PHARMACEUTICAL BIOLOGY
·
2020
·
IF 2.971
Yucheng Li,Baoying Wang,Jiduo Shen,Ming Bai,Erping Xu
Context Berberine is an alkaloid that possesses various pharmacologic effects.Objective To explore the mechanism of berberine to improve insulin sensitivity in fructose-fed mice.Materials and methods Sixty male ICR mice were randomly divided into 6 groups (10 mice in each group): control, fructose, pioglitazone (10 mg/kg) and berberine (50, 100, and 200 mg/kg). Except for the control group, the mice received 20% fructose drinking for 10 weeks. Pioglitazone and berberine were orally administered once daily during the last 4 weeks. The insulin sensitivity was evaluated using an oral glucose tolerance test (OGTT). The serum levels of fasting glucose and insulin, blood lipids, and hormones were determined. The hepatic AMP and ATP contents were detected using high performance liquid chromatography (HPLC) analysis, and the protein expression was examined by immunoblotting.Results Berberine significantly reversed the insulin resistance induced by fructose, including lowering fasting insulin levels (from 113.9 to 67.4) and area under the curve (AUC) during OGTT (from 1310 to 1073), decreasing serum leptin (from 0.28 to 0.13) and increasing serum adiponectin levels (from 1.50 to 2.80). Moreover, berberine enhanced the phosphorylation levels of protein kinase B (PKB/AKT; 2.27-fold) and glycogen synthase kinase-3β (GSK3β; 2.56-fold), and increased hepatic glycogen content (from 0.19 to 1.65). Furthermore, berberine upregulated the protein expression of peroxisome proliferator activated receptor gamma coactivator 1α (PGC1α; 2.61-fold), phospho-AMP-activated protein kinase (p-AMPK; 1.35-fold) and phospho-liver kinase B1 (p-LKB1; 1.41-fold), whereas it decreased the AMP/ATP ratio (from 4.25 to 1.82).Conclusion The present study demonstrated the protective effects of berberine against insulin resistance induced by fructose. Our findings may provide an experimental basis for the application of berberine in the treatment of insulin resistance.
研究领域:
药理学
·
代谢紊乱
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Haotian Zhang,Xiaoying Chen,Hua Rong,Baojia Chen,Junfeng Guang,Qing Pan,Xiaobo Wen,Lijun Ning
Unlike predictability in mammals, the responses of PPARα activation treatment in fish varies between different fish species. Existing results indicated that the varied effects may result from fish feeding habits difference within their varied dietary protein content, while the exact mechanism remains obscure. In this study, we conducted an in vivo 8-week trial of low protein 30 % (LP) or high protein 38 % (HP) diet fed tilapia (8.83 ± 0.02 g) supplemented with or without fenofibrate and in vitro 24-h of BCAA (leucine, valine and isoleucine) treated primary cell trial, aiming to reveal the unknown mechanism. The in vivo results showed that, in LP group, fenofibrate significantly increased serum levels of TG, glucose, AST, ALT, MDA and liver TG ( P < 0.05), while decreased liver, muscle and serum BCAA, liver mitochondria quantity, glucose tolerance ( P < 0.05). Moreover, fenofibrate notably lifted the hepatic bckdha , bckdhb , mff , fis , fas and pparγ expression ( P < 0.05), while decreased genes expression of pgc1α , tfam , parkin , pink , foxo3a, sod2, cat , ir and irs ( P < 0.05). No great impact was found in aco , cyp4a3 and cytb ( P > 0.05). In HP group, fenofibrate improved lipid and glucose metabolism along with unaltered BCAA, increased expression of aco , cytb , cpt1a , pparβ , foxo3a , sod2 , nrf1 , mfn1 and fis ( P < 0.05). In vitro findings revealed that the PGC1α and PPARα could be activated by BCAA, particular for leucine ( P < 0.05). Taken together, we conclude that: 1) increased lipid deposition, lipid peroxidation, liver damage and glucose intolerance in fenofibrate-LP group could be ascribed to decreased BCAA and done through PGC1α/FOXO3, PGC1α/MQC regulation; 2) improved lipid-lowering and glucose tolerance in fenofibrate-HP group would be attributed to the enhanced PGC1α/MQC, organelles proliferation and fatty acid β-oxidation.
研究领域:
分子生物学
·
营养学
·
代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CANCER RESEARCH
·
2023
·Vol. 83
·期 7
·1094-1110
·
IF 11.2
Zhao Mengjie,Li Yanhui,Lu Chenfei,Ding Fangshu,Xu Miao,Ge Xin,Li Mengdie,Wang Zhen,Yin Jianxing,Zhang Junxia,Wang Xiefeng,Ge Zehe,Xiao Hong,Xiao Yong,Liu Hongyi,Liu Wentao,Cao Yuandong,Wang Qianghu,You Yongping,Wang Xiuxing,Yang Kun,Shi Zhumei,Qian Xu
Radiotherapy is a major component of standard-of-care treatment for gliomas, the most prevalent type of brain tumor. However, resistance to radiotherapy remains a major concern. Identification of mechanisms governing radioresistance in gliomas could reveal improved therapeutic strategies for treating patients. Here, we report that mitochondrial metabolic pathways are suppressed in radioresistant gliomas through integrated analyses of transcriptomic data from glioma specimens and cell lines. Decreased expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α), the key regulator of mitochondrial biogenesis and metabolism, correlated with glioma recurrence and predicted poor prognosis and response to radiotherapy of patients with glioma. The subpopulation of glioma cells with low-mitochondrial-mass exhibited reduced expression of PGC1α and enhanced resistance to radiotherapy treatment. Mechanistically, PGC1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC1α by facilitating its binding to the E3 ligase RNF34. Restoring PGC1α activity with expression of PGC1α S636A, a phosphorylation-resistant mutant, or a small-molecule PGC1α activator ZLN005 increased radiosensitivity of resistant glioma cells by reactivating mitochondria-related reactive oxygen species production and inducing apoptotic effects both in vitro and in vivo . In summary, this study identified a self-protective mechanism in glioma cells in which radiotherapy-induced degradation of PGC1α and suppression of mitochondrial biogenesis play a central role. Targeted activation of PGC1α could help improve response to radiotherapy in patients with glioma. Significance: Glioma cells reduce mitochondrial biogenesis by promoting PGC1α degradation to promote resistance to radiotherapy, indicating potential therapeutic strategies to enhance radiosensitivity.
研究领域:
肿瘤学
·
分子生物学
·
放射生物学
·
神经肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Jiajun Yang,Siyu Hou,Yuhui Zhao,Zhaoyang Sun,Lilin Zhang,Yan Deng,Xiaoli Shang,Hanjie Yu,Zheng Li,Hongmei Li
The antidiabetic activity of the novel Buckwheat protein-derived peptide (Ala-Phe-Tyr-Arg-Trp, AFYRW) and its associated protein glycosylation have been verified. Our preliminary study demonstrates the potential of AFYRW as a therapeutic agent for diabetes, but the mechanism needs further investigation. Given the vital role of O-linked N -acetylglucosamine transferase (OGT) in diabetes mellitus and insulin resistance (IR), we focused on the underlying molecular mechanisms of them in ameliorating IR. We found AFYRW protects against hyperglycemia in diabetic mice and improves glucose metabolism in an IR cell model. Mechanistically, we demonstrated that AFYRW decreases glutamine-fructose-6-phosphate amidotransferase (GFAT) expression via X-box binding protein 1 (XBP1) in the hexosamine biosynthesis pathway (HBP), consequently decreasing OGT and stimulating the SIRT1/PGC1α pathway. Of note, the overlapping roles of increased SIRT1 and decreased OGT caused by AFYRW ameliorated IR. The data presented here show that AFYRW contributes to metabolism by directly controlling glucose homeostasis. Taken together, our study unveils that AFYRW protects against both insulin resistance and diabetes mellitus-induced hyperglycemia through OGT to regulate the SIRT1/PGC1α pathway, which provides a mechanistic basis for novel AFYRW to be a potential therapeutic agent.
研究领域:
内分泌学
·
分子生物学
·
糖尿病研究
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEUROIMMUNOMODULATION
·
2021
·Vol. 29
·期 4
·317-326
·
IF 2.492
Wu Xiuwen,Liu Xiaopeng,Yang Liang,Wang Yuanyu
Background: Elevation of AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) signaling can suppress intracerebral hemorrhage (ICH)-induced neurological impairments. As an isoquinoline alkaloid, Berberine exerts neuroprotective effects in neurological disease models with activated AMPK/PGC1α signaling. Aim: We aim to study the effect of Berberine on ICH-induced brain injury and explore the potential molecular mechanism. Methods: ICH model was established in mice through intracerebral injection of autologous whole blood, followed by treatment with Berberine. Neurological impairments were assessed by the modified neurological severity score and behavioral assays. Brain edema and blood-brain barrier (BBB) integrity were assessed by water content in the brain, amount of extravasated Evans blue, and BBB tight junction components. Neuroinflammatory responses were assessed by inflammatory cytokine levels. AMPK/PGC1α signaling was examined by AMPK mRNA expression and phosphorylated AMPK and PGC1α protein levels. Results: Berberine (200 mg/kg) attenuated ICH-induced neurological deficits, motor and cognitive impairment, and BBB disruption. Berberine also suppressed ICH-induced inflammatory responses indicated by reduced production of inflammatory cytokines. Finally, Berberine drastically elevated AMPK/PGC1α signaling in the hemisphere of ICH mice. Conclusion: Our findings suggest that Berberine plays an important neuroprotective role against ICH-induced neurological impairments and BBB injury, probably by inhibition of inflammation and activation of AMPK/PGC1α signaling
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2017
·
IF 4.581
Shuai Wang,Xue Yuan,Danyi Lu,Lianxia Guo,Baojian Wu
Sulfotransferase 1E1 (SULT1E1, also known as estrogen sulfotransferase) plays an important role in metabolism and detoxification of many endogenous and exogenous compounds (e.g., estrogens and flavonoids). Here we aimed to assess the effects of farnesoid X receptor (FXR) activation on SULT1E1 expression, and to determine the mechanism thereof. Treatment with specific FXR agonists (i.e., GW4064 and CDCA) significantly decreased both mRNA and protein levels of SULT1E1 in HepG2 cells. This was accompanied by a decrease in the enzymatic activity. The inhibitory effect was potentiated by FXR overexpression but attenuated by FXR knockdown, confirming FXR-dependent regulation of SULT1E1. Surprisingly, direct regulation of SULT1E1 by FXR was unlikely because FXR did not bind to SULT1E1 promoter or enhancer as revealed by chromatin immunoprecipitation (ChIP). Interestingly, SULT1E1 regulation was abolished when HNF4α (hepatocyte nuclear factor 4α, a known activator of SULT1E1) was silenced, supporting a critical role for HNF4α in FXR regulation of SULT1E1. Furthermore, a combination of ChIP, luciferase reporter and co-immunoprecipitation assays showed that FXR inhibited HNF4α transactivation of SULT1E1 by suppressed binding of the co-activator PGC1α (peroxisome proliferator-activated receptor-γ coactivator 1α) to HNF4α. In conclusion, FXR transcriptionally regulates SULT1E1 through inhibition of PGC1α binding to HNF4α. Targeting the FXR-SULT1E1 axis may represent a promising approach for management of estrogen-related diseases.
研究领域:
分子生物学
·
药理学
·
内分泌学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF NATURAL PRODUCTS
·
2022
·
IF 4.803
Yichen Tong,Wentao Zhu,Tianzhi Wen,Zere Mukhamejanova,Fang Xu,Qi Xiang,Jiyan Pang
Nonalcoholic fatty liver disease (NAFLD) represents a class of disorders including hepatic steatosis, steatohepatitis, and liver fibrosis. Previous research suggested that xyloketal B (Xyl-B), a marine-derived natural product, could attenuate the NAFLD-related lipid accumulation. Herein, we investigated the protective mechanism of Xyl-B in a high-fat diet (HFD) mice fatty liver model by combining a quantitative proteomic approach with experimental methods. The results showed that the administration of Xyl-B (20 and 40 mg·kg–1·day–1, ip) ameliorated the hepatic steatosis in HFD mice. Proteomic profiling together with bioinformatics analysis highlighted the upregulation of a cluster of peroxisome proliferator-activated receptor-α (PPARα) downstream enzymes mainly related to fatty acid oxidation (FAO) as key changes after the treatment. These changes were subsequently confirmed by bioassays. Moreover, further results showed that the expression levels of PPARα and PPARγ coactivator-1α (PGC1α) were increased after the treatment. The related mode-of-action was confirmed by PPARα inhibition. Furthermore, we evaluated the PPARα-mediated anti-inflammatory and antifibrosis effect of Xyl-B in methionine-choline-deficient (MCD) mice hepatitis and liver fibrosis models. According to the results, the histological features were improved, and the levels of inflammatory factors, adhesion molecules, as well as fibrosis markers were decreased after the treatment. Collectively, these results indicated that Xyl-B ameliorated different phases of NAFLD through activation of the PPARα/PGC1α signaling pathway. Our findings revealed the possible metabolism-regulating mechanism of Xyl-B, broadened the application of xyloketal family compounds, and may provide a new strategy to curb the development of NAFLD.
✓ 已验证
DOI
PubMed
高影响因子
FASEB JOURNAL
·
2021
·Vol. 35
·期 2
·e21316
·
IF 5.192
Qianhong Ye,Xiangfang Zeng,Shuai Wang,Xiangzhou Zeng,Guangxin Yang,Changchuan Ye,Shuang Cai,Meixia Chen,Siyu Li,Shiyan Qiao
Maintaining ovarian steroidogenesis is of critical importance, considering that steroid hormones are required for successful establishment and maintenance of pregnancy and proper development of embryos and fetuses. Investigating the mechanism that butyrate modulates the ovarian steroidogenesis is beneficial for understanding the impact of lipid nutrition on steroidogenesis. Herein, we identified that butyrate improved estradiol and progesterone synthesis in rat primary ovarian granulosa cells and human granulosa KGN cells and discovered the related mechanism. Our data indicated that butyrate was sensed by GPR41 and GPR43 in ovarian granulosa cells. Butyrate primarily upregulated the acetylation of histone H3K9 (H3K9ac). Chromatin immune-precipitation and sequencing (ChIP-seq) data of H3K9ac revealed the influenced pathways involving in the mitochondrial function (including cellular metabolism and steroidogenesis) and cellular antioxidant capacity. Additionally, increasing H3K9ac by butyrate further stimulated the PPARγ/CD36/StAR pathways to increase ovarian steroidogenesis and activated PGC1α to enhance mitochondrial dynamics and alleviate oxidative damage. The improvement in antioxidant capacity and mitochondrial dynamics by butyrate enhanced ovarian steroidogenesis. Collectively, butyrate triggers histone H3K9ac to activate steroidogenesis through PPARγ and PGC1α pathways in ovarian granulosa cells.
研究领域:
生殖生物学
·
内分泌学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
·
2021
·
IF 4.698
Xixi Song,Minghui Wang,Hongchao Jiao,Jingpeng Zhao,Xiaojuan Wang,Hai Lin
Ghrelin, classically known as a central appetite-stimulating hormone, has recently been recognized to play an important role in peripheral tissue energy metabolism. In chicken, contrary to mammal, ghrelin acts as an anorexia signal, increased by fasting and further elevated after refed. In the present study, the effect of ghrelin on glucose/lipid utilization by peripheral tissues was investigated. Injection of exogenous acyl ghrelin reduced plasma triglyceride and glucose levels of chickens at both fasting and fed status. In the in vitro cultured chicken primary hepatocytes, adipocytes, and myoblasts, ghrelin suppressed glucose uptake , stimulated fatty acids uptake and oxidation , and decreased TG content. In hepatocyte, ghrelin increased the activities of LPL and HL, and upregulated the expression levels of gene ACC , CPT1 , and PPARα . Ghrelin treatment markedly increased the protein level of p-ACC, PPARγ, PGC1α, and CPT1 in hepatocytes, adipocytes and myoblasts. Inhibition of AMPK activity by Compound C had no influence on glucose uptake by hepatocyte, adipocyte, and myoblast, but further amplified the stimulated fatty acid uptake of adipocyte by ghrelin. The present result demonstrates that ghrelin facilitates the uptake and oxidation of fatty acid and cut down the utilization of glucose by the liver, muscle, and adipose tissues. The result suggests that ghrelin functions as a signal of fatty acid oxidation. The study provides a vital framework for understanding the intrinsic role of ghrelin as a crucial factor in the concerted regulation of metabolic substrate of hepatocytes, adipocytes, and myoblasts.
研究领域:
内分泌学
·
代谢
·
动物生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2026
·
IF 6.2
Longfei Lv,Sijie Zhang,Bing Huang,Li Ren,Jie Zhang,Zheng Ma
Cigarette consumption remains a preeminent global public health concern, as prolonged exposure to cigarette smoke is fundamentally implicated in the etiology of chronic pulmonary diseases and the manifestation of various malignancies. Apigenin, a bioactive dietary flavonoid widely distributes in botanical sources such as celery, demonstrates significant histoprotective effect. Nevertheless, the underlying mechanism governing apigenin's ability to counteract incipient pulmonary injury induced by cigarette smoke extract (CSE) remains to be delineated. By employing a novel CSE exposure system to establish reproducible in vivo and in vitro injury models, this study demonstrated that apigenin administration dose-dependently attenuates pulmonary apoptosis, as evidenced by the restoration of the Bax/Bcl-2 ratio and the suppression of Caspase-3 activation. Furthermore, apigenin treatment reversed the CSE-induced downregulation of PPARγ and its downstream effector, FATP2. Apigenin also restored intestinal mucosal integrity, promoted the enrichment of the probiotic Clostridia vadinBB60 group, and elevated intestinal difluprednate levels, which strongly correlated with increased glucocorticoid receptor (GR) expression in lung tissue. Mechanistically, apigenin facilitated the recruitment of PGC1α to PPARγ, thereby promoting PPARγ nuclear translocation and subsequent FATP2 activation in CSE-challenged MLE-12 cells. In RAW264.7 macrophages, difluprednate mediated GR nuclear translocation, subsequently suppressing the mRNA expression of the pro-inflammatory cytokines IL-1β and IL-6. Collectively, these findings identify apigenin as a dual-pathway modulator that bridges PPARγ/FATP2-mediated metabolic homeostasis with GR-dependent anti-inflammatory signaling, highlighting its therapeutic potential against smoking-related pulmonary dysfunction and supporting its application as a functional food intervention.
✓ 已验证
DOI
高影响因子
Frontiers in Nutrition
·
2022
·
IF 6.59
Suwen Liu,Fanna Meng,Dong Zhang,Donglin Shi,Junyi Zhou,Shuo Guo,Xuedong Chang
Exercise fatigue can exert deleterious effects on the body. This study evaluated the effects and mechanisms by which Lonicera caerulea berry polyphenols extract (LCBP) improved the treadmill endurance of mice. Comparison was performed between the effects at 25°C and low temperatures (-5°C). Energy storage, product metabolism, and other biochemical indices were determined using vitamin C (VC) as a positive control. Co-immunoprecipitation was performed to detect the interaction between different proteins. Dietary supplementation with LCBP significantly prolonged the exhaustion time during treadmill exercise by 20.4% (25 °C) and 27.4% (-5 °C). LCBP significantly regulated the expression of antioxidant and inflammatory proteins, Bcl-2 /Bax apoptosis proteins, and the PKCα -NOx2 / Nox4 pathway proteins, and activated the expression of AMPK-PGC1α -NRF1-TFAM proteins in skeletal muscle mitochondria. The gene and protein expression of miRNA-133a/IGF-1/PI3K/Akt/mTOR in skeletal muscle cells was also activated. Molecular docking confirmed that the main components of LCBP such as cyanidin-3-glucoside, catechin, and chlorogenic acid, have strong binding affinity toward AMPKα. LCBP alleviates exercise fatigue in mice by reducing oxidative stress, inflammation, and apoptosis of skeletal muscle cells, enhances mitochondrial biosynthesis and cell proliferation, reduces fatigue, and enhances performance. These effects are also significant in a low-temperature environment (Graphical Abstract). Consequently, these results provide novel insights into the anti- fatigue roles of LCBP in exercise fatigue.
研究领域:
药理学
·
生理学
·
生物化学
·
分子生物学
·
运动科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Metabolism
·
2022
·
IF 31.373
Zu-Guo Zheng,Yin-Yue Xu,Wen-Ping Liu,Yang Zhang,Chong Zhang,Han-Ling Liu,Xiao-Yu Zhang,Run-Zhou Liu,Yi-Ping Zhang,Meng-Ying Shi,Hua Yang,Ping Li
Summary sn-1,2-diacylglycerol (sn-1,2-DAG)-mediated activation of protein kinase Cε (PKCε) is a key pathway that is responsible for obesity-related lipid metabolism disorders, which induces hepatic insulin resistance and type 2 diabetes. No small molecules have been previously reported to ameliorate these diseases through this pathway. Here, we screened and identified the phytochemical atractylenolide II (AT II) that reduces the hepatic sn-1,2-DAG levels, deactivates PKCε activity, and improves obesity-induced hyperlipidemia, hepatosteatosis, and insulin resistance. Furthermore, using the ABPP strategy, the diacylglycerol kinase family member DGKQ was identified as a direct target of AT II. AT II may act on a novel drug-binding pocket in the CRD and PH domains of DGKQ to thereby allosterically regulate its kinase activity. Moreover, AT II also increases weight loss by activating DGKQ-AMPK-PGC1α-UCP-1 signaling in adipose tissue. These findings suggest that AT II is a promising lead compound to improve obesity-induced insulin resistance.
研究领域:
药理学
·
代谢
·
内分泌学
·
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）