BIOLOGICAL & PHARMACEUTICAL BULLETIN
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2020
·Vol. 43
·期 7
·1027-1034
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IF 1.863
Mingzhi Luo,Peili Yu,Kai Ni,Yang Jin,Lei Liu,Jingjing Li,Yan Pan,Linhong Deng
Excessive contraction of airway smooth muscle cells (ASMCs) is a hallmark feature of asthma. Intriguing, the activation of bitter taste receptor (TAS2R) in ASMCs can relax ASMCs. However, there is a lack of potent TAS2R agonists that can be used in asthma therapies since those tested agonists cannot relax ASMCs at the dose below a few hundred micromolar. Considering that sanguinarine (SA) is a bitter substance often used in small doses for the treatment of asthma in folk medicine, the present study was to determine the rapid relaxation effect of SA on ASMCs and to reveal the underlying mechanisms associated with TAS2R signaling. Here, cell stiffness, traction force, calcium signaling, cAMP levels, and the mRNA expression were evaluated by using optical magnetic twisting cytometry, traction force microscopy, Fluo-4/AM labeling, enzyme-linked immunosorbent assay (ELISA), and quantitative (q)RT-PCR, respectively. We found that 0.5 µM SA immediately decreased cell stiffness and traction force, which is comparable with the effect of 5 µM isoproterenol. In addition, 0.5 µM SA immediately increased intracellular free calcium concentration ([Ca2+]i) and decreased the mRNA expression of contractile proteins such as calponin and α-smooth muscle actin after the treatment for 24 h. Furthermore, SA-mediated decrease in cell stiffness/traction force and increase in [Ca2+]i were significantly blunted by inhibiting the TAS2Rs signaling. These findings establish the rapid relaxation effect of SA at low concentration (<1 µM) on cultured ASMCs depending on TAS2R signaling, indicating that SA might be developed as a useful bronchodilator in asthma therapy.
研究领域:
药理学
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呼吸医学
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细胞生物学
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PubMed
高影响因子
Nature Communications
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2025
·Vol. 16
·期 1
·1-12
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IF 15.7
Tian Ran,Zhang Tong,Dong Hao,Seim Inge,Yang Guang
Blubber is a hydrostatic pressure-resistant and insulating vascularized layer of subcutaneous adipose tissue beneath the skin found in cetaceans, pinnipeds, and sirenians. Little is known about the molecular genetics of blubber formation, and it is unclear when the blubber observed today began to develop during the evolution of the marine mammal groups. Here we screen for genes lost in cetaceans and find that ADRB3 (β 3 -adrenergic receptor), a gene essential for adipose tissue lipolysis and thermogenesis, acquired inactivating mutations in crown cetaceans 20 million years after its downstream effector uncoupling protein 1 ( UCP1 ) gained partial loss-of-function mutations in semi-aquatic stem cetaceans. Both in vivo and in vitro experiments indicate that cetacean ADRB3 is not functional, suggesting that crown cetaceans abolished cold-induced non-shivering thermogenesis to favor lipid storage for thermal insulation. Our study supports that cetacean blubber evolved stepwise along their transition to an aquatic environment and implies that ADRB3 loss was critical for the radiation and dispersal of toothed and baleen whales.
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高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2025
·
IF 8.2
Longyan Yang,Ruili Yin,Ziyu Shan,Anqi Feng,Kun Li,Yan Wang,Ke Yu,Yongsong Xu,Lin Mao,Jianan Lang,Baoyu Zhang,Dong Zhao
Aims Overweight and obesity are closely associated with hyperuricemia (HUA). However, the effect of obesity-induced adipokine on the level of serum uric acid (UA) has not been fully elucidated. This study aimed to determine the role of adipokine in the pathogenesis of HUA. Methods Omental adipose tissues from HUA patients with obesity were collected for data- independent acquisition (DIA) proteomics analysis, and the secreted protein angiopoietin-like protein (ANGPTL2) was identified and further validated via Western blot and ELISA. Angptl2 knockout (ko) and adipocyte-specific ANGPTL2 overexpression mice were generated to establish HUA models. HK2 cells and primary renal tubule epithelial cells (RTECs) were applied to induce HUA cell model and treated with recombinant human ANGPTL2 or supernatants derived from C3H10 cells differentiated into adipocytes. Result ANGPTL2 levels were significantly elevated in the omental adipose tissue from HUA with obesity patients compared to control participants. Circulating ANGPTL2 levels were also increased, and positively correlated with serum UA levels, especially in male participants. Plasma UA levels were significantly decreased in Angptl2 ko mice, coinciding with up-regulated expression of ATP binding cassette subfamily G member 2 (ABCG2) and down-regulated glucose transporter 9 (GLUT9) in renal tissue. However, plasma UA levels were significantly increased, accompanied by decreased ABCG2 expression and enhanced GLUT9 expression after adipocyte-specific ANGPTL2 overexpression. Furthermore, adipocyte- derived ANGPTL2 increased UA level in cell supernatants through the inhibition of protein kinase B (AKT)/ABCG2 signaling in RTECs and HK2 cells. Conclusion Adipokine ANGPTL2 levels were significantly elevated in HUA patients with obesity. Circulating ANGPTL2 concentrations were independently associated with serum UA levels, particularly in obese males. Adipocyte-secreted ANGPTL2 promoted the level of UA through AKT/ABCG2 signaling in renal tubular cells. These findings establish ANGPTL2 as a critical adipokine linking obesity to hyperuricemia and suggest its potential as a novel therapeutic target for HUA.
研究领域:
内分泌学
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代谢研究
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分子生物学
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PubMed
高影响因子
BMC Complementary Medicine and Therapies
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2021
·Vol. 21
·期 1
·1-11
·
IF 0
Lou Hai-xia,Fu Wen-cheng,Chen Jia-xiang,Li Tian-tian,Jiang Ying-ying,Liu Chun-hui,Zhang Wen
Background Alisol A 24-acetate (AA-24-a), one of the main active triterpenes isolated from the well-known medicinal plant Alisma orientale (Sam.) Juz., exhibits multiple biological activities including hypolipidemic activity. However, its effect on lipid metabolism in adipocytes remains unclear. The present study aimed to clarify the effect of AA-24-a on adipocyte lipolysis and to determine its potential mechanism of action using 3 T3-L1 cells. Methods We assayed the release of glycerol into culture medium of 3 T3-L1 cells under treatment with AA-24-a. Protein and mRNA expression and phosphorylation levels of the main lipases and kinases involved in lipolysis regulation were determined by quantitative polymerase chain reaction and western blotting. Specific inhibitors of protein kinase A (PKA; H89) and extracellular signal-regulated kinase (ERK; PD98059), which are key enzymes in relevant signaling pathways, were used to examine their roles in AA-24-a-stimulated lipolysis. Results AA-24-a significantly stimulated neutral lipolysis in fully differentiated adipocytes. To determine the underlying mechanism, we assessed the changes in mRNA and protein levels of key lipolysis-related genes in the presence or absence of H89 and PD98059. Both inhibitors reduced AA-24-a-induced lipolysis. Moreover, pretreatment with H89 attenuated AA-24-a-induced phosphorylation of hormone-sensitive lipase at Ser660, while pretreatment with PD98059 attenuated AA-24-a-induced downregulation of peroxisome proliferator-activated receptor-γ and perilipin A. Conclusions Our results indicate that AA-24-a promoted neutral lipolysis in 3 T3-L1 adipocytes by activating PKA-mediated phosphorylation of hormone-sensitive lipase and ERK- mediated downregulation of expression of perilipin A.
研究领域:
药理学
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细胞生物学
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分子生物学
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PubMed
JOURNAL OF CELLULAR PHYSIOLOGY
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2019
·Vol. 234
·期 12
·21860-21876
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IF 4.522
Kaimin Wu,Ruiyi Zhang,Yanhui Lu,Lulu Wen,Yanfei Li,Ranran Duan,Yaobing Yao,Yanjie Jia
Mesenchymal stem cells (MSCs) transplantation has emerged as a potential therapeutic approach for Alzheimer's disease (AD). However, the poor proliferation capacity and low survival rate of engrafted MSCs in the hostile microenvironment of AD limit their therapeutic efficiency. Lin28B is a conserved RNA-binding protein associated with cell self-renewal and survival. The purpose of the present study was to explore whether lin28B might influence the functions of implanted MSCs and strengthen their neuroprotective potential in AD. A gain-of-function assay was used to upregulate lin28B expression in MSCs by lentiviral transfection. Our in vitro results indicated that lin28B promoted MSCs proliferation and migration, and protected MSCs against Aβ1–42-induced cell death by upregulating insulin-like growth factor-2 (IGF-2). Blockage of IGF-2 partially abrogated the above effects of lin28B. After intracerebroventricular injection into amyloid precursor protein/presenilin 1 mice, implanted MSCs were monitored using bioluminescence imaging. We observed that administration of MSCs transfected with lin28B significantly stimulated their proliferation and prolonged cell retention after delivery. Moreover, administration of the transfected MSCs markedly mitigated cognitive deficits, promoted amyloid plaque clearance, decreased the activation of microglia, and reduced neuronal cell death. The data above confirmed our hypothesis that lin28B is a crucial modulator determining the fate of transplanted MSCs by regulating IGF-2-associated pathways and thereby enhancing their protective effects against AD.
研究领域:
神经科学
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干细胞生物学
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分子生物学
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神经退行性疾病
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PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2019
·
IF 6.361
Kun Feng,Chen Li,Yun-Shan Wei,Min-Hua Zong,Hong Wu,Shuang-Yan Han
Advances in pharmaceutical technology have promoted the development of colon-targeted delivery system for oral administration of bioactive peptides or proteins to enhance their bioavailability. In this study, a multi-unit nanofiber mat was fabricated by coaxial electrospinning and its feasibility as the colon-targeted delivery system for a bioactive peptide, salmon calcitonin (sCT), was investigated. Sodium alginate and sCT-loaded liposome coated with pectin served as the shell layer and core layer, respectively. An in vitro study demonstrated that the encapsulated sCT was released in a sustained and colon-targeted way. Analysis using different mathematical models showed that release followed a complex mechanism. In addition, greater amounts of sCT were released from the core-shell nanofiber mat into simulated colon fluid (SCF) than was released from a uniaxial nanofiber mat (65.2% vs. 47.8%). The use of a core-shell nanofiber mat further alleviated the burst release of sCT into simulated gastric and intestinal fluid (SGF and SIF), demonstrating the superiority of a multi-unit vehicle for colon-targeted delivery of sCT. Furthermore, 88% of the bioactivity of encapsulated sCT was retained. This multi-unit vehicle offers a better-designed vehicle for the colon-targeted sustained release of bioactive peptides or proteins and, thus, should improve oral bioavailability.
研究领域:
药剂技术
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纳米技术
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药物递送系统
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生物药剂学
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2021
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IF 5.279
Jing Zhou,Ji Zhang,Jiayi Li,Yiqiu Guan,Ting Shen,Fu Li,Xueqin Li,Xiaojun Yang,Weicheng Hu
Ginsenoside F2 (GF2) is a protopanaxdiol saponin from Panax ginseng leaves and possesses many potential pharmacological properties. GF2 may prevent obesity by directly binding to the peroxisome proliferator-activated receptor-γ (PPARγ) and inhibiting adipocyte differentiation. However, the mechanism by which GF2 alleviates obesity is unknown. We therefore explored the anti-adipogenesis and anti-obesity effects of GF2 in vitro and in vivo. GF2 inhibited differentiation and reduced the triglyceride (TG) content of 3T3-L1 preadipocytes in the early stage of adipogenesis. Administration of GF2 (50 and 100 mg/kg) to obese mice for 4 weeks reduced the body weight gain, weight of adipose tissues, adipocyte size, and total cholesterol, TG, and AST levels in serum. RNA sequencing and real-time quantitative PCR indicated that GF2 decreased the expression levels of adipokines, including PPARγ, fatty acid synthase, and adiponectin. KEGG enrichment and western blot analyses demonstrated that GF2 accelerated the phosphorylation of AMPK and ACC in vitro and in vivo. Moreover, GF2 promoted the biosynthesis of mitochondria in 3T3-L1 adipocytes and increased the expression of antioxidant enzymes such as SOD and GSH-Px in the liver of obese mice. Therefore, GF2 suppressed adipogenesis and obesity by regulating the expression of adipokines and activating the AMPK pathway. Hence, the findings suggest that GF2 may have potential therapeutic implications to treat obesity.
研究领域:
药理学
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分子生物学
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细胞生物学
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代谢
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PubMed
高影响因子
ACS Biomaterials Science & Engineering
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2021
·
IF 4.749
Zhenhua Ding,Maohua Chen,Xinyan Tao,Yuan Liu,Jie He,Tao Wang,Xiaohong Li
Obesity is a primary risk factor for type 2 diabetes, cardiovascular diseases, cancer, and other chronic diseases. Current antiobesity medications need frequent administration and show limited efficacy with severe side effects. Herein, browning agent rosiglitazone (Rsg) and antioxidant manganese tetroxide nanoparticles (MnNPs, around 250 nm) are integrated into electrospun short fibers (SF@Rsg-Mn) with a 1.5 μm width and a 20 μm length. Upon injection into inguinal adipose tissues, SF@Rsg-Mn are well retained in the local depots to sustainably release Rsg in 30 days for adipose tissue browning, while MnNPs on the fiber surface continuously scavenge adipose reactive oxygen species (ROS) for an extended period of time. Synergistic inhibition of fat accumulation through ROS scavenging and white adipocyte browning has been demonstrated for the first time, and the optimal synergistic ratio of Rsg and MnNPs is determined to be 1/14 via combination index examination. SF@Rsg-Mn inhibit lipid accumulation through downregulation of adipogenic gene PPARγ while promoting energy expenditure through upregulation of brown-specific gene UCP1 and mitochondrial function gene COX7A1. In a diet-induced obesity mouse model, a single injection of SF@Rsg-Mn into inguinal adipose tissues has accomplished a synergistic effect on body weight loss, fat reduction, glucose, and lipid metabolic improvement while minimizing adverse effects on other tissues, thereby paving the way to efficacious, safe, and practical treatment of obesity.
研究领域:
药理学
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代谢研究
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纳米医学
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肥胖研究
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高影响因子
NUTRITION RESEARCH
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2015
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IF 2.472
Qian Wang,Shuang-ting Wang,Xin Yang,Pan-pan You,Wen Zhang
Myricetin (MyR), a naturally occurring flavonol widely distributed in fruits, vegetables, and medicinal plants , has anticancer, anti-inflammatory, antihyperlipidaemic , and antiobesity activities. In the present study, we hypothesized that the antiobesity property of MyR is mediated via suppression of differentiation of preadipocytes into adipocytes and promotion of lipolysis of mature adipocytes, which effectively decrease the intracellular triglyceride concentration of adipocytes. Accordingly, the aim of this work was to investigate the effects of MyR on adipocyte differentiation and lipolysis in differentiated 3 T3-L1 adipocytes. Our results showed that MyR inhibited differentiation of 3 T3-L1 preadipocytes in a concentration-dependent manner. Myricetin downregulated the mRNA and protein levels of CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor γ , both of which are major adipogenic transcription factors. Furthermore, the mRNA levels of other adipogenesis-related transcription factors, namely, CCAAT/enhancer-binding protein β , sterin regulatory element binding protein 1-c, peroxisome proliferator-activated receptor γ coactivator–1, adipocyte protein 2 , lipoprotein lipase and glucose transporter 4 , were also reduced by MyR treatment. Moreover, MyR significantly inhibited the phosphorylation of extracellular signal–regulated kinase, Jun N-terminal kinase, and p38 during the differentiation process. On the other hand, MyR induced a dose-dependent increase in glycerol release in fully differentiated adipocytes, indicating its stimulatory effect on adipocyte lipolysis. Furthermore, MyR downregulated mRNA level of perilipin A and enhanced the phosphorylation level of extracellular signal–regulated kinase, Jun N-terminal kinase, and p38 during lipolysis. Taken together, these findings indicate that MyR exerts antiobesity activity in adipocytes.
研究领域:
药理学
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细胞生物学
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分子生物学
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营养学
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2020
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IF 3.263
Minchi Liu,Wenjun Qian,Selvaraj Subramaniyam,Shuang Liu,Wenkuan Xin
Bitter taste receptors (Tas2rs) initiate a bitter taste signaling involving the activation of taste-specific G protein gustducin and phosphodiesterases (PDEs); it leads to the decrease of cytosolic level of cyclic adenosine monophosphate (cAMP) in taste cells. Recent studies have identified the expression of Tas2rs in a variety of non-lingual tissues including vascular smooth muscle (VSM), pulmonary smooth muscle and airway smooth muscle. The current study aims to determine the expression of Tas2rs and gustducin in rat aortic smooth muscle tissue and to investigate the effect of Tas2rs agonist denatonium on the tone of isolated denuded aorta rings. Here we reported the expression of six subtypes of Tas2r mRNA and the taste receptor-associated G proteins in endothelium-denuded aorta. Immunostaining experiments showed that the protein of gustducin expressed in vascular smooth muscle cells (VSMCs). Furthermore, denatonium increased the tone of freshly isolated denuded aorta rings in a concentration-dependent manner, and the potentiation effect of denatonium was blocked by a Tas2rs antagonist adenosine 5′-monophosphate (5′-AMP), by the cAMP-hydrolyzing PDE inhibitors , and by a cAMP-synthesizing enzyme activator forskolin , respectively. The blockade of G βγ signaling did not have a negative impact on the denatonium-induced tonic contractions. These findings suggested that the functional Tas2rs and gustducin are expressed in rat aortic smooth muscle and that denatonium might increase the smooth muscle tone through a Tas2rs signaling pathway involving the activation of PDEs.
研究领域:
药理学
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生理学
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心血管研究
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PubMed
高影响因子
CELLULAR & MOLECULAR BIOLOGY LETTERS
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2022
·Vol. 27
·期 1
·1-13
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IF 8.702
Zhu Shenglong,Wang Wei,Zhang Jingwei,Ji Siyu,Jing Zhe,Chen Yong Q.
Background A comprehensive understanding of the molecular mechanisms of adipogenesis is a critically important strategy for identifying new targets for obesity intervention. Methods Transcriptomic and lipidomic approaches were used to explore the functional genes regulating adipogenic differentiation and their potential mechanism of action in OP9 cells and adipose-derived stem cells. Oil Red O staining was used to detect oil droplets in adipocytes. Results RNA sequencing (RNA-seq) showed that Slc25a5 expression was significantly upregulated in adipogenic differentiation. Depletion of Slc25a5 led to the suppressed expression of adipogenesis-related genes, reduced the accumulation of triglycerides, and inhibited PPARγ protein expression. Moreover, the knockdown of Slc25a5 resulted in significant reduction of oxidative phosphorylation (OXPHOS) protein expression (ATP5A1, CQCRC2, and MTCO1) and ATP production. The RNA-seq and real-time quantitative polymerase chain reaction (RT–qPCR) results suggested that adipogenic differentiation is possibly mediated by ERK1/2 phosphorylation, and this hypothesis was confirmed by intervention with PD98059 (an ERK 1/2 inhibitor). Conclusions This study indicates that Slc25a5 inhibits adipogenesis and might be a new therapeutic target for the treatment of obesity.
研究领域:
分子生物学
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细胞生物学
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肥胖研究
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PubMed
高影响因子
JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
·
2022
·Vol. 78
·期 2
·377-388
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IF 5.08
Zhu Shenglong,Zhang Jingwei,Wang Wei,Jiang Xuan,Chen Yong Q.
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with an increasing global prevalence associated with tremendous clinical, economic, and health-related quality-of-life burden. Currently, no effective pharmacological therapy is available for NAFLD. Adipogenesis process is accompanied by fat synthesis which may participate in the occurrence and development of NAFLD. Despite intensive investigations, numerous mechanistic aspects of adipogenesis remain unclear and many potential therapeutic targets are yet to be discovered. In this study, the transcriptomics and lipidomics approaches were used to explore the functional genes regulating adipogenesis and the potential mechanism in OP9 cells and adipose-derived stem cells. We find that NADH:ubiquinone oxidoreductase subunit b9 ( Ndufb9 ) is up-regulated in adipogenesis ( p < 0.001), and silencing Ndufb9 (83% silencing efficiency) inhibits adipogenesis. The effect of Ndufb9 is mediated through stearoyl-CoA desaturase 1 ( Scd1 ). Aramchol, a SCD1 inhibitor, significantly blocks adipogenesis (markedly TG decrease, p < 0.001). Our study broadens the understanding of the role of Ndufb9 in adipogenesis and provides a new target for the treatment of NAFLD.
研究领域:
分子生物学
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细胞生物学
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药理学
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代谢性疾病
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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）