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.
研究领域:
肝病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
NEUROSCIENCE LETTERS
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2022
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IF 3.197
Tianyi Yang,Guang Yue,Yu Ge,Yue Zhang,Peng Xu,Youmei Wang,Bo Li,Bin Di
Nitrous oxide (N 2 O) has a long history of abuse, but its abuse mechanism has not been clear yet. This research aimed at the possibility of mesolimbic dopaminergic system (MLDS) involved in the rewarding effect of N 2 O. In this work, the rewarding behavior of N 2 O in mice was evaluated using a typical gas-administered conditioned place preference (CPP) procedure. SCH 23390, a Dopamine D1 receptor (D1R) antagonist, and Haloperidol, a Dopamine D2 receptor (D2R) antagonist were administered during CPP to evaluate the role of dopamine receptors in the N 2 O-induced CPP. The accompanying changes in phosphorylation of extracellular signal-regulated kinase (ERK) in MLDS related brain regions, including the ventral tegmental area (VTA), caudate putamen (CPu), prefrontal cortex (PFC), and nucleus accumbens (NAc) were measured to assess the neural plasticity changes in the CPP mice by Western blot analysis. Results revealed that 60% N 2 O induced CPP in the gas-administered mice and promoted the ERK phosphorylation (p-ERK) in the NAc and CPu during the test session of the CPP test. Pretreatment of SCH 23390 (0.5 mg/kg) inhibited the acquisition of N 2 O-induced CPP and the enhanced p-ERK in NAc. It suggested that Dopamine D1 receptor may play an important role in the acquisition of N 2 O-induced CPP and the accompanied ERK activation in the NAc, which provide insight into the molecular mechanism in the rewarding properties of nitrous oxide.
研究领域:
神经科学
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药理学
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行为科学
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产品关联
DOI
PubMed
高影响因子
BRAIN RESEARCH BULLETIN
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2018
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IF 3.44
Tianhang Wang,Jiling Cheng,Shuyu Wang,Xudong Wang,Hongquan Jiang,Yueqing Yang,Ying Wang,Chunting Zhang,Weiwei Liang,Honglin Feng
Amyotrophic lateral sclerosis (ALS) is a degenerative disease with a progressive loss of motor neurons in the central nervous system (CNS). However, there are unsolved problems with the therapies for this disease. α-Lipoic acid (LA) is a natural, universal antioxidant capable of scavenging hydroxyl radicals as well as regenerating a series of antioxidant enzymes that has been widely used in clinical settings. This study aimed to evaluate the antioxidant and neuroprotective effects of LA in ALS cell and Drosophila models with mutant G85R and G93A hSOD1 genes. The biological effects of LA and the protein levels of several antioxidant factors were examined, as were those of phospho-Akt and phospho-ERK. Furthermore, specific inhibitors of the PI3K/Akt and MEK/ERK signaling pathways were used to analyze their effects on LA-induced antioxidant expression in vivo and in vitro . Evidences showed that the mutant hSOD1 resulted in the increased oxidative stress, abnormal antioxidant signaling and pathological behaviors in motor performance and survival compared with non-mutant hSOD1 models, treatment with LA improved motor activity and survival in transgenic flies, prevented NSC34 cells from mutant hSOD1 or H 2 O 2 induced decreased antioxidant enzymes as well as increased ROS levels. In addition, LA regulated the expression levels of antioxidant proteins in a dose- and periodical time-dependent manner, which might be mediated by ERK/Akt pathway activation and independent from the mutant hSOD1 gene. Our observations suggest that LA exerts strong and positive antioxidant and neuroprotective effects through the activation of the ERK-Akt pathway in hSOD1 ALS models.
研究领域:
神经科学
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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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产品关联
DOI
PubMed
高影响因子
INFLAMMATION
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2025
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IF 5
Li Ying,Wang Lei,Guan Tianyue,Chen Yaru,Zhu Wenting,Liu Xiao,Li Yusa,Huang Hongyu,Dong Zibo,Zhang Honggang
Diabetic cardiomyopathy (DCM) is a major complication of diabetes, characterized by myocardial inflammation, oxidative stress, fibrosis, apoptosis, and RhoA activation, ultimately leading to heart failure. This study aimed to evaluate whether higenamine hydrochloride (HGN), a natural alkaloid with anti-inflammatory and antioxidant properties, could alleviate DCM and elucidate its underlying mechanisms. A DCM model was established via streptozotocin injection in mice, followed by HGN administration. Fasudil, a RhoA inhibitor, was used to assess pathway involvement. Histology, biochemical assays, flow cytometry, immunoblotting, ELISA, and qPCR were employed for evaluation. Results showed that HGN effectively alleviated cardiac histological abnormalities and myocardial injury in DCM mice. Further analysis revealed that HGN attenuated DCM-induced cardiac inflammation, oxidative stress, fibrosis, and apoptosis ( p < 0.05). In vitro, HGN also reduced high glucose-induced inflammation, oxidative stress, fibrosis, and apoptosis in H9C2 cardiomyocytes ( p < 0.05). Mechanistically, these protective effects were mediated by inhibition of RhoA, through which HGN suppressed the MEK/ERK signalling pathway, thereby mitigating cardiomyocyte injury ( p < 0.05). However, the RhoA inhibitor fasudil hydrochloride abolished the cardioprotective effects of HGN in DCM mice, specifically, fasudil hydrochloride reversed the HGN-induced improvements in cTnT, CK, and LDH levels. Additionally, echocardiographic parameters (IVSD, LVPWd, LVPWs, LVIDd, LVIDs, IVSs, EF, and FS) were also reversed to levels seen in untreated DCM mice, further confirming that HGN exerts its therapeutic actions via the RhoA/MEK/ERK axis ( p < 0.05). Overall, HGN mitigates cardiac inflammation, oxidative stress, fibrosis, and apoptosis in DCM by inhibiting the MEK/ERK pathway through RhoA. This study provides a scientific basis for developing DCM treatments and highlights the therapeutic potential of HGN. Graphical
研究领域:
心血管研究
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分子生物学
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药理学
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内分泌学
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糖尿病并发症
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产品关联
DOI
PubMed
高影响因子
NEUROTOXICOLOGY
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2023
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IF 3.4
Tong Zhang,Chunmei Zhang,Yuyou Luo,Shuping Liu,Siyuan Li,Lixia Li,Yuxin Ma,Jing Liu
The present study aimed to investigate the protective effect of rutin on the injury of spinal motor neuron in rats exposed to acrylamide (ACR) the underlying mechanism. Fifty male Sprague-Dawley rats, aged 7–8 weeks, were randomly divided into control group, ACR group (20 mg/kg), low dose(100 mg/kg), medium dose (200 mg/kg) and high dose(400 mg/kg) rutin groups, ten rats in each group. The rats were given intragastric administration for 21 days. Every week, a neurobehavioral test was conducted. Nissl staining was used to observe the morphological changes in motor neurons in the L4-L6 segment of the spinal cord . Immunohistochemistry was used to identify AChE and ChAT in the rat spinal cord. Western blot was used to identify the expression of AChE, ChAT, P-ERK, ERK, and Nrf2 proteins in the rat spinal cord. The commercial kits were used to detect the presence of SOD, GSH, and LDH in the rat spinal cord. At the start of the second week, the medium and high dosage rutin group's rats' gait scores significantly decreased as compared to those of the ACR group. When rutin dosage was increased, the Nissl staining revealed that Nissl bodies was staining intensified compared to the ACR group. Immunohistochemistry and Western blot analysis revealed that AChE and ChAT expression changed when rutin dose was raised, but P-ERK and Nrf2 expression steadily increased in the spinal cord of rats in the medium and high dose groups compared to the ACR group. In the spinal cord of rats in each dosage group compared to the ACR group, the findings of the oxidative stress indices demonstrated that the expression levels of SOD and GSH rose with the increase of rutin dose, while the expression of LDH reduced with the rise of rutin dose. Rutin has an anti-oxidative impact through up-regulating the expression of P-ERK and Nrf2 proteins in the ERK/Nrf2 pathway, which may be connected to its protective action on motor neurons in the spinal cord of rats exposed to ACR.
研究领域:
神经科学
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药理学
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毒理学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2021
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IF 5.811
Jiang Yuhong,Zhuo Xin,Fu Xiujuan,Wu Yue,Mao Canquan
Drug resistance can notably restrict clinical applications of gefitinib that is a commonly used EGFR-tyrosine kinase inhibitors (EGFR-TKIs) for non-small cell lung cancer (NSCLC). The attempts in exploring novel drug targets and reversal strategies are still needed, since gefitinib resistance has not been fully addressed. Protease-activated receptor 2 (PAR2), a G protein-coupled receptor, possesses a transactivation with EGFR to initiate a variety of intracellular signal transductions, but there is a lack of investigations on the role of PAR2 in gefitinib resistance. This study established that protease-activated receptor 2 (PAR2), actively participated in NSCLC resistant to gefitinib. PAR2 expression was significantly up-regulated when NSCLC cells or tumor tissues became gefitinib resistance. PAR2 inhibition notably enhanced gefitinib to modulate EGFR transactivation, cell viability, migration and apoptosis in gefitinib-sensitive and-resistant NSCLC cells, suggesting its reversal effects in gefitinib resistance. Meanwhile, the combination of a PAR2 inhibitor (P2pal-18S) and gefitinib largely blocked ERK phosphorylation and epithelial-mesenchymal transition (EMT) compared to gefitinib alone. Importantly, we probed its underlying mechanism and uncovered that PAR2 blockade sensitized gefitinib and reversed its resistance mainly via β-arrestin-EGFR-ERK signaling axis. These effects of PAR2 inhibition were further confirmed by the in vivo study which showed that P2pal-18S reactivated gefitinib to inhibit tumor growth via restricting ERK activation. Taken together, this study could not only reveal a new mechanism of receptor-mediated transactivation to modulate drug resistance, but also provide a novel drug target and direction for overcoming gefitinib resistance in NSCLC.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
Current Molecular Pharmacology
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2023
·Vol. 16
·期 7
·712-724
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IF 2.7
Song Jin,Xu Xiaolong,He Shasha,Wang Ning,Bai Yunjing,Chen Zhaoxia,Li Bo,Zhang Shengsheng
Background: Myristicin is a type of natural compound showing anti-proliferative, anti-microbial, and anti-inflammatory effects. However, its role in gastric cancer treatment remains unknown. Objective: In this study, the effect of myristicin on gastric cancer as well as its underlying
mechanism was investigated. Methods: Human gastric cancer cells were exposed to various concentrations of myristicin (0, 7.8125, 15.625, and 31.25 μM) for 48 h. Then CCK-8, fluorescence-activated cell sorting, and Hoechst staining were performed to evaluate the cell proliferation and
apoptosis. The levels of proteins associated with cell cycle, apoptosis, endoplasmic reticulum (ER) stress, and EGFR/ERK signaling pathway were detected by western blot. JC-1 staining was conducted to determine the mitochondrial membrane potential. On the other hand, the effect of myristicin
on gastric cancer growth and apoptosis was also determined in vivo. Results: Myristicin retarded proliferation and induced ER stress and apoptosis in gastric cancer cells, with decreased expression of cyclins, increased Bax expression, activated caspases, and enhanced cytochrome C release
and mitochondrial ROS. Furthermore, the EGFR/ERK signaling pathway was restrained by myristicin. In addition, EGFR over-expression abolished the inhibitory function of myristicin on proliferation, apoptosis, and ER stress. Also, myristicin inhibited the growth of gastric cancer cells as well
as the EGFR/ERK signaling pathway in vivo. Conclusion: Myristicin exerts an anti-cancer effect on gastric cancer cells by restraining the EGFR/ ERK signaling pathway. It may have the potential to be applied as a novel drug in gastric cancer treatment.
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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分子生物学
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DOI
PubMed
高影响因子
International Journal of Polymeric Materials and Polymeric Biomaterials
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2024
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IF 2.5
Sizhen Huang,Haodi Kou,Zhichao Zheng,Ming Lu,Lihong Wu,Huade Zheng
Angiogenesis within the wound site is a necessary prerequisite for skin tissue regeneration during the process of wound healing. Skin vessels provide adequate nutrients and soluble bioactive factors to the wounded area and remove metabolites. In this study, we prepared a double-cross-linked hydrogel based on GelMA and PVAMA to load Myeloid-derived growth factor (MYDGF). Additionally, we evaluated the healing-promoting effect of the hydrogel using a full-thickness skin injury mouse model. Compared with the control and MYDGF-free hydrogels, the MYDGF-loaded hydrogels significantly increased the percentage of wound healing and promoted granulation tissue proliferation and epidermization. In vitro experiments have shown that MYDGF may augment the migration and angiogenesis of human umbilical vein endothelial cells (HUVECs) by upregulating the expression of phosphorylated ERK and phosphorylated P38. These findings indicate that MYDGF-loaded hydrogels promote wound healing by accelerating angiogenesis.
研究领域:
生物材料学
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再生医学
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细胞生物学
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产品关联
DOI
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
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2021
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IF 4.739
Rui Yu,Mi Tian,Ping He,Jie Chen,Zixia Zhao,Yongzhe Zhang,Beiru Zhang
Tubulointerstitial fibrosis is a common pathway of chronic kidney disease (CKD) and is closely related to the progression of CKD. LMCD1, acting as an intermediary, has been reported to play a role in cardiac fibrosis. However, its role in renal fibrosis is yet to be deciphered. Based on the GEO database, we found the expression of LMCD1 is increased in kidney tissues of CKD patients and in human proximal tubular epithelial (HK-2) cells treated with transforming growth factor-β1 (TGF-β1), suggesting that LMCD1 may be involved in tubulointerstitial fibrosis. Herein, we investigated the role of LMCD1 in mice with unilateral ureteral obstruction (UUO) and in TGF-β1-stimulated HK-2 cells. In the UUO model, the expression of LMCD1 was upregulated. UUO-induced renal histopathological changes were mitigated by knockdown of LMCD1. LMCD1 silence alleviated renal interstitial fibrosis in UUO mice by decreasing the expression of TGF-β1, fibronectin, collagen I, and collagen III. LMCD1 deficiency suppressed cell apoptosis in kidney to prevent UUO-triggered renal injury. Furthermore, LMCD1 deficiency blocked the activation of ERK signaling in UUO mice. In vitro, LMCD1 was upregulated in HK-2 cells after TGF-β1 stimulation. LMCD1 silence abrogated TGF-β1-mediated upregulation of fibrotic genes. Treatment of HK-2 cells with ERK-specific inhibitor SCH772984 and agonist TPA validated LMCD1 exerted its function via activating ERK signaling. Together, our findings suggest that inhibition of LMCD1 protects against renal interstitial fibrosis by impeding ERK activation.
研究领域:
肾病学
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分子生物学
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细胞生物学
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病理学
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DOI
PubMed
高影响因子
Chinese Medicine
·
2022
·Vol. 17
·期 1
·1-18
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IF 4.546
Pan Boyu,Xia Yafei,Gao Zilu,Zhao Gang,Wang Liangjiao,Fang Senbiao,Liu Liren,Yan Shu
Background Colon cancer (CC) ranks the second highest mortality rate among malignant tumors worldwide, and the current mainstream treatment regimens are not very effective. The unique efficacy of Chinese herb medicine (CHM) for cancer has recently attracted increasing attention. Cinnamomi Ramulus (CR), as a classic CHM, has been widely used in the treatment of a variety of diseases for hundreds of years in China, but its specific pharmacological mechanism against CC needs to be fully evaluated.Methods TCMSP and China National Knowledge Infrastructure database were utilized to predict the candidate ingredients of CR, and TCMSP and SwissTargetPrediction database were also employed to predict the drug targets of the candidate ingredients from CR. We subsequently evaluated the therapeutic effect of CR by orally administrating it on CC-bearing mice. Next, we further identified the potential CC-related targets by using Gene Expression Omnibus (GEO) database. Based on these obtained targets, the drug/disease-target PPI networks were constructed using Bisogenet plugin of Cytoscape. The potential core therapeutic targets were then identified through topological analysis using CytoNCA plugin. GO and KEGG enrichment analyses were performed to predict the underlying mechanism of CR against CC. Furthermore, these in silico analysis results were validated by a series of cellular functional and molecular biological assays. UPLC–MS/MS method and molecular docking analysis were employed to identify the potential key components from CR.Results In this study, we firstly found that CR has potential therapeutic effect on cancer. Then, oral administration of CR could inhibit the growth of CC cells in C57BL/6 mice, while inhibiting the viability and motility of CC cells in vitro. We obtained 111 putative core therapeutic targets of CR. Subsequent enrichment analysis on these targets showed that CR could induce apoptosis and cell cycle arrest in CC cells by blocking Akt/ERK signaling pathways, which was further experimentally verified. We identified 5 key components from the crude extract of CR, among which taxifolin was found most likely to be the key active component against CC.Conclusion sOur results show that CR as well as its active component taxifolin holds great potential in treatment of CC.
研究领域:
肿瘤学
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药理学
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分子生物学
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中医药
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DOI
PubMed
高影响因子
EXPERIMENTAL DERMATOLOGY
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2019
·Vol. 29
·期 2
·149-157
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IF 2.868
Jinpeng Lv,Ying Fu,Yan Cao,Songzhou Jiang,Ying Yang,Guoqiang Song,Changjun Yun,Rongyin Gao
Isoliquiritigenin (ISL), a flavonoid component from the hydrolysis products of licorice root. It has been reported that ISL inhibited melanogenesis by suppressing the tyrosinase activity in human melanocytes. Recently, ISL was found to induce melanin degradation in human epidermal keratinocytes. However, the role of ISL in pigmentation is not fully understood. In the current study, we aimed to investigate the effects of ISL on pigmentation, and further explored the underlying mechanism. Our results suggested that ISL suppressed basal and α-MSH-, ACTH- and UV-induced melanin synthesis, in addition to inhibiting melanocyte dendricity and melanosome transport. ISL played these roles mainly by activating the extracellular signal-regulated protein kinase pathway. Once activated, it induced microphthalmia-associated transcription factor degradation and decreased the expression of tyrosinase, TRP-1, DCT, Rab27a and Cdc42, finally inhibited melanogenesis, melanocyte dendricity and melanosome transport. Our findings suggested that ISL exhibited no cytotoxicity in our research, it may prove quite useful as a safer natural skin-whitening agent.
研究领域:
药理学
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细胞生物学
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皮肤病学
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2017
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IF 2.759
Yanmei Li,Nianwei Chang,Yanqi Han,Mengge Zhou,Jie Gao,Yuanyuan Hou,Min Jiang,Tiejun Zhang,Gang Bai
Background Shufengjiedu Capsule (SFJD) is a type of Chinese traditional medicine compound for the treatment of acute upper respiratory tract infection . The present work aims to decipher the mechanism of SFJD. Methods In this study, we used target prediction and RNA sequence (RNA-Seq) based on transcriptome analysis to clarify the inflammation–eliminating mechanism of SFJD. Firstly, Pseudomonas aeruginosa (PAK) was used to induce acute lung injury in KM mice . After being treated by SFJD, the differently expressed genes were analyzed by RNA-Seq. Secondly, the chemical constituents of SFJD were identified by ultra-performance liquid chromatography quadrupole/time of flight mass spectrometry (UPLC/Q-TOF-MS) and submitted to PharmMapper to predict targets. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and String 9.1 websites were employed to establish the interaction network of inflammation of these targets. Results The results indicated that SFJD alleviated PAK induced lung injury in KM mice. We infer that the mechanism is a complex network containing 15 pathways related to inflammation regulated by 16 types of components from six types of herbs via 29 proteins. The ERK signaling pathway was a key pathway among them, which was predicted to be regulated by 14 types of components in SFJD. Phillyrin, emodin , and verbenalin were screened out by binding capacity, and the synergistic effect of them was further confirmed. Conclusions Various components of SFJD ameliorated PAK induced upper respiratory tract infection via multiple targets, of which ERK phosphorylation might be the key event regulated specifically by verbenalin, phillyrin and emodin.
研究领域:
药理学
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分子生物学
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中医中药
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传染病学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）