MOLECULES
·
2023
·Vol. 28
·期 8
·3395
·
IF 4.6
Yi Ou,Zonglin You,Min Yao,Yingfan Cao,Xiu Xue,Min Chen,Rihui Wu,Lishe Gan,Dongli Li,Panpan Wu,Xuetao Xu,Wingleung Wong,Vincent Kam Wai Wong,Wenfeng Liu,Jiming Ye,Jingwei Jin
Naproxen is widely used for anti-inflammatory treatment but it can lead to serious side effects. To improve the anti-inflammatory activity and safety, a novel naproxen derivative containing cinnamic acid (NDC) was synthesized and used in combination with resveratrol. The results showed that the combination of NDC and resveratrol at different ratios have a synergistic anti-inflammatory efficacy in RAW264.7 macrophage cells. It was indicated that the combination of NDC and resveratrol at a ratio of 2:1 significantly inhibited the expression of carbon monoxide (NO), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), induced nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2) and reactive oxygen species (ROS) without detectable side effects on cell viability. Further studies revealed that these anti-inflammatory effects were mediated by the activation of nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt) signaling pathways, respectively. Taken together, these results highlighted the synergistic NDC and resveratrol anti-inflammatory activity that could be further explored as a strategy for the treatment of inflammatory disease with an improved safety profile.Keywords:naproxen derivative;resveratrol;synergistic;anti-inflammatory;mechanism
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EXPERIMENTAL NEUROLOGY
·
2023
·
IF 5.3
Jing Zhao,Meini Le,Jie Li,Qiong Huang,Haocong Chen,Wenyi Zhang,Huiwen Mao,Qing Sun,Aiguo Li,Yingmin Zhao,Lingling Yu,Mingjiang Yi,Jie Wang,Xinyuan Li,Guangming Zhang,Jun Ma,Xiaohua Dong
Hypoxic-ischemic encephalopathy (HIE) is an important factor leading to permanent damage of central nervous system (CNS) and even neonatal death . Long non-coding RNAs (lncRNAs) has been shown to get involved in the pathogenesis of nervous system diseases . LINC00938 is an intergenic lncRNA which is reported to be involved in neurodegenerative disease . However, the potential role of LINC00938 in nerve injury of neonatal HIE is undetermined. Here, we found that the expression of LINC00938 in the whole blood of neonates with HIE was downregulated compared with the non-HIE group. Functional study revealed that the expression of LINC00938 was significantly decreased in oxygen-glucose deprivation (OGD)-induced SH-SY5Y. Knockdown of LINC00938 induced the neural cell apoptosis by increased the protein level of Bax, Cleaved-Caspase3 and decreased the expression of Bcl-2. In addition, overexpression of LINC00938 prevented the apoptosis of SH-SY5Y from OGD injury. RNA-seq analysis showed that MAPK signaling was involved in the anti-apoptosis function of LINC00938. LINC00938 knockdown induced the activation of c-Jun-N-terminal kinase (JNK), p38 mitogen-activated protein kinase, and inhibited the activation of ERK signaling. However, LINC00938 play neuroprotective role in OGD-induced SH-SY5Y by suppression the phosphorylation of JNK and p38 MAPK rather than regulation of ERK signaling pathway . Further analyses illustrated that the cell apoptosis of neuronal cell was dependent on the elevation of reactive oxygen species (ROS) and result in mitochondria dysfunction in LINC00938 knockdown SH-SY5Y. Pretreated with ROS inhibitor N -acetylcysteine amide (NACA) dramatically suppressed LINC00938 knockdown induced oxidative stress and mitochondria dysfunction which induced cell apoptosis. In addition, NACA treatment significantly reduced the expression of p-JNK and p-p38 in OGD-induced SH-SY5Y. Furthermore, overexpression of LINC00938 displayed a notably neuroprotective effect by suppress central nervous system cell apoptosis via alleviating oxidative stress in CoCl 2 -induced hypoxic HIE model of zebrafish. Taken together, these results suggested that LINC00938 can act as a neuroprotective factor to inhibit oxidative stress and apoptosis of CNS under HIE conditions.
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LIFE SCIENCES
·
2023
·
IF 6.1
Haijie Wu,Xiaohu Shi,Yingda Zang,Xiaodi Zhao,Xikun Liu,Weida Wang,Wenying Shi,Clarence T.T. Wong,Li Sheng,Xiaoguang Chen,Sen Zhang
Aims Cisplatin is a widely-used drug in the clinical treatment of tumors, but kidney nephrotoxicity is one of the reasons that limits its widespread use. We previously found that 7-hydroxycoumarin-β-D-glucuronide (7-HCG) was one of metabolites of skimmin and highly enriched in the kidneys and maintained a high blood concentration in skimmin-treated rats. Therefore, we investigated whether 7-HCG has a protective effect on cisplatin-induced acute kidney injury. Materials and methods Male C57BL/6 mice were continuously administered 7-HCG for five days, and on the third day, an intraperitoneal injection of cisplatin was given to induce acute kidney injury. After 72 h, the mice were sacrificed for analysis. Serum and renal tissue were collected for renal function evaluation. RNA sequencing was used to explore mechanism, and further validated by western blot and immunohistochemistry. In addition, pharmacokinetic study of oral 7-HCG administration was performed to examine how much 7-hydroxycoumarin (7-HC) was metabolized and 7-HC possible effect on renal protection. Key findings 7-HCG significantly reduced serum BUN and SCR levels, and alleviated pathological damage in renal tissue, and reduced the renal index. RNA sequencing revealed that 7-HCG could reverse p38 MAPK regulation and apoptosis. By western blotting, it was found that 7-HCG could reduce renal injury by reducing p-p38, p-ERK, p-JNK, cleaved-caspase3 and Bax. The immunohistochemical results of cleaved-caspase3 were consistent with western blotting. 7-HCG also significantly reduced the production of ROS in kidney tissue. Pharmacokinetic experiments have shown that 7-HCG in the blood increased rapidly and was eliminated slowly, with an average t 1/2β of 18.3 h. And the concentration of 7-HCG in the target organ kidney was about 4 times higher than that in blood. Significance Our findings indicate that 7-HCG could exert its protective effect against cisplatin-induced acute kidney injury by inhibiting apoptosis via p38 MAPK regulation and elucidates its pharmacokinetics.
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Frontiers in Pharmacology
·
2022
·
IF 5.988
Zuoxing Wu,Chen Li,Yu Chen,Qian Liu,Na Li,Xuemei He,Weibin Li,Rong Shen,Li Li,Chenming Wei,Siyuan Shao,Fangsheng Fu,Jiaxin Ding,Xiaochen Sun,Dairong Wang,Guixin Yuan,Yiji Su,Jinmin Zhao,Jiake Xu,Ren Xu,Xin Xu,Feng Xu
Bone homeostasis only exists when the physical function of osteoblast and osteoclast stays in the balance between bone formation and resorption. Bone resorption occurs when the two processes are uncoupled, shifting the balance in favour of bone resorption. Excessive activation of osteoclasts leads to a range of osteolytic bone diseases including osteoporosis, aseptic prosthesis loosening, rheumatoid arthritis, and osteoarthritis. Receptor activator of nuclear factor kappa-B ligand (RANKL) and its downstream signaling pathways are recognized as key mediators that drive the formation and activation of osteoclastic function. Hence, osteoclast formation and/or its function remain as dominant targets for research and development of agents reaching the treatment towards osteolytic diseases. Chrysin (CHR) is a flavonoid with a wide range of anti-inflammatory and anti-tumor effects. However, its effect on osteoclasts remains unknown. In this study, we found the effects of CHR on inhibiting osteoclast differentiation which were assessed in terms of the number and size of TRAcP positive multinucleated osteoclasts (OCs). Further, the inhibitory effects of CHR on bone resorption and osteoclast fusion of pre-OC were assessed by hydroxyapatite resorption pit assay and F-actin belts staining; respectively. Western blotting analysis of RANKL-induced signaling pathways and immunofluorescence analysis for p65 nuclear translocation in response to RANKL-induced osteoclasts were used to analyze the mechanism of action of CHR affecting osteoclasts. Lastly, the murine calvarial osteolysis model revealed that CHR could protect against particle-induced bone destruction in vivo . Collectively, our data strongly suggested that CHR with its promising anti-tumor effects would also be a potential therapeutic agent for osteolytic diseases.
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JOURNAL OF ETHNOPHARMACOLOGY
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2022
·
IF 5.195
Jing Han,Haotian Zhang,Yu Zhang,Zan Zhang,Maomao Yu,Sijie Wang,Fei Han
Ethnopharmacological relevance Alzheimer's disease (AD) is recognized as one of the most prevalent neurodegenerative diseases . Lingguizhugan decoction (LGZGD) is a classical traditional Chinese medicine (TCM). Many studies have shown that LGZGD can alleviate the symptoms of AD. Aim of the study The aim of this study was to assess the neuroprotective effects of LGZGD and elucidate its molecular mechanism on Aβ 25-35 -induced PC12 cells. Materials and methods PC12 cells were used MTT assays, ELISA , fluorescence probe analyses, Hoechst 33342 staining, immunofluorescent staining and western blot analyses were systematically conducted to evaluate the underlying mechanisms of LGZGD. Results In Aβ 25-35 -induced PC12 cells, LGZGD remarkably increased cell viability, reduced the generation of TNF-α, IL-1β, IL-6, MDA and ROS , increased the activity of GSH-Px, inhibited cell apoptosis , downregulated the expression of Bax and cleaved caspase-3, and upregulated the expression of Bcl-2. Moreover, LGZGD modulated the NF-κB/MAPK signaling pathways by upregulating the levels of IκBα and phospho-ERK, while downregulating the levels of phospho-p65, phospho-IκBα, and phospho-p38. Furthermore, LGZGD repressed the nuclear translocation activity of NF-κB p65. Meanwhile, LGZGD increased the expression of phospho-GSK-3β and reversed the hyperphosphorylation of Tau proteins by inhibiting the activation of the ERK MAPK pathway. Conclusions Taken together, the present study suggested that LGZGD may be a valuable drug candidate that can attenuate the neurotoxicity induced by Aβ 25-35 by modulating the NF-κB/MAPK signaling pathways in PC12 cells.
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Marine Drugs
·
2022
·Vol. 20
·期 2
·110
·
IF 6.085
Chunlei Li,Sirui Zhang,Jianhua Zhu,Weijuan Huang,Yuanyuan Luo,Hui Shi,Dongbo Yu,Liguo Chen,Liyan Song,Rongmin Yu
Colorectal carcinoma (CRC) is one of the major causes of cancer-related incidence and deaths. Here, we identified a novel antitumor peptide, P6, with a molecular weight of 2794.8 Da from a marine Chinese medicine,Arca inflataReeve. The full amino acid sequence and secondary structure of P6 were determined by tandem mass de novo sequencing and circular dichroism spectroscopy, respectively. P6 markedly inhibited cell proliferation and colony formation, and induced apoptosis in CRC cells. Mechanistically, transcriptomics analysis and a serial functional evaluation showed that P6 induced colon cancer cell apoptosis through the activation of the p38-MAPK signaling pathway. Moreover, it was demonstrated that P6 exhibited antitumor effects in a tumor xenograft model, and induced cell cycle arrest in CRC cells in a concentration-dependent mode. These findings provide the first line of indication that P6 could be a potential therapeutic agent for CRC treatment.Keywords:Arca inflata;antitumor peptide;apoptosis;MAPK signaling;calmodulin;colorectal cancer
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ENVIRONMENTAL TOXICOLOGY
·
2023
·
IF 4.5
Shuang Wang,Xueyan Gu,Jianhua Ma,Zhangyu Gu,Rui Zhang,Ruifen Li,Jun Bai,Peng Li,Linyu Wei,Yixing Ye,Yan Wang,Li Zhang,Li Su,Changhao Liang
The present study was designed to investigate the role of miR-708-5p/p38 mitogen-activated protein kinase (MAPK) pathway during the mechanism of selenium nanoparticles (Nano-Se) against nickel (Ni)-induced testosterone synthesis disorder in rat Leydig cells. We conducted all procedures based on in vitro culture of rat primary Leydig cells. After treating Leydig cells with Nano-Se and NiSO 4 alone or in combination for 24 h, we determined the cell viability, reactive oxygen species (ROS) levels, testosterone production, and the protein expression of key enzymes involved in testosterone biosynthesis: steroidogenic acute regulatory (StAR) and cytochrome P450 cholesterol side chain cleavage enzyme (CYP11A1). The results indicated that Nano-Se antagonized cytotoxicity and eliminated ROS generation induced by NiSO 4 , suppressed p38 MAPK protein phosphorylation and reduced miR-708-5p expression. Importantly, we found that Nano-Se upregulated the expression of testosterone synthase and increased testosterone production in Leydig cells. Furthermore, we investigated the effects of p38 MAPK and miR-708-5p using their specific inhibitor during Nano-Se against Ni-induced testosterone synthesis disorder. The results showed that Ni-inhibited testosterone secretion was alleviated by Nano-Se co-treatment with p38 MAPK specific inhibitor SB203580 and miR-708-5p inhibitor, respectively. In conclusion, these findings suggested Nano-Se could inhibit miR-708-5p/p38 MAPK pathway, and up-regulate the key enzymes protein expression for testosterone synthesis, thereby antagonizing Ni-induced disorder of testosterone synthesis in Leydig cells.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2021
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IF 5.279
Jinwen Yuan,Siyan Che,Li Zhang,Zheng Ruan
Luteolin, a dietary flavonoid, has gained increasing interest as an intestinal protectant. This study aimed to evaluate the reparative effect of luteolin against ethanol-induced intestinal barrier damage in a Caco-2 cell monolayer model and the potential mechanisms. Luteolin attenuated ethanol-induced intestinal barrier injury, by increasing transepithelial monolayer resistance (TEER, 27.75 ± 14.75% of the ethanol group, p < 0.01), reducing Lucifer yellow flux (13.21 ± 1.23% of ethanol group, p < 0.01), and upregulating the expression of tight junction (TJ) proteins zonulin occludin-1 (ZO-1), occludin, and claudin-1 (37.963 ± 8.62%, 17.69 ± 7.35%, and 29.40 ± 8.08% of the ethanol group, respectively, p < 0.01). Further mechanistic studies showed that luteolin suppressed myosin light chain 2 (MLC) phosphorylation, myosin light chain kinase (MLCK) activation, nuclear factor kappa-B (NF-κB) nuclear translocation, and mitogen-activated-protein-kinase (MAPK) phosphorylation. Moreover, luteolin also acted as antioxidants indirectly by upregulating antioxidant-responsive-element (ARE) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation to relieve ethanol-induced oxidative damage and TJ dysfunction. The results of the study indicate that luteolin may play an effective role in relieving intestinal barrier damage, and this effect is at least partially due to its indirect antioxidant capacity.
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AMERICAN JOURNAL OF CHINESE MEDICINE
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2020
·Vol. 48
·期 06
·1455-1473
·
IF 3.682
Xiao-Wei Zhang,Mei Zhou,Lin An,Ping Zhang,Ping Li,Jun Chen
Uric acid nephropathy (UAN) is caused by excessive uric acid, which results in the damage of renal tissue via urate crystals deposition in the kidneys. The roots and rhizomes of Salvia miltiorrhiza Bunge ( S. miltiorrhiza ) have been clinically used in many prescriptions to treat uric acid-induced renal damage. This study investigates the uricosuric and nephroprotective effects of the ethyl acetate extract of S. miltiorrhiza (EASM) and tanshinone IIA (a major component of S. miltiorrhiza , Tan-IIA) on UAN and explores the underlying molecular mechanism. Both EASM and Tan-IIA significantly decreased serum uric acid (SUA), serum creatinine (SCR), urine uric acid (UUA), and increased urine creatinine (UCR), and blood urea nitrogen (BUN) levels in experimental UAN mice. In adenine and potassium oxonate-induced mice, EASM and Tan-IIA treatment alleviated renal dysfunction and downregulated the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Moreover, EASM treatment significantly prevented excessive reactive oxygen species (ROS) production in uric acid-induced HK-2 cells and suppressed the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). EASM also suppressed ROS-activated mitogen-activated protein kinases (MAPKs) in vivo and in vitro . These results suggest that both EASM and Tan-IIA demonstrated inhibitory effects on UAN through relieving NOX4-mediated oxidative stress and suppressing MAPK pathways activation.
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Marine Drugs
·
2020
·Vol. 18
·期 6
·328
·
IF 4.073
Jing Ye,Donghui Chen,Zhicheng Ye,Yayan Huang,Na Zhang,Edmund M. K. Lui,Changhu Xue,Meitian Xiao
Fucoidan has been reported to have a variety of biological activities. However, different algae species, extraction methods, harvesting seasons, and growth regions lead to the structural variation of fucoidan, which would affect the bioactivities of fucoidan. To date, the anti-inflammatory properties and the underlying mechanism of fucoidan from brown algaSaccharina japonica(S. japonica) remain limited. The aims of the present study were to investigate the structure, the anti-inflammatory properties, and the potential molecular mechanisms of fucoidan isolated fromS. japonica(SF6) against lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. SF6 was characterized using high performance liquid gel permeation chromatography (HPGPC), Fourier transform infrared spectroscopy (FTIR), and nuclear magnetic resonance spectroscopy (NMR), and observed to be rich in fucose, galactose, and sulfate. Additionally, results showed that SF6 remarkably inhibited LPS-induced production of various inflammatory mediators and pro-inflammation cytokines, including nitric oxide (NO), NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-β (IL-β), and interleukin-6 (IL-6). A mechanism study showed that SF6 could effectively inhibit inflammatory responses through blocking LPS-induced inflammation pathways, including nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and Janus kinase (JAK)-2 and signal transducer and activator of transcription (STAT)-1/3 pathways. These results suggested that SF6 has the potential to be developed as an anti-inflammatory agent applied in functional food.Keywords:fucoidan;Saccharina japonica;anti-inflammation;mechanism
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International Journal of Biological Sciences
·
2021
·
IF 6.582
Yadong Liu,Huiyan Lv,Xingyi Li,Jiannan Liu,Song Chen,Yaodong Chen,Yinshan Jin,Ruihua An,Shiliang Yu,Zhigang Wang
Of all pathological types of renal cell cancer (RCC), clear cell renal cell carcinoma (ccRCC) has the highest incidence. Cyclovirobuxine (CVB), a triterpenoid alkaloid isolated from Buxus microphylla , exhibits antitumour activity against gastric cancer and breast cancer; however, the mechanism by which CVB inhibits ccRCC remains unclear. The aim of our study was to explore the antitumour effects of CVB on ccRCC and to elucidate its exact mechanism. Cell viability, proliferation, cell cycle distribution, apoptosis, wound healing and invasion were evaluated. Furthermore, Western blotting, immunofluorescence staining, immunohistochemical staining, and bioinformatics analyses were utilized to comprehensively probe the molecular mechanisms. The in vivo curative effect of CVB was explored using a 786-O xenograft model established in nude mice. CVB reduced cell viability, proliferation, angiogenesis, the epithelial-mesenchymal transition (EMT), migration and invasion. In addition, CVB induced cell cycle arrest in S phase and promoted apoptosis. The expression of the EMT-related transcription factor Snail was significantly downregulated by CVB via the inhibition of the AKT, STAT3 and MAPK pathways. We revealed that insulin-like growth factor binding protein 3 (IGFBP3) was the true therapeutic target of CVB. CVB exerted anti-ccRCC effects by blocking the IGFBP3-AKT/STAT3/MAPK-Snail pathway. Targeted inhibition of IGFBP3 with CVB treatment may become a promising therapeutic regimen for ccRCC.
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INFLAMMATION
·
2021
·Vol. 44
·期 5
·2018-2032
·
IF 4.092
Zhou Changkai,Gao Jing,Ji Hongyan,Li Wenjing,Xing Xiaomin,Liu Donghua,Guo Qie,Zhou Lihua,Jing Fanbo
Previous studies have shown that benzoylaconine (BAC), a representative monoester alkaloid, has a potential anti-inflammatory effect. This study investigated the underlying molecular mechanisms using the mode of LPS-activated RAW264.7 macrophage cells. Our findings showed that BAC significantly suppressed the release of pro-inflammatory cytokines and mediators, including IL-6, TNF-α, IL-1β, ROS, NO, and PGE 2 . BAC treatment also effectively downregulated the elevated protein levels of iNOS and COX-2 induced by LPS in a dose-dependent manner. In this study, we found that BAC inhibited LPS-induced NF-κB activation by reducing the phosphorylation and degradation of IκBα by western blotting and blocking the nuclear translocation of p65 using an immunofluorescence assay. The elevated protein levels of JNK, p38, and ERK phosphorylation after LPS stimulation were restored effectively by BAC treatment. The protein expression of Toll-like receptor 4 (TLR4) and LPS-induced phosphorylation of TAK1, which is a crucial upstream regulatory factor of TLR-induced MAPK and NF-κB signaling, were inhibited by BAC in activated RAW264.7 macrophages. Moreover, BAC decreased the levels of TAK1 phosphorylation and pro-inflammatory cytokines and mediators associated with MAPK and NF-κB activation, similar to TLR4 inhibitor TAK-242. These findings demonstrated that BAC exhibited an anti-inflammatory effect by the inhibition of TLR-induced MAPK and NF-κB pathways, indicating that it could potentially be used for treating inflammatory diseases.
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