BIOORGANIC CHEMISTRY
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2026
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IF 5.1
Sheng-Li Wu,Xiao-Feng He,Pianchou Gongpan,Xiao-Yan Huang,Chang-An Geng
DCA stimulated GLP-1 secretion in STC-1 and NCI-H716 cells. • DCA decreased fasting blood glucose levels by promoting GLP-1 secretion in db/db mice. • DCA ameliorated glucose intolerance and insulin resistance and lowered serum TC levels. • DCA promoted GLP-1 secretion through specific activation on TGR5/PKA/MEK/ERK pathway. Type 2 diabetes mellitus (T2DM) is a heterogeneous metabolic disorder characterized by insulin resistance and progressive β cell dysfunction. Deoxycalyxin A (DCA), a unique diarylheptanoid-chalcone hybrid isolated from Alpinia katsumadai , was identified as a novel stimulator of GLP 1 secretion in both STC-1 (EC 50 : 10.7 μM) and NCI-H716 (EC 50 : 13.4 μM) cells. Oral administration of DCA (40 and 80 mg/kg) in db/db mice significantly reduced fasting blood glucose, ameliorated glucose intolerance and insulin resistance by enhancing endogenous GLP-1 secretion, and lowered the total serum cholesterol levels. Mechanistic study demonstrated that DCA identify the TGR5 receptor, which induces a significant increase in intracellular cyclic AMP (cAMP) levels, which activates PKA with subsequent sequential phosphorylation of MEK1/2 and ERK activation, ultimately enhancing GLP-1 secretion. Our findings identify DCA as a novel TGR5 agonist to stimulate GLP-1 secretion via the TGR5/PKA/MEK/ERK pathway, which has the potential to be developed as a promising antidiabetic lead with a distinct mechanism of action. DCA, a unique diarylheptanoid-chalcone from Alpinia katsumadai , is a novel TGR5 agonist to stimulate GLP-1 secretion via PKA/MEK/ERK pathway, which has the potential to be developed as a promising antidiabetic candidate. Download: Download high-res image (123KB) Download: Download full-size image
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Molecular Cancer
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2022
·Vol. 21
·期 1
·1-17
·
IF 41.444
Pan Zhenzhen,Wang Kai,Wang Xiniao,Jia Zhirong,Yang Yuqi,Duan Yalei,Huang Lianzhan,Wu Zhuo-Xun,Zhang Jian-ye,Ding Xuansheng
Background The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) brings remarkable benefits for the survival of patients with advanced NSCLC harboring EGFR mutations. Unfortunately, acquired resistance seems to be inevitable and limits the application of EGFR-TKIs in clinical practice. This study reported a common molecular mechanism sustaining resistance and potential treatment options to overcome EGFR-TKIs resistance.Methods EGFR-TKIs resistant NSCLC cells were established and confirmed by MTT assay. Cholesterol content was detected and the promotional function of cholesterol on NSCLC growth was determined in vivo. Then, we identified ERRα expression as the downstream factor of cholesterol-mediated drug resistance. To dissect the regulatory mechanism, we conducted experiments, including immunofluorescence, co-immunoprecipitation, luciferase reporter assay and chromatin immunoprecipitation assay.Results Long-term exposure to EGFR-TKIs generate drug resistance with the characteristic of cholesterol accumulation in lipid rafts, which promotes EGFR and Src to interact and lead EGFR/Src/Erk signaling reactivation-mediated SP1 nuclear translocation and ERRα re-expression. Further investigation identifies ERRα as a target gene of SP1. Functionally, re-expression of ERRα sustains cell proliferation by regulating ROS detoxification process. Lovastatin, a drug used to decrease cholesterol level, and XCT790, an inverse agonist of ERRα, overcome gefitinib and osimertinib resistance both in vitro and in vivo.Conclusion sOur study indicates that cholesterol/EGFR/Src/Erk/SP1 axis-induced ERRα re-expression promotes survival of gefitinib and osimertinib-resistant cancer cells. Besides, we demonstrate the potential of lowing cholesterol and downregulation of ERRα as effective adjuvant treatment of NSCLC.
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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2022
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IF 6.633
Huiwen Wang,Jian Zhang,Xiaoxun Zhang,Nan Zhao,Zongtao Zhou,Lijian Tao,Lei Fu,Shifang Peng,Jin Chai
Cholestasis is characterized by intrahepatic accumulation of bile acids (BAs), resulting in liver injury, fibrosis, and liver failure. To date, only ursodeoxycholic acid and obeticholic acid have been approved for the treatment of cholestasis. As fluorofenidone (AKF-PD) was previously reported to play significant anti-fibrotic and anti-inflammatory roles in various diseases, we investigated whether AKF-PD ameliorates cholestasis. A mouse model of cholestasis was constructed by administering a 0.1 % 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) diet for 14 days. Male C57BL/6 J mice were treated with either AKF-PD or pirfenidone (PD) orally in addition to the DDC diet. Serum and liver tissues were subsequently collected and analyzed. We found that AKF-PD significantly reduced the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bile salts (TBA), as well as hepatic bile acids (BAs) levels. Hepatic histological analyses demonstrated that AKF-PD markedly attenuated hepatic inflammation and fibrosis. Further mechanistic analyses revealed that AKF-PD markedly inhibited expression of Cyp7a1, an enzyme key to BAs synthesis, by increasing Fxr nuclear translocation, and decreased hepatic inflammation by attenuating Erk/-Egr-1-mediated expression of inflammatory cytokines and chemokines Tnfα, Il-1β, Il-6, Ccl2, Ccl5 and Cxcl10. Moreover, AKF-PD was found to substantially reduce liver fibrosis via inhibition of Tgfβ1/Smad pathway in our mouse model. Here, we found that AKF-PD effectively attenuates cholestasis and hepatic fibrosis in the mouse model of DDC-induced cholestasis. As such, AKF-PD warrants further investigation as a candidate drug for treatment of cholestasis.
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Frontiers in Pharmacology
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2021
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IF 5.811
Lv Jinpeng,Yang Ying,Jia Bingyi,Li Siqi,Zhang Ximei,Gao Rongyin
The therapeutic use of curcumin and chemically modified curcumin (CMC) for suppressing melanogenesis and tyrosinase activity have been recognized. J147 is a modified version of curcumin with superior bioavailability and stability. However, there is no report about the effects of J147 on pigmentation in vitro and in vivo. In our studies, we investigated the hypopigmentary effects of J147 treatment on melanocytes and explored the underlying mechanism. The present studies suggested that J147 suppressed both basal and α-MSH-induced melanogenesis, as well as decreased melanocyte dendricity extension and melanosome transport. J147 played these roles mainly by activating the extracellular signal-regulated protein kinase (ERK) pathway. Once activated, it resulted in MITF degradation and further down-regulated the expression of tyrosinase, TRP-1, TRP-2, Myosin Va, Rab27a and Cdc42, ultimately inhibited melanin synthesis and melanosome transport. Furthermore, the hypopigmentary effects of J147 were demonstrated in vivo in a zebrafish model and UVB-induced hyperpigmentation model in brown guinea pigs. Our findings also suggested that J147 exhibited no cytotoxicity in vitro and in vivo. Taken together, these data confirmed that J147 may prove quite useful as a safer natural skin-whitening agent.
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Frontiers in Endocrinology
·
2025
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IF 4.6
Pengyu Wang,Zhen Sun,Qing Lan,Shuo Zhang,Yan Song,Leiming Yang,Mi Chen,Jianfen Shen,Qi Huang,Youzhi Zhang
Objective: Diabetic liver injury, a chronic complication of diabetes mellitus (DM), has been extensively documented. Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, has shown significant therapeutic benefits in clinical trials for the management of diabetes However, the specific mechanism on the treatment of diabetic liver injury with dapagliflozin is not fully understood. Therefore, this study aims to further explore the potential mechanism of dapagliflozin on diabetic liver injury based on bioinformatics analysis and experimental verification.Methods: Diabetic liver injury was induced by a high-fat diet combined with STZ in mice. Biochemical kit detection and H&E staining were used to observe lipid aggregation and oxidative stress in liver tissue. Moreover, the expression of inflammatory and apoptosis-related factors was detected using western blotting (WB) and quantitative polymerase chain reaction (qPCR). Subsequently, differential expressions genes analysis, weighted gene co-expression network analysis (WGCNA), molecular docking, as well as molecular dynamics was conducted based on the Gene Expression Omnibus (GEO) and pharmacology databases. Finally, WB and qPCR were performed to validate the mechanism of dapagliflozin on diabetic liver injury in vivo and in vitro.Results: Dapagliflozin alleviated diabetic liver injury by decreasing lipid deposition, oxidative stress levels, the inflammatary and apoptosis-related proteins and mRNA levels, while it also reducing blood glucose. Mechanically, 78 overlapping genes of dapagliflozin and diabetic liver injury were obtained. Notably, Mapk3, Mapk1, Ikbkb, and Nfkb1 as the hub genes involved in dapagliflozin attenuating diabetic liver injury were identified, and dapagliflozin exhibited better affinity with these proteins. Moreover, dapagliflozin inhibited the elevated protein (genes) levels of ERK1/2 (Mapk3, Mapk1), IKKβ(Ikbkb), and NF-κB (Nfkb1), which are induced by diabetic liver injury, as confirmed by both in vivo and in vitro experiments.Conclusion: Dapagliflozin ameliorated diabetic liver injury by inhibiting the ERK/IKKβ/NF-κB signalling pathway, as demonstrated by bioinformatics analysis combined with in vivo and in vitro experiments.
研究领域:
医学
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药理学
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分子生物学
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CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
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2021
·Vol. 99
·期 12
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IF 2.273
Dongdong Zhang,Dongxu Qi,Yi Xu,Chunhe Hu,Xiao Zhang,Qingjian Yang,Zikun Shang,Guisheng Zhang
Skin flap transfer is an important method to repair and reconstruct various tissue defects; however, avascular necrosis largely affects the success of flap transfer. The sphingosine 1-phosphate receptor 1 (S1PR1) agonist SEW2871 has been proven to ameliorate ischemic injury; however, its effect on flap survival has not been reported. In this study, an experimental skin flap model was established in rats to investigate the roles of SEW2871. The results indicated that SEW2871 greatly increased the survival of the skin flap, alleviated pathological injury, promoted the angiogenesis, and inhibited cells apoptosis in skin flap tissues. SEW2871 activated S1PR1 downstream signaling pathways, including heat shock protein 27 (HSP27), extracellular regulated protein kinases (ERK), and protein kinase B (Akt). In addition, SEW2871 promoted the expression of S1PR1. These findings may provide novel insights for skin flap transfer.
研究领域:
药理学
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外科手术
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分子生物学
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ACS Applied Materials & Interfaces
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2019
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IF 8.456
Fei Jia,Suya Lin,Xuzhao He,Jiamin Zhang,Shuxian Shen,Zhiying Wang,Bolin Tang,Cheng Li,Yongjun Wu,Lingqing Dong,Kui Cheng,Wenjian Weng
The surface electric potential of biomaterials has been extensively proven to play a critical role in stem cells’ fate. However, there are ambiguous reports on the relation of stem cells’ osteogenic capacity to surface potential characteristics (potential polarity and intensity). To address this, we adopted a surface with a wide potential range and both positive/negative polarity in a comprehensive view to get insight into surface potential-regulating cellular osteogenic differentiation. TbxDy1–xFe2 alloy/poly(vinylidene fluoride-trifluoroethylene) magnetoelectric films were prepared, and the film could provide controllable surface potential characteristics with positive or negative polarity and potential (ϕME) intensity variation from 0 to ±120 mV as well as keep the surface chemical composition and microstructure unchanged. Cell culture results showed that osteogenic differentiation of mesenchymal stem cells on both positive and negative potential films was obviously upregulated when the /ϕME/ intensities were set from 0–55 mV. Differently, the highest upregulated osteogenic differentiation on the positive potential films corresponded to the /ϕME/ intensity from 35–55 mV and was better than that on the negative potential films whereas the highest on the negative potential films corresponded to the /ϕME/ intensity from 0–35 mV and was better than that on the positive potential films. This fact could illustrate why previous reports appeared ambiguously; i.e., the comparative result in osteogenic differentiation between the positive and negative potential films strongly depends on the selection of surface potential intensity. On the basis of assaying of the exposed functional sites (RGD and PHSRN) of the adsorbed fibronectin (FN) and the expression of cellular integrin α5 and β1 subunits, the difference in the behavior between the positive and negative potential films was attributed to the distinct conformation of adsorbed fibronectin (FN) and the opposite changing trend with /ϕME/ for the two films, which triggers the osteogenesis-related FAK/ERK signaling pathway to a different extent. This study could provide new cognition for the in-depth understanding of the regulation mechanism underlying surface potential characteristics in cell behaviors.
研究领域:
生物材料学
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细胞生物学
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组织工程学
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Oncotarget
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2017
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IF 5.168
Chen Zhu,Yi Wang,Hua Liu,Haiman Mu,Yue Lu,Jiayi Zhang,Jianhua Huang
Although Ginsenoside Rg1 has been reported to have protective cardiac effects, its effects on cardiac toxicity induced by doxorubicin needs to be studied. The present study investigated the effects of oral administration of Rg1 on the heart in mice treated with doxorubicin and found improved fractional shortening and ejection fraction of the heart and decreased cardiac apoptosis in mice treated with doxorubicin. The underlying mechanisms include increased phosphorylation of Akt and Erk by Rg1, increased ratio of Bcl-2 and Bax, and decreased release of cytochrome c from mitochondria, thereby protecting the heart from doxorubicin-induced apoptosis. This phenotype suggested that the oral administration of Rg1 may be a potential method preventing the cardiac toxicity caused by doxorubicin in clinical practice.
研究领域:
药理学
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心脏病学
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肿瘤学
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高影响因子
MOLECULES
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2021
·Vol. 26
·期 13
·3915
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IF 4.412
Yiou Wang,Bingxue Zhang,Yibing Huang,Wenjun Yao,Fei Tao,Yuxin Chen
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Studies have shown that bradykinin (BK) is highly expressed in liver cancer. We designed the novel BK receptor inhibitors J051-71 and J051-105, which reduced the viability of liver cancer cells and inhibited the formation of cancer cell colonies. J051-71 and J051-105 reduced cell proliferation and induced apoptosis in HepG2 and BEL-7402 cells, which may be due to the inhibition of the extracellular regulated protein kinase (ERK) signaling pathway. In addition, these BK receptor inhibitors reversed the cell proliferation induced by BK in HepG2 and BEL-7402 cells by downregulating B1 receptor expression. Inhibiting B1 receptor expression decreased the protein levels of p-ERK and reduced the malignant progression of HCC, providing a potential target for HCC therapy.Keywords:bradykinin receptor inhibitor;hepatocellular carcinoma;apoptosis;bradykinin B1 receptor;ERK signaling pathway
研究领域:
肿瘤学
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药理学
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细胞生物学
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高影响因子
GENE
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2022
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IF 3.913
Xiang Li,Nan Wang,Yutong Wu,Yidan Liu,Ruoyu Wang
Background Aldehyde dehydrogenase 6 family member A1 (ALDH6A1) is associated with multiple diseases, but its pathogenesis in colon cancer (CC) is ambiguous and needs further study so that this research explores the function of ALDH6A1 in CC. Methods The level of ALDH6A1 in colon adenocarcinoma (COAD), CC tissues, and cells was measured by starBase v2.0, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot. Post transfection with overexpressed (oe)-ALDH6A1, cell biological behaviors, as well as apoptosis-, matrix metalloproteinase (MMP)-, and rat sarcoma virus (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway-related markers were measured by cell function experiments, qRT-PCR, and western blot. Next, the effects of small interfering RNA targeting ALDH6A1 (si-ALDH6A1) and RAS/RAF inhibitor (MCP110) on cell biological behaviors, as well as apoptosis-, MMP-, and RAS/RAF/MEK/ERK pathway-related markers were detected again. Results ALDH6A1 was low-expressed in COAD, CC tissues, and cells. Oe-ALDH6A1 weakened cell vitality, migration and invasionbut facilitated apoptosis; while it reduced expression levels of Bcl-2, MMP-2, MMP-9 and the RAS/RAF/MEK/ERK pathway-related markers but promoted Bax level. However, the regulation of si-ALDH6A1 on cell biological behaviors and related genes was opposite to that of oe-ALDH6A1. Moreover, MCP110 rescued the regulation of si-ALDH6A1 on cell biological behaviors, expressions of apoptosis- MMP- as well as RAS/RAF/MEK/ERK pathway-related markers. To sum up, ALDH6A1 attenuated CC progression by down-regulating the expressions of RAS/RAF/MEK/ERK pathway-related markers.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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高影响因子
PHARMACOLOGICAL RESEARCH
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2020
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IF 5.893
Xiaotian Qi,Mengyue Fan,Nana Huang,Xinyu Zhang,Jing Liu,Xiaoyu Li,Rong Sun
Cancer chemotherapy induced neutropenia (CCIN) is one of the most common toxicity caused by cytotoxic anticancer agents . Despite granulocyte colony-stimulating factor (GCSF) is widely used in clinical practice, the infection and infection-related mortality rate is still high for lack of functionally mature neutrophils. Saikosaponin d (SSD) is one of the major bioactive constituents of Radix Bupleuri (RB), which exerts immune-modulatory properties. We explored the function of SSD in CCIN therapy, we found that SSD contributed to generate functional mature neutrophils which capable of fighting infection both in vitro and in vivo . Network pharmacology was employed to explore the mechanism, 61 signal pathways might play an important role in CCIN treatment. Western Blot was employed to further confirm the potential pathway involved. We found CBL-ERK1/2 pathway was activated by SSD, followed by upregulating PU.1 and CEBPβ expression and leading to neutrophil differentiation. Our findings suggest a natural regimen SSD which could regenerate microbicidal neutrophils to effectively reduce CCIN-associated infection via activating CBL-ERK1/2, providing a rationale for future therapeutic approaches.
研究领域:
肿瘤学
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药理学
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免疫学
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分子生物学
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高影响因子
Journal of Oncology
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2022
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IF 4.501
Hongliang You,Dao Wang,Linlin Wei,Jiao Chen,Huanhuan Li,Yufeng Liu
Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer, with a feature of easy to induce multidrug resistance and relapse. Abundant studies have proved that iron overload strengthens the growth and metastasis of tumor cells. Herein, we found that deferoxamine (DFO) effectively decreased the concentration of intracellular iron in ALL cells. DFO inhibited proliferation, induced apoptosis, and obstructed cell cycle of ALL cells, whereas DFO and dextriferron (Dex) used in combination significantly decreased the sensitivity of ALL cells to DFO. Reactive oxygen species (ROS) level was reduced in ALL cells treated with DFO, and the combination of DFO and Dex reversed the effects of DFO. In vivo, DFO inhibited mouse tumor growth. Besides, cyclinD1, β-catenin, c-Myc, hypoxia inducible factor 1 (HIF-1), p-p38MAPK, and p-ERK1/2 protein levels were significantly downregulated, and the levels of prolyl hydroxylase-2 (PHD-2) were upregulated after treated with DFO, whereas Dex treatment reversed those in vivo and in vitro. In conclusion, DFO inhibited the proliferation and ALL xenograft tumor growth, obstructed the cell cycle, and induced apoptosis of ALL cells, probably via inactivating the ROS/HIF-1α, Wnt/β-catenin, and p38MAPK/ERK signaling.
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