Experimental and Therapeutic Medicine
·
2022
·Vol. 24
·期 6
·1-8
·
IF 2.751
Na Ren,Shanshan Shi,Na Zhao,Lingyan Zhang
Dual specificity phosphatase 22 (DUSP22) regulates fibrosis and inflammation, which may be implicated in the development of diabetic nephropathy (DN). Hence, the current study aimed to assess the effect of DUSP22 on cell proliferation, apoptosis, fibrosis and inflammation in mouse mesangial cell line (SV40‑MES13) under both high glucose (HG) and low glucose (LG) conditions. SV40‑MES13 cells were treated with HG and LG, then HG‑group cells were transfected with DUSP22 overexpression and control plasmids, meanwhile LG‑group cells were transfected with DUSP22 and control siRNAs. Then, cell proliferation using Cell Counting Kit‑8, cell apoptosis by TUNEL assay, protein expression using western blotting, inflammatory cytokines using ELISA and RNA using reverse transcription‑quantitative PCR were determined. DUSP22 mRNA and protein were decreased in SV40‑MES13 cells under the HG condition compared with those under the LG condition. Under the HG condition, DUSP22 overexpression suppressed SV40‑MES13 cell proliferation at 48 and 72 h as well as Bcl2, but it facilitated TUNEL‑reflected apoptotic rate and cleaved‑caspase‑3; besides, DUSP22 overexpression restrained proteins of fibronectin 1, collagen I, transforming growth factor beta 1, and their corresponding mRNAs. As to the inflammation, DUSP22 overexpression downregulated TNF‑α, IL‑1β, IL‑6 and IL‑12 under the HG condition. By contrast, DUSP22 siRNA promoted SV40‑MES13 cell proliferation, fibrosis and inflammation, but attenuated apoptosis in SV40‑MES13 cells under the LG condition. Additionally, DUSP22 overexpression inactivated phosphorylated (p)‑ERK, p‑JNK, and p‑P38 in HG‑treated SV40‑MES13 cells; differently, DUSP22 small interfering RNA facilitated them under the LG condition. In conclusion, DUSP22 suppresses HG‑induced mesangial cell hyperproliferation, fibrosis, inflammation and the MAPK pathway, implying its potency in DN treatment.
研究领域:
分子生物学
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细胞生物学
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糖尿病研究
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肾病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Omega
·
2023
·
IF 4.1
Wei Wang,Han Li,Jiamin Lv,Ghulam Jilany Khan,Hong Duan,Juan Zhu,Nina Bao,Kefeng Zhai,Zhenglian Xue
Isodon suzhouensis from Suzhou, China, is a traditional Chinese herb with wide applications in medicine and food. The antioxidant activity against oxidative stress of the leaves of Isodon suzhouensis is a myth since long and is not explored earlier thoroughly. The present study is focused to explore the active components in Isodon suzhouensis leaf extracts responsible for antioxidant effects against oxidative stress and the potential mechanism of this activity. We obtained the chromatograms of Isodon suzhouensis leaf extracts by the high-performance liquid phase (HPLC) for possible detection of antioxidant constituents. Some compounds in Isodon suzhouensis leaf extracts were then further assessed through the luminol luminescence mechanism combined with HPLC analysis as well as with SwissTargetPrediction database that helped to screen out the other constituents. The targets for effects against oxidative stress were then further screened through the GeneCards database, and the PPI network was constructed. The targets were analyzed by GO and KEGG using the David database. The obtained results were then further studied by employing in vitro experimentation and protein expression analyses by Western blotting. It is found that Isodon suzhouensis leaf extracts contain rutin, isoquercetin, glaucocalyxin A, glaucocalyxin B, and other compounds with antioxidant activity. The activity map of the free radical scavenging signals from Isodon suzhouensis showed a strong ability to scavenge free radicals with the highest capacity of glaucocalyxin B followed by isoquercetin succeeding the glaucocalyxin A supervening the rutin. Further network pharmacological analyses and in vitro experimentation showed that Isodon suzhouensis leaf extracts interfere with TNF and the p38 MAPK signaling pathway for antioxidant effects against oxidative stress. Conclusively, it is found that Isodon suzhouensis leaf extracts possess strong antioxidant potential via targeting TNF and p38 MAPK signaling pathways against oxidative stress, providing scientific foundation for further studies on Isodon suzhouensis for the further therapeutic approach.
研究领域:
药理学
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生物信息学
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植物科学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food & Function
·
2022
·Vol. 13
·期 16
·8593-8604
·
IF 6.317
Yanfang Yu,Yuhuan Chen,Xuping Shi,Chuan Ye,Junwen Wang,Jinzhi Huang,Bing Zhang,Zeyuan Deng
This study investigated the hepatoprotective effects of various mulberry (Morus alba L.) leaf extracts (MLEs), including mulberry ethanol extract (MEE), aqueous extract (MAE) and a combination extract (MCE) against D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced acute liver injury in rats. It aimed to explore the possible molecular mechanism of the liver-protecting function of mulberry leaves and provide a reference for choosing the appropriate extraction method. The results showed that the three extracts contained different amounts of phenolic compounds, 1-deoxynojirimycin (DNJ) and polysaccharides. MLEs markedly improved the pathological status of rat liver tissue, decreased the levels of AST, ALT, TNF-α, IL-1β, IL-6 and MDA, while increased the levels of GSH, SOD and CAT in the D-GalN/LPS-treated rats at the same time. MEE, with the highest amount of total phenolics, exhibited the highest antioxidant activity corresponding to the protein expression level of Nrf2 and HO-1. MCE significantly suppressed the expression of apoptosis-related dot-like protein (ASC) and Caspase-1 and inhibited the phosphorylation of p38 MAPK and ERK1/2, thereby showing high anti-inflammatory activity. These results indicated that the active components from mulberry leaves protected rats against acute liver injury, attributed to a reduction in both oxidative stress and inflammatory response. The protective effect may be implicated in regulating the Nrf2, NLRP3 and MAPK signaling pathways.
研究领域:
药理学
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肝病学
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生物化学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2024
·Vol. 28
·期 23
·e70271
·
IF 4.3
Zongrui Yang,Yuanyuan Feng,Mingcai Zhang,Yongming Liu,Yizhe Xiong,Xiang Wang,Ying Shi,Bo Chen,Zhengming Wang,Haiya Ge,Hongsheng Zhan,Zhibi Shen,Guoqing Du
HBP-A is the main active component of a traditional Chinese medicine Huaizhen Yanggan Capsule, for the remarkable treatment of knee osteoarthritis (KOA). This study aimed to elucidate the ameliorative effect of HBP-A on meniscus hypertrophy and mineralisation in KOA and the molecular mechanism of its action. An Hartley guinea pig model of KOA that underwent anterior cruciate ligament transection (ACLT) and a model of rat primary meniscus fibrochondrocytes (PMFs) were used to investigate the ameliorative effect of HBP-A on meniscal hypertrophy and calcification and its signal transduction mechanism of action. The results show that Guinea pig's meniscus width, as well as the area of meniscus calcification and meniscus and articular cartilage injury score, were significantly reduced in the HBP-A intervention group compared to the ACLT group. The expression levels of mtrix metalloproteinase 13 (MMP13), runt-related transcription factor 2 (Runx2), Indian hedgehog (Ihh), alkaline phosphatase (ALP), and ankylosis homologue (ANKH) at the protein and gene level significantly decreased in the HBP-A intervention group compared to the ACLT group. In vitro study, apoptosis, hypertrophy, and calcification of rat PMFs after 10% stretch force were significantly improved with HBP-A intervention. Western blot and RT-qPCR showed that hypertrophy, calcification, and p38 MAPK signalling pathway-related markers of PMFs were incredibly depressed in the HBP-A intervention group compared to the 10% stretch force group. In conclusion, HBP-A can slow down meniscus hypertrophy and mineralisation induced by abnormal mechanical loading, and its mechanism of action may be through the p38-MAPK signalling pathway.
研究领域:
药理学
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骨科
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分子生物学
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传统中药
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2020
·
IF 10.317
Guangzhen Yang,Mengni Fan,Jingwu Zhu,Chen Ling,Lihuang Wu,Xin Zhang,Ming Zhang,Jiayi Li,Qingqiang Yao,Zhongwei Gu,Xiaojun Cai
Specifically inhibiting the proliferation of activated macrophages and clearing the high levels of reactive oxygen species (ROS) secreted by macrophages is crucial for osteoarthritis (OA) treatment. Moreover, if the clearance of these high levels of ROS can be simultaneously used to induce oxidation-responsive release of anti-inflammatory drugs, the therapeutic effect of OA may be further improved. Here, a multifunctional anti-inflammatory drug (CPHs) based on a peptide dendrimer nanogel was constructed by physically encapsulating CORM-401 and wrapping its surface with folic acid (FA)-modified hyaluronic acid (HA). CPHs is capable of efficiently entering activated macrophages via FA- and HA-mediated specific targeting effects and then rapidly release large amounts of CO by massive consumption of H 2 O 2 . The generated CO effectively suppresses the secretion of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α by inhibiting cell proliferation ; inducing the activation of heme oxygenase (HO-1), and downregulating the expression of p38 MAPK , NF-kB (p50/p65) and TLR-2. In vivo experiments further confirmed that CPHs can massively deplete ROS in OA joints and effectively suppress the degradation of articular cartilage and their extracellular matrix. More importantly, CPHs is non-toxic to normal macrophages, and the high levels of CO generated in the joints do not result in notable changes in the HbCO levels in blood. Together, these results show that CPHs is an effective and safe anti-inflammatory drug and has essential application prospects in OA treatment.
研究领域:
药理学
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炎症
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纳米技术
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骨科
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2021
·
IF 5.194
Jing Guan,Xin Tong,Yi Zhang,Fan Xu,Yuxin Zhang,Xiurui Liang,Jiaqi Jin,Hongyan Jing,Liuxian Guo,Xinrui Ni,Jihua Fu
As a widely used anticancer drug in the clinic, cisplatin has obvious side effects, especially nephrotoxicity . Previous studies have suggested that the accumulation of intracellular reactive oxygen species (ROS) is a hallmark of cisplatin-induced acute kidney injury . This study aimed to investigate the relationship between ROS accumulation induced by cisplatin and 5-HT degradation. In vivo, by HE and TUNEL staining, we found that cisplatin-induced renal lesions and apoptotic regions, which were located in proximal tubular epithelial cells, were also the regions in which tryptophan hydroxylase 1 (Tph1), aromatic l -amino acid decarboxylase (AADC), 5-HT 2A receptor (5-HT 2A R) and monoamine oxidase A (MAO-A) were overexpressed, as determined by immunohistochemistry. Notably, the 5-HT 2A R antagonist sarpogrelate hydrochloride (SH) and the AADC inhibitor carbidopa (CDP) significantly attenuated cisplatin-induced increases in serum creatinine and blood urea nitrogen levels, renal ROS levels, oxidative stress (SOD activity and MDA), proinflammatory cytokine levels (NF-κB, TNF-α and IL-1β), proapoptotic factor levels (Bax, Bcl-2, C-caspase 3 and C-caspase 9) and the phosphorylation of p38 and STAT3 , as well as renal lesions and apoptosis . The combination of SH and CDP could almost abolish the effects of cisplatin challenge. In vitro, the effects of cisplatin challenge and the inhibitory effects of SH and CDP were also observed in HK-2 cells. Additionally, similar to the combination of SH and CDP, the MAO-A inhibitor clorgyline could also abolish the effects of cisplatin challenge. More importantly, by western blotting , we detected that the upregulation of Tph1, AADC and MAO-A expression induced by cisplatin both in vivo and in vitro could be obviously suppressed by SH to decrease 5-HT synthesis and mitochondrial 5-HT degradation. Altogether, these findings suggested that cisplatin-induced nephrotoxicity is due to the activation of the 5-HT degradation system in proximal tubular epithelial cells, including 5-HT 2A R and 5-HT synthesis and degradation. 5-HT 2A R plays a role by mediating the expression of MAO-A and the 5-HT synthases Tph1 and AADC.
研究领域:
药理学
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肾病学
·
肿瘤学
·
细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Reproductive Biology
·
2018
·
IF 1.446
Zhen Luo,Wenli Luo,Shaohua Li,Sen Zhao,Takami Sho,Xue Xu,Jing Zhang,Weina Xu,Jianxiong Xu
Intrauterine growth restriction (IUGR) remains a significant obstacle in pig production; however, information regarding the relationship between reactive oxygen species (ROS)-induced placental dysfunction and IUGR is still unknown. This study aimed to explore the placental redox status, mitochondrial content, cellular progression, and mitogen-activated protein kinase (MAPK) pathways in IUGR. Placental tissues were collected from normal intrauterine gestation (NIUG) and IUGR fetuses at delivery. Compared with the NIUG, placental ROS production, lipid peroxidation , and DNA damage were increased in IUGR. Placental mitochondrial DNA (mtDNA) content and mtDNA-encoded gene expression decreased in IUGR. Moreover, p21 phosphorylation increased, cyclin E expression decreased in IUGR cases, which showed senescence characteristics. Analysis of signaling pathways showed that the ERK1/2 phosphorylation increased whereas the p38 and JNK phosphorylation decreased in IUGR. In cultured porcine trophectoderm (pTr) cells, exogenous H 2 O 2 increased intracellular ROS production, decreased cell viability in a dose-dependent manner. Cell cycle distribution was found to arrest in S and G2/M phases. Our findings suggested that IUGR was associated with greater placental ROS and oxidative injury, which might be a factor that resulted in lower mitochondrial content, microvilli loss and senescence, and activation of MAPK pathways.
研究领域:
动物科学
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生殖生物学
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分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHEMICAL NEUROANATOMY
·
2022
·
IF 3.097
Liaoxi Tan,Yixin Hu,Xinyi Zhang,Chunlei Zhang,Chuchu Xi,Zhao Yang,Zhengyu Cao,Fang Zhao
Background and purpose Microglial activation plays an important role in the onset and progression of neuropathic pain by producing a variety of pro-inflammatory cytokines that interact with neurons to enhance neuronal hyperexcitability. Corydalis decumbens (Thunb.) pers., a traditional Chinese medicine has been used to treat mild cancer pain, dementia and to remit cerebral ischemia in clinics. Phenylphthalide isoquinolines are the major type of metabolites of C. decumbens and one of the derivatives, Corydecumine G (Cor G) has been shown to inhibit neuronal excitability . The present study aims to investigate the analgesic efficacy of Cor G in neuropathic pain rat model, the effects of Cor G on microglia activation and the possible mechanisms. Experimental approach Neuropathic pain was modeled using chronic constriction sciatic nerve injury (CCI) in rats. Western blot , immunofluorescence, and qRT-PCR were used to evaluate the levels of protein and mRNA. Key results Intraperitoneal administration of Cor G concentration-dependently ameliorates mechanical and thermo allodynia , suppresses CCI-induced p38/ERK phosphorylation and spinal cord microglia activation, and attenuates the expression levels of NO, inos , Tnf-α , Pge 2 in dorsal horn of L4-L6 spinal cord on the ligation side in CCI rats. Pretreatment with 30 μM Cor G decreased LPS-induced BV2 microglia activation, which occurred via the inos , Tnf-α , Il-1β , Il-6 and phospho-p38/ERK pathways. Conclusions and implications Taken together, we suggest that Cor G, the specific phthalide isoquinoline from traditional Chinese medicine Corydalis Decumbentis Rhizoma, may be promising for treatment of neuropathic pain.
研究领域:
药理学
·
神经科学
·
传统中药
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Xu Zhang,Huan Yang,Ye He,Dan Zhang,Guifang Lu,Mudan Ren,Yi Lyu,Zhang Yuan,Shuixiang He
Excessive oxidative stress, dysregulated immune homeostasis, and disruption of the intestinal epithelial barrier are crucial features of inflammatory bowel disease (IBD). Traditional treatments focusing solely on inflammation resolution remain unsatisfactory. Herein, a yeast-inspired orally administered nanocomposite was developed. First, the MD@MPDA core was fabricated by integrating manganese dioxide (MnO2) nanozymes onto diallyl trisulfide (H2S prodrug)-loaded mesoporous polydopamine nanoparticles (MPDA). Then, yeast cell wall (YCW) was chosen to encapsulate MD@MPDA, namely, YMD@MPDA. The β-glucan embedded in the YCW shell not only protected the nanocomposite from the harsh gastrointestinal environment but also allowed the targeting enrichment in the inflamed colon. Furthermore, M1 macrophages triggered the intracellular GSH-responsive H2S release in the pathological microenvironment. MD@MPDA effectively alleviated inflammatory responses by MnO2-mediated ROS-scavenging and H2S-participated immunomodulation. The synergistic action contributed to macrophage mitochondrial function restoration and M2 polarization by suppressing NOX4 signaling and p38 MAPK pro-inflammatory signaling. In the mice model of dextran sulfate sodium (DSS)-induced IBD, the multipronged manner of scavenging oxidative stress, remodeling innate and adaptive immune homeostasis, and reshaping gut microbiota caused by YMD@MPDA effectively ameliorated inflammation and restored intestinal barrier functions. Overall, the YMD@MPDA nanocomposite provides a promising codelivery strategy of antioxidative nanozymes and gas prodrugs for the comprehensive management of IBD.
研究领域:
纳米医学
·
胃肠病学
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免疫学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2024
·Vol. 9
·期 1
·1-17
·
IF 40.8
Peng Fu,Liao Minru,Jin Wenke,Liu Wei,Li Zixiang,Fan Zhichao,Zou Ling,Chen Siwei,Zhu Lingjuan,Zhao Qian,Zhan Gu,Ouyang Liang,Peng Cheng,Han Bo,Zhang Jin,Fu Leilei
Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide + (NAD + )-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis, myocardial fibrosis and even heart failure (HF), through its deacetylation modifications. Accordingly, discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed. Herein, we identified a new small-molecule activator of SIRT3 (named 2-APQC) by the structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models. Importantly, in SIRT3 knockout mice, 2-APQC could not relieve HF, suggesting that 2-APQC is dependent on SIRT3 for its protective role. Mechanically, 2-APQC was found to inhibit the mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-β (TGF-β)/ small mother against decapentaplegic 3 (Smad3) pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis. Based upon RNA-seq analyses, we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis was closely assoiated with HF. By activating PYCR1, 2-APQC was shown to enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated protein kinase (p38MAPK) pathway and thereby protecting against ISO-induced mitochondrialoxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase (AMPK)-Parkin axis to inhibit ISO-induced necrosis. Together, our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis, which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.
研究领域:
心血管药理学
·
分子生物学
·
细胞生理学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）