CELLULAR AND MOLECULAR LIFE SCIENCES
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2024
·Vol. 81
·期 1
·1-17
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IF 6.2
Li Long,Liu Huimin,Chai Quanyou,Wei Junyi,Qin Yuqiao,Yang Jingyao,Liu He,Qi Jia,Guo Chunling,Lu Zhaoyang
Vascular calcification is a complication that is frequently encountered in patients affected by atherosclerosis, diabetes, and chronic kidney disease (CKD), and that is characterized by the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). At present, there remains a pressing lack of any effective therapies that can treat this condition. The sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin (DAPA) has shown beneficial effects in cardiovascular disease. The role of this inhibitor in the context of vascular calcification, however, remains largely uncharacterized. Our findings revealed that DAPA treatment was sufficient to alleviate in vitro and in vivo osteogenic transdifferentiation and vascular calcification. Interestingly, our study demonstrated that DAPA exerts its anti-calcification effects on VSMCs by directly targeting SGLT2, with the overexpression of SGLT2 being sufficient to attenuate these beneficial effects. DAPA was also able to limit the glucose levels and NAD + /NADH ratio in calcified VSMCs, upregulating sirtuin 1 (SIRT1) in a caloric restriction (CR)-dependent manner. The SIRT1-specific siRNA and the SIRT1 inhibitor EX527 attenuated the anti-calcification effects of DAPA treatment. DAPA was also to drive SIRT1-mediated deacetylation and consequent degradation of hypoxia-inducible factor-1α (HIF-1α). The use of cobalt chloride and proteasome inhibitor MG132 to preserve HIF-1α stability mitigated the anti-calcification activity of DAPA. These analyses revealed that the DAPA/SGLT2/SIRT1 axis may therefore represent a viable novel approach to treating vascular calcification, offering new insights into how SGLT2 inhibitors may help prevent and treat vascular calcification. Graphical abstract Dapagliflozin attenuated vascular smooth muscle cells osteogenic transdifferentiation and vascular calcification through the SIRT1-mediated deacetylation and degradation of HIF-1α in a manner dependent on caloric restriction.
研究领域:
心血管疾病
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糖尿病
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慢性肾病
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分子生物学
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药理学
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DOI
PubMed
高影响因子
MOLECULAR DIVERSITY
·
2025
·
IF 3.8
Qin Fei,Zeng Huicong,Zhou Li,Zhou Zhenhua,Mao Yongxin,Zeng Youyan,Guo Rongxiang,Chen Kaixian,Zhao Dongyu,Yao Weiwei,Zhang Bin,Zhou Qian,Li Bo
The sodium–glucose co-transporter 2 (SGLT2) plays an important role in mediating glucose reabsorption within the renal filtrate and regulating blood glucose levels, which makes it a well-known target for diabetes mellitus. A number of SGLT2 inhibitors (SGLT2i) have been established as important antidiabetic drugs, and research on new SGLT2i with high affinity is ongoing. Herein, 101 compounds were screened from a compound library (approximately 16,000 compounds) using a virtual screening workflow that integrated various docking programs, pharmacophore modeling, and druggability filter. To verify the results of virtual screening, we established a HK-2 cell model with d-glucose derivative 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) for measuring glucose uptake via SGLT2. 12 candidate compounds were selected and purchased for subsequent experimental validation. Among these, 3 non-glycoside compounds significantly inhibited the 2-NBDG uptake in a dose-dependent manner and their IC 50 values for SGLT2 were 71.43 μM, 72.66 μM, and 91.44 μM, respectively. Mechanism studies demonstrated that all 3 compounds significantly downregulated SGLT2 level and activated silent information regulator 1 (SIRT1) expression in high-glucose-induced cell injury models. These findings confirmed the ability of these compounds to bind to SGLT2 and also revealed their potential mechanisms in regulating oxidative stress and metabolism. Furthermore, molecular dynamics simulation indicated the high binding stability of SGLT2 and 3 compounds complexes during a 100-ns simulation period. In conclusion, our results identified 3 potential SGLT2i and preliminarily elucidated their mechanism of action, which lays the foundation for the development of novel and potent non-glycoside SGLT2i in future. Graphical
研究领域:
药理学
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药物化学
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分子生物学
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糖尿病研究
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转化医学
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计算机辅助药物设计
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PubMed
高影响因子
CARDIOVASCULAR RESEARCH
·
2023
·
IF 10.8
Chen An,Lan Zirong,Li Li,Xie Luting,Liu Xiaoyu,Yang Xiulin,Wang Siyi,Liang Qingchun,Dong Qianqian,Feng Liyun,Li Yining,Ye Yuanzhi,Fu Mingwei,Lu Lihe,Yan Jianyun
AimsVascular calcification is prevalent in pathological processes such as diabetes, chronic kidney disease (CKD) and atherosclerosis, but effective therapies are still lacking by far. Canagliflozin (CANA), an SGLT2 inhibitor, has been approved for the treatment of type 2 diabetes mellitus and exhibits beneficial effects against cardiovascular disease. However, the effect of CANA on vascular calcification remains unknown. In this study, we hypothesize that CANA protects against vascular calcification.Methods and ResultsMicro-computed tomography analysis and alizarin red staining revealed that CANA treatment prevented aortic calcification in CKD rats and in VitD3-overloaded mice. Moreover, CANA alleviated calcification of rat and human arterial rings. Alizarin red staining revealed that calcification of rat and human vascular smooth muscle cells (VSMCs) was attenuated by CANA treatment and this phenomenon was confirmed by calcium content assay. In addition, CANA downregulated the expression of osteogenic differentiation markers Runx2 and BMP2. Of interest, qPCR and western blot analysis revealed that CANA downregulated the expression of NLRP3, and the downstream signaling molecules Caspase-1 and IL-1β in VSMCs as well. Both NLRP3 inhibitor MCC950 and knockdown of NLRP3 by siRNA independently resulted in decreased calcification of VSMCs. By contrast, activation of NLRP3 exacerbated VSMC calcification, and this effect was prevented by addition of CANA.ConclusionsOur study for the first time demonstrates that CANA exerts a protective effect on vascular calcification at least partially via suppressing NLRP3 signaling pathway. Therefore, supplementation of CANA as well as inhibition of NLRP3 inflammasome presents a potential therapy for vascular calcification.
研究领域:
药理学
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心血管疾病
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糖尿病
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肾病
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF OBESITY
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2026
·
IF 3.8
Li Qiuyu,Li Mengya,Zhou Jie,Huang Jianling,Xu Xiaohui,Zhang Zhongxiang,Jiang Longyang,Huang Yilan,Yang Xuping
Background Adipose lipolysis, a process involving the degradation of triglycerides and the release of fatty acids and glycerol, is an important biological event in lipid metabolism. Canagliflozin (Cana), an oral antidiabetic drug, regulates blood glucose by inhibiting sodium-glucose cotransporter 2 (SGLT2) in renal tubules and has also been shown to improve lipid metabolism in adipocytes. This study aims to determine whether Cana directly affects adipose lipolysis and to explore the underlying mechanistic pathways. Method Primary mature adipocytes and differentiated preadipocytes isolated from the epididymal fat pads of Sprague-Dawley rats were used as in vitro models. The effects of Cana on glycerol release and lipase activity were evaluated using ELISA and Western blot analyses. Results Cana treatment directly inhibited basal glycerol release and lipase activity in both primary adipocytes and topically administered adipose tissue, achieving a dose-dependent 35% to 65% suppression of lipolysis. This was associated with a 2.3-fold decrease in the level of HSL phosphorylated at the Ser660 site. Using differentiated adipocytes derived from the human Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell line, we found that Cana significantly attenuated glycerol release (~32% to 53% reductions) induced by lipolysis. Moreover, Cana exerted antilipolytic effects in models of both acute (isoprenaline-induced) and chronic (tumor necrosis factor-α-induced) lipolysis. Mechanistically, the antilipolytic effect of Cana was mediated through activation of the PI3K/AKT pathway and reduction of cAMP production. Conclusion In conclusion, Cana regulates adipocyte lipolysis via an SGLT2-independent signaling pathway, which enhances our understanding of its role in modulating lipid metabolism.
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高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2023
·
IF 7.3
Guang-Jing Feng,Yang-Fan Guo,Yuming Tang,Min Li,Yufei Jia,Zhimeng Li,Shuangshuang Wang,Hongmei Liu,Yuzhou Wu,Hai Dong
In this study, we have investigated the potential of two classes of thioglucoside analogues of gliflozins as antidiabetic drugs, one with substitutions of S-atoms in meta-positions (similar to C-glucoside SGLT2 inhibitors, TAGs A, B, and C) and the other with substitutions of S-atoms in ortho-positions (similar to O-glucoside SGLT2 inhibitors, TAGs D, E, F, and G). These TAGs were confirmed to show good stability against β-glucosidase and to have no acute toxicity to cultured cells. Most importantly, TAGs D, E, F, and G all showed high inhibitory activity against SGLT2 (IC50: 2.0–5.9 nM) and thus have great potential to be developed as new gliflozin drugs. Compared with the synthesis of C-glucoside gliflozins, the synthesis of TAGs is simple, efficient, and associated with low costs, high yields, and very mild reaction conditions.
研究领域:
药理学
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药物化学
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生物化学
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PubMed
高影响因子
PLoS One
·
2026
·Vol. 21
·期 6
·e0350400
·
IF 2.8
Xin Zhou,Yanru Deng,Caihui Guo,Ying Li,Yuhao Fu,Zhi Wang,Zhanjun Dong
Background
Patients with type 2 diabetes mellitus (T2DM) usually accompany with the occurrence of high blood pressure, necessitating a combination of treatments. This includes sodium-glucose co-transporter 2(SGLT2) inhibitors like empagliflozin, ertugliflozin, and henagliflozin, and antihypertensives like telmisartan. Both classes interact with transporters like P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), with telmisartan further inhibiting several, including organic anion transporting poly-peptide (OATP) 1B1/1B3.
Objective
Despite their common use, pharmacokinetic interactions between these drugs remain underexplored. This study aims to investigate the potential pharmacokinetic interaction between three specific SGLT2 inhibitors and telmisartan.
Methods
Rats were divided into twelve groups, with six rats per group, and received different combinations of empagliflozin, ertugliflozin, henagliflozin, and telmisartan. Drug concentrations were measured using ultra-performance liquid chromatography-tandem mass spectrometry, and mRNA expressions through quantitative reverse transcription polymerase chain reaction (RT-qPCR).
Results
Our study manifested that telmisartan increased the plasma concentration-time curves (AUC 0-t and AUC 0–∞ ) and the maximum plasma concentrations (C max ) of empagliflozin, whereas the apparent clearance (CL z/F ) and apparent volume of distribution (V z ) significantly decreased(all p ＜ 0.05). Similarly, telmisartan increased the AUC 0-t , AUC 0-∞ and C max of henagliflozin and decreased the CL z/F (all p ＜ 0.05). When coadministered with ertugliflozin or henagliflozin, the AUC 0-t and AUC 0–∞ of telmisartan decreased significantly and the CL z/F increased significantly(all p ＜ 0.05). Furthermore, PCR results demonstrated that telmisartan decreased the expression of BCRP expression in liver, intestines and kidney, P-gp expression in the intestines and kidney and OATP1B2 expression in liver tissue.
Conclusions
Our findings highlight the importance of these drug interactions, which could inform dose adjustments to enhance safety in patients with T2DM and hypertension.
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
·
IF 5.7
Wanxian Wang,Yanfang Liu,Dian Liu,Han Zhou,Yan Li,Wenjie Yuan,Suowen Xu,Jixia Wang,Xinmiao Liang,Jianping Weng
Pueraria lobata (Willd.) Ohwi, known as kudzu and used as a “longevity powder” in China, is an edible plant which is rich in flavonoids and believed to be useful for regulating blood sugar and treating diabetes, although the modes of action are unknown. Here, a total of 53 flavonoids including 6 novel compounds were isolated from kudzu using multidimensional preparative liquid chromatography. The flavonoid components were found to lower blood sugar levels, promote urine sugar levels in mice, and reduce the urine volume. Molecular docking and in vitro assays suggested that the antidiabetic effect of kudzu was attributed to at least three targets: sodium-dependent glucose transporter 2 (SGLT2), protein tyrosine phosphatase-1B (PTP1B), and alpha-glucosidase (AG). This study suggests a possible mechanism for the antidiabetic effect that may involve the synergistic action of multiple active compounds from kudzu.
研究领域:
药理学
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生物化学
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植物科学
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PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2026
·Vol. 40
·期 3
·e70366
·
IF 1.7
Zhiyuan Li,Qing Shao,Hongqun Qiao
A sensitive and robust HPLC-MS/MS method was developed and validated for the simultaneous determination of YWS22026 and its major metabolite M3 in rat plasma using protein precipitation. Chromatographic separation was achieved on a Shim-pack Scepter C18 column (4.6 × 50 mm, 3 μm) with a gradient elution program (mobile phase A: 0.2% formic acid in water; mobile phase B: methanol) at a flow rate of 0.9 mL/min. Detection was performed via positive electrospray ionization (ESI+) in multiple reaction monitoring (MRM) mode. The method demonstrated excellent specificity, accuracy (relative error, %RE < 9.1%), precision (relative standard deviation, %RSD < 9.9%), and linearity (5–2000 ng/mL for both analytes). The lower limit of quantification (LLOQ) was 5 ng/mL. Stability studies confirmed that plasma samples remained stable under various storage conditions (at room temperature for 10 h, −20°C for 22 days, three freeze–thaw cycles, and 4°C autosampler storage for 73 h). This validated method was successfully applied to a 26-week concomitant toxicokinetic study in Sprague–Dawley rats, which revealed significant sex-related differences in exposure for both YWS22026 and M3. These findings provide valuable insights for informing the safety assessment of YWS22026 in subsequent clinical trials.
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高影响因子
BIOFACTORS
·
2023
·
IF 6
Zichen Gui,Jiawen Wang,Yue Zhang,Binbin Wan,Zhiqiang Ke,Zhanhong Ren,Xiaosong Yang,Min Lei,Xiying Guo,Xiufen Liu,Changhan Ouyang,Ninghua Wu,Qingjie Chen
Cognitive impairment is increasingly recognized as an important comorbidity of diabetes progression; however, the underlying molecular mechanism is unclear. Dapagliflozin, an inhibitor of sodium-glucose co-transporter 2 (SGLT2), has shown promising effects against diabetes in rodent experiments and human clinical assays. This study aimed to determine the underlying mechanism and examine the effect of dapagliflozin on diabetic cognitive impairment. To create an in vivo model of diabetic cognitive impairment, streptozotocin (STZ)-induced diabetic mice were used. Dapagliflozin was administered to mice for 8 weeks. The context fear condition and Morris water maze test was used to evaluate mice's behavioral change. Western blotting was used to evaluate protein expression. Hematoxylin and eosin (HE) and Nissl staining were applied to monitor morphological and structural changes. Congo red staining was performed to identify the formation of senile plaques. Mitochondria morphology was examined using a transmission electron microscope, and blood flow in the mouse cerebral cortex was measured using a laser Doppler imaging assay. Comparison to the diabetes mellitus (DM) group, the dapagliflozin group had lower glucose levels. Behavioral studies have shown that dapagliflozin can restore memory deficits in diabetic mice. The murky cell membrane edges and Nissl bodies more difficult to identify in the DM group were revealed by HE and Nissl staining, which were both improved by dapagliflozin treatment. Dapagliflozin inhibited the progression of Aβ generation and the reduced cerebral blood flow in the DM group was rescued. After dapagliflozin treatment, damaged mitochondria and lack of SGLT2 in the hippocampus and cortex of diabetic mice were repaired. Diabetes-induced cognitive dysfunction was attenuated by dapagliflozin and the effect was indirect rather than direct.
研究领域:
药理学
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神经科学
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糖尿病研究
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DOI
PubMed
高影响因子
PHYSIOLOGY & BEHAVIOR
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2023
·
IF 2.9
Bo Pang,Lu-Lu Zhang,Bin Li,Feng-Xian Sun,Zhi-Da Wang
An antidiabetic agent sodium glucose co-transporter 2 (SGLT2) inhibitor ertugliflozin has been revealed to bind to catalytic anionic site of acetylcholinesterase (AChE), which is considered to be associated with the cognitive decline in neurodegenerative diseases, such as Alzheimer's disease (AD). The aim of the present study was thus to probe the effect of ertugliflozin on AD. Intracerebroventricular injection of streptozotocin (STZ/i.c.v) (3 mg/kg) was done bilaterally in male Wistar rats at 7–8 weeks of age. Two treatment doses (5 mg/kg and 10 mg/kg) of ertugliflozin were given intragastrically to STZ/i.c.v-induced rats for 20 days daily for behavioral assessment. Biochemical estimations of cholinergic activity, neuronal apoptosis, mitochondrial function and synaptic plasticity were performed. Behavioral results with ertugliflozin treatment revealed attenuation of cognitive deficit. Ertugliflozin also inhibited hippocampal AChE activity, downregulated pro-apoptotic marker expression, as well as mitigated mitochondrial dysfunction and synaptic damage in STZ/i.c.v rats. Importantly, we found that the hyperphosphorylation of tau in the hippocampus of STZ/i.c.v rats was decreased after oral administration of ertugliflozin, which was accompanied by decreased Phospho.IRS-1 Ser307 /Total.IRS-1 ratio and increased Phospho.Akt Ser473 /Total.Akt and Phospho.GSK3β Ser9 /Total.GSK3β ratios. Our results indicated that treatment with ertugliflozin reversed AD pathology, which may be associated with inhibition of insulin signaling disruption-induced tau hyperphosphorylation.
研究领域:
神经科学
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药理学
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神经退行性疾病
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认知障碍
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PubMed
高影响因子
Journal of the American Heart Association
·
2022
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IF 6.106
Xin‐Lin Zhang,Ting‐Yu Wang,Zheng Chen,Hong‐Wei Wang,Yong Yin,Lian Wang,Yong Wang,Biao Xu,Wei Xu
BackgroundHeart failure with preserved ejection fraction (HFpEF) remains an increasing public health problem with substantial morbidity and mortality but with few effective treatments. A novel inflammatory mechanism has been proposed, but the inflammatory signals promoting the development of HFpEF remain greatly unknown.Methods and ResultsSerum of patients with HFpEF was collected for measurement of circulating neutrophils and markers of neutrophil extracellular traps (NETs). To induce HFpEF phenotype, male C57BL/6 mice underwent uninephrectomy, received a continuous infusion of d‐aldosterone for 4 weeks, and maintained on 1.0% sodium chloride drinking water. Heart tissues were harvested, immune cell types determined by flow cytometry, NETs formation by immunofluorescence, and western blotting. Differentiated neutrophils were cultured to investigate the effect of HMGB1 (high mobility group protein B1) and SGLT2 (sodium‐glucose cotransporter‐2) inhibitor on NETs formation in vitro. Circulating neutrophils and NETs markers are elevated in patients with HFpEF, as are cardiac neutrophils and NETs formation in HFpEF mice. NETs inhibition with deoxyribonuclease 1 in experimental HFpEF mice reduces heart macrophages infiltration and inflammation and ameliorates cardiac fibrosis and diastolic function. Damage‐associated molecular pattern HMGB1 expression is elevated in cardiac tissue of HFpEF mice, and HMGB1 inhibition reduces heart neutrophil infiltration and NETs formation and ameliorates diastolic function. Lastly, SGLT2 inhibitor empagliflozin down‐regulates heart HMGB1 expression, attenuates NETs formation and cardiac fibrosis, and improves diastolic function in HFpEF mice.ConclusionsNETs contribute to the pathogenesis of HFpEF, which can be ameliorated by HMGB1 inhibition and SGLT2 inhibitors. Thus, HMGB1 and NETs may represent novel therapeutic targets for the treatment of HFpEF.
研究领域:
心脏病学
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免疫学
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药理学
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PubMed
高影响因子
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