian Cheng,Yangjie Liu,Fuliang Han
Anthocyanins are substances with multiple physiological activities widely present in red wine, but the influence of structure (methylation, hydroxylation, acylation, glycosylation) on the transport remains ill-defined. In the present study, Caco-2 monolayers were used as an in vitro model of the absorptive intestinal epithelium to transport different types of anthocyanin samples. Results showed that both methylation and acetylation promote the level of transport. Monoglycoside standard exhibited higher transport amount and rate compared to diglycoside standard while the transport level of the monoglycoside mixture was unexpectedly lower than that of the diglycoside mixture. Caco-2 monolayers appeared to be more capable of transporting the single standard than the mixed standard. Meanwhile, the transport of anthocyanins in Caco-2 cell model showed time- and concentration-dependent trends. Anthocyanin treatment had a greater effect on sodium-dependent glucose transporter 1 (SGLT1) mRNA expression than glucose transporter 2 (GLUT2), and significantly down-regulated the protein expression of SGLT1. Although the low bioavailability of anthocyanins requires much more research, further evidence of the role of structure is provided.Keywords:wine;anthocyanins;Caco-2 cell monolayer;absorption;SGLT1;GLUT2
研究领域:
食品科学
·
药理学
·
营养学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF FOOD SCIENCE
·
2025
·Vol. 90
·期 2
·e70046
·
IF 3.4
En-Zhong Chi,Li Wang,Jia-jian Pan,Qiang Zhang,Jiangxiong Zhu,Xin-huai Zhao
This study investigated the structural characteristics and hypoglycemic activity of polysaccharides isolated from Ganpu tea (GPT) in different storage periods. Three polysaccharide fractions (GPTPS1-E2, GPTPS3-E2, and GPTPS5-E2, representing 1, 3, and 5 years of storage, respectively, where GPTPS is Ganpu tea polysaccharides) were extracted and purified from GPT. Chemical composition analysis revealed that all fractions were predominantly acidic polysaccharides with total sugar content exceeding 90%. Monosaccharide composition analysis showed galacturonic acid as the primary component, along with significant amounts of galactose and arabinose. Molecular weight distribution showed that different fractions had distinct distributions, with GPTPS1-E2 and GPTPS3-E2 showing the highest and lowest molecular weights, respectively. Fourier-transform infrared and nuclear magnetic resonance spectroscopy provided insights into the structural characteristics of the polysaccharides. Scanning electron microscopy and X-ray diffraction analyses revealed distinct surface morphologies and crystalline structures. The hypoglycemic activity was evaluated using a Caco-2 cell model, demonstrating potential antidiabetic properties via the IRS1-GLUT2-SGLT1 axis. Comparative analysis revealed that storage time could influence the structural characteristics and hypoglycemic activity of GPTPSs, with a certain storage time generally associated with the transformation of structural characteristics related to hypoglycemic activity and the enhanced hypoglycemic effect. This research contributes to the understanding of GPTPS and their potential applications in functional foods and nutraceuticals.
研究领域:
食品科学
·
营养保健品
·
生物化学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Xiaochun Wu,Yan Xu,Dandan Zhu,Weiye Zhang,Yanjun Yang,Liang Feng,Bing Yang,Xiaobin Jia
Understanding the absorption of natural polysaccharides is crucial for advancing their development and application. However, their oral absorption mechanisms and potential applications remain unclear. In this study, Astragalus homogeneous polysaccharide (APS3a) was isolated and characterized. Based on the structural analysis, in vitro and in vivo tracking of APS3a was conducted using FITC- and Cy7 amine labeling to investigate its transport and absorption mechanisms. The results indicated that APS3a can traverse the intestinal mucus layer and is mainly absorbed in the jejunum, subsequently distributing gradually to the liver and kidneys. Further investigation of its transport mechanism revealed that APS3a undergoes energy-dependent active transport, utilizing transcellular transport pathways such as caveolin-mediated endocytosis, macropinocytosis, and sodium-glucose cotransporter 1 (SGLT1)-mediated endocytosis. Additionally, APS3a has the capacity to reversibly open tight junction proteins, facilitating transport through the paracellular transport pathway. Moreover, APS3a can function as an excipient, self-assembling with flavonoids from Astragalus Radix to form complexes, thereby enhancing the permeability and absorption of these flavonoids. These findings provide valuable insights into the oral absorption of APS3a and its potential applications, which are significant for the development and application of polysaccharides.
研究领域:
药剂学
·
分子药理学
·
生物药剂学
·
天然产物化学
·
药物代谢
·
肠道吸收
·
纳米药物递送
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Lei Liu,Zhifang Ma,Qiaoyi Han,Wei Meng,Haozheng Wang,Xinghua Guan,Qiang Shi
Restoration of blood-brain barrier (BBB) dysfunction, which drives worse outcomes of ischemic stroke, is a potential target for therapeutic opportunities, whereas a sealed BBB blocks the therapeutics entrance into the brain, making the BBB protection strategy paradoxical. Post ischemic stroke, hypoxia/hypoglycemia provokes the up-regulation of transmembrane glucose transporters and iron transporters due to multiple metabolic disorders, especially in brain endothelial cells. Herein, we develop a myricetin oligomer-derived nanostructure doped with Ce to bypass the BBB which is cointermediated by glucose transporters and iron transporters such as glucose transporters 1 (GLUT1), sodium/glucose cotransporters 1 (SGLT1), and transferrin(Tf) reporter (TfR). Moreover, it exhibits BBB restoration capacity by regulating the expression of tight junctions (TJs) through the activation of protective autophagy. The myricetin oligomers scaffold not only acts as targeting moiety but is the prominent active entity that inherits all diverse pharmacological activities of myricetin. The suppression of oxidative damage, M1 microglia activation, and inflammatory factors makes it a multitasking nanoagent with a single component as the scaffold, targeting domain and curative components.
研究领域:
神经科学
·
药理学
·
纳米技术
·
干细胞生物学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Wang Mengting,Mao Haiguang,Ke Zhijian,Wang Jinbo
Background: The hypoglycemic effects of Chinese bayberry leaves proanthocyanidins (BLPs) have been demonstrated. It is unclear, nevertheless, whether BLPs reduced postprandial blood glucose levels by regulating glucose uptake and glucose transport.
Method: This study investigated the effect of BLPs (25, 50 and 100 μg/mL) on glucose uptake and glucose transport in human intestinal epithelial cells (Caco-2 cells). The uptake of 2-Deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl) amino]-D-glucose (2-NBDG) and disaccharidases activity in Caco-2 cells were measured. The glucose transport ability across the cell membrane was determined using the established Caco-2 monolayer model. The transcript and protein levels of key glucose transporters were analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively.
Results: The results showed that BLPs significantly decreased glucose uptake and disaccharidases activity (p<0.05). Otherwise, BLPs treatment obviously inhibited glucose transport across the Caco-2 monolayer in both simulated-fast (5 mM glucose) and simulated-fed (25 mM glucose) conditions. It was attributed to the suppression of glucose transporter2 (GLUT2) and sodium-dependent glucose cotransporter 1 (SGLT1) by BLPs. BLPs were found to significantly downregulated the transcript level and protein expression of glucose transporters (p<0.05). Meanwhile, the mRNA expression of phospholipase C (PLC) and protein kinase C (PKC) involved in the signaling pathway associated with glucose transport were decreased by BLPs.
Conclusion: These results suggested that BLPs inhibited intestinal glucose transport via inhibiting the expression of glucose transporters. It indicated that BLPs could be potentially used as a functional food in the diet to modulate postprandial hyperglycemia.
研究领域:
药理学
·
营养学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2021
·Vol. 476
·期 6
·2479-2489
·
IF 3.396
Chai Qian,Meng Ziang,Lu Dexue,Zhang Ziying,Liu Meili,Wu Weihua
Cardiomyocyte death is an important pathogenic process in cardiac complications of diabetes. Diabetic patients often suffer glycemic variability. Pyroptosis is a form of programmed cell death triggered by inflammasomes and related with caspase-1 and gasdermin D activation. The present study was designed to examine the effects of intermittent high glucose simulating glycemic variability on the pyroptosis of cardiomyocytes in vitro. Rat H9C2 cardiomyocytes were incubated with normal glucose (NG), constant high glucose (CHG) and intermittent high glucose (IHG). Results showed that compared to CHG treatment, IHG further inhibited cell proliferation and promoted cell death of H9C2 cardiomyocytes. In addition, IHG upregulated higher levels of the expressions of inflammasome NLR family pyrin domain containing 3 (NLRP3) and adaptor protein apoptosis-associated speck-like protein containing CARD domain (ASC) and increased higher levels of activated caspase-1 and gasdermin D than CHG treatment. Moreover, the production of reactive oxygen species (ROS) and activation of NF-κB that is induced by IHG were significantly higher than that induced by CHG. Knockdown of sodium–glucose cotransporters 1 (SGLT1) in H9C2 cardiomyocytes was performed and the effects of SGLT1 on IHG-induced pyroptosis was evaluated. The results demonstrated that knockdown of SGLT1 partially reduced IHG-induced pyroptosis, ROS generation and NF-κB activation. Our results indicated that IHG is harmful to cardiomyocytes and it might be partially because of the SGLT1-depedent pyroptosis in cardiomyocytes.
研究领域:
心脏病学
·
糖尿病
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Baolin Huang,Zimin Lin,Zhenzhen Chen,Jiasheng Chen,Birui Shi,Jingjing Jia,Yuan Li,Yueqing Pan,Yuntao Liang,Zheng Cai
Designing oral drug delivery systems using intestinal glucose transporters (IGTs) may be one of the strategies for improving oral bioavailability of drugs. However, little is known about the biological factors affecting the drug transport capacity of IGTs. Gastrodin is a sedative drug with a structure very similar to glucose. It is a highly water-soluble phenolic glucoside. It can hardly enter the intestine through simple diffusion but exhibits good oral bioavailability of over 80%. We confirmed that gastrodin is absorbed via the intestinal glucose transport pathway. It has the highest oral bioavailability among the reported glycosides’ active ingredients through this pathway. Thus, gastrodin is the most selective drug substrate of IGTs and can be used to evaluate the drug transport capacity of IGTs. Obviously, strain is one of the main biological factors affecting drug absorption. This study firstly compared the drug transport capacity of IGTs between SD rats and Wistar rats and between C57 mice and KM mice by pharmacokinetic experiments and single-pass intestinal perfusion experiments of gastrodin. Then, the sodium-dependent glucose transporter type 1 (SGLT1) and sodium-independent glucose transporters type 2 (GLUT2) in the duodenum, jejunum, ileum and colon of these animals were quantified using RT-qPCR and Western blot. The results showed that the oral bioavailability of gastrodin in Wistar rats was significantly higher than in SD rats and significantly higher in KM mice than in C57 mice. Gastrodin absorption significantly differed among different intestinal segments in SD rats, C57 mice and KM mice, except Wistar rats. RT-qPCR and Western blot demonstrated that the intestinal expression distribution of SGLT1 and GLUT2 in SD rats and C57 mice was duodenum ≈ jejunum > ileum > colon. SGLT1 expression did not differ among different intestinal segments in KM mice, whereas the intestinal expression distribution of GLUT2 was duodenum ≈ jejunum ≈ ileum > colon. However, the expression of SGLT1 and GLUT2 did not differ among different intestinal segments in Wistar rats. It was reported that the intestinal expression distribution of SGLT1 and GLUT2 in humans is duodenum > jejunum > ileum > colon. Hence, the intestinal expression distribution of SGLT1 and GLUT2 of SD rats and C57 mice was more similar to that in humans. In conclusion, the drug transport capacity of IGTs differs in different strains of rats and mice. SD rats and C57 mice are more suitable for evaluating the pharmacokinetics of glycosides’ active ingredients absorbed via the intestinal glucose transport pathway.
研究领域:
药理学
·
药物递送系统
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）