AQUACULTURE
·
2024
·
IF 3.9
Lanfei Xiao,Chuan Chen,Yongjun Liang,Kun Wu,Xiaobo Wen
Ammonia‑nitrogen has become a global issue with feed-dependent intensive culture modes, which may cause toxicity in aquatic animals by affecting immune regulation. Although numerous studies have investigated the acute and short-term toxic effect of ammonia‑nitrogen in fish, there is a lack of research on the long-term effects of exposure to low concentration of ammonia‑nitrogen. In this study, yellow catfish ( Pelteobagrus fulvidraco ) were exposed to water supplemented with ammonia (NH 4 Cl was used as the ammonia source) at concentrations of 0 (control), 8, 10, 12, 14, 16 and 18 mg/L for eight-weeks, and the effects on growth performance, histopathology, antioxidant and immune capacities of yellow catfish were investigated. The results showed that long-term ammonia exposure resulted in decreased weight gain rate (WGR) and serum antioxidant capacity, increased feed coefficient (FC), serum and tissue ammonia levels. They caused extensive histopathological changes and significantly impaired inflammatory and immune responses. On the other hand, ammonia exposure significantly affected the respiratory burst and the content of reactive oxygen species (ROS) of head kidney macrophages. Still, the above phenomenon can be reversed by inhibiting tumor necrosis factor- α ( TNFα ), indicating that TNFα may play a key role in this process. In conclusion, our findings indicate that extended exposure to ammonia nitrogen, even at low concentrations, has a detrimental effect on the well-being of aquatic organisms. This finding underscores the necessity of long-term environmental toxicological investigations of ammonia‑nitrogen.
研究领域:
水生毒理学
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免疫学
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环境科学
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产品关联
DOI
高影响因子
JOURNAL OF PHARMACOLOGICAL SCIENCES
·
2025
·
IF 2.9
Jingwei Liu,Cheng Qiu,Xiaoxiong Wang,Ziqian Xiang,Junyuan Sun,Mingzheng Chang,Qingliang Ma,Yan Zhuang,Yunpeng Zhao,Qiang Yang,Lianlei Wang,Xinyu Liu
Fracture is a common type of traumas and alternative therapies to boost bone fracture healing is necessary. The aim of this study is to elucidate the role of sulfasalazine in bone fracture healing by using MC3T3-E1 cells in vitro and murine femoral fracture model in vivo . Western blotting, flow cytometry, RNA sequencing, Calcein AM/PI staining, Alizarin-Red-S staining, ALP activity assay, transmission electron microscope, histological staining, immunohistochemistry, immunofluorescence and Surface plasmon resonance analysis were performed in this study. Sulfasalazine failed to elicit ferroptosis in osteoblasts within acceptable dose manner while promoted osteogenic differentiation. Furthermore, sulfasalazine was identified to inhibit inflammation by declination of inflammatory biomarkers. Besides, TNFα was verified as a potential downstream target for sulfasalazine and the adverse effect of TNFα on osteogenic differentiation could be largely salvaged by sulfasalazine due to direct binding between these two molecules. RNA-seq further implied decreased transcription of genes related to NF-κB pathway. Murine study showed sulfasalazine promotes fracture healing as evidenced by increased bone remodeling both histologically and radiologically. Overall, sulfasalazine accelerates osteogenic differentiation and promotes bone healing by direct binding to and thus inhibiting TNFα, which subsequently suppresses NF-κB signaling. Therefore, sulfasalazine shows a promising outcome for the treatment of bone fracture.
研究领域:
药理学
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分子生物学
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免疫学
·
骨科学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2020
·
IF 3.647
Xuemei Ji,Tianzhen Han,Nannan Kang,Song Huang,Yu Liu
Aims Triple-negative breast cancer (TNBC) is not sensitive to current endocrine treatments, so new treatment strategies need to be explored. Based on previous antitumour studies on anti-TNFα nanobody, we designed a novel fusion nanobody to enhance antitumour activity of the anti-TNFα nanobody in TNBC. Main methods The RGD4C contains RGD sequence, which is the smallest recognition unit binding to the αvβ3 receptor on tumour cell membranes and involved in tumour cell adhesion, proliferation, and metastasis. RGD4C was fused to anti-TNFα nanobody to investigate the antitumour activity in vitro and in vivo . Key findings The antitumour effects of fusion nanobody V-L-R-H could effectively bind to αvβ3 and inhibit cell migration and proliferation of MDA-MB-231, which had satisfying purification efficiency and approving antigen or receptor binding activity. V-L-R-H could inhibit the TNFα-mediated PI3K/AKT/NF-κB signal pathway and integrin αvβ3 correlative FAK focal adhesion signal pathway. Mouse xenograft tumour experiments showed that the V-L-R-H could inhibit tumour proliferation and metastasis; reduce the TNFα, HIFα, Ki67, and CD31 concentrations in tumour; and inhibit the process of epithelial-mesenchymal transition. Significance The fusion nanobody enhanced antitumour activity of the anti-TNFα nanobody on TNBC. It provided a reference for the design of dual functional fusion proteins and development of tumour treatment strategies of antagonistic TNFα and αvβ3, and a new therapeutic strategy and research direction for the treatment of TNBC.
研究领域:
肿瘤学
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分子生物学
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药理学
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癌症治疗
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Jun Weng,Geng Miaomiao,Xiaoyu Hu,Yang Hu,Yi Yang,Banbin Xing,Wu Zhiyong,Zigong Wei
TNFα inhibitors have been successfully developed and used in the clinical treatment of autoimmune disorders. However, the use of TNFα blockade may be accompanied by side effects. The cases of bacterial and viral infections, lymphoproliferative disorders, and anti-TNFα-induced lupus, have been reported among the rheumatoid arthritis or Crohn's disease patients treated with TNFα blockers. Therefore, alternative therapeutic strategy is highly desirable. TNFα signaling via TNFR1 induces proinflammatory responses, and selective inhibition of TNFR1 signaling may be beneficial for managing autoimmune diseases. To this end, we developed minibinder proteins targeting soluble ectodomain of TNFR1 (sTNFR1) by de novo computational designing. Top-rated designed minibinders targeting to two hydrophobic sites on sTNFR1 were selected and expressed in E. coli . Purified top-ranked minibinders are thermostable in solution and presented micromolar to sub-micromolar affinity to sTNFR1. All designs showed the potency of blocking TNFα signaling in L929 cell-based assays, and one of the designs targeting to hydrophobic Site I called S1B2 exhibited higher potency than other minibinders with IC 50 of 4.32 nM. Our work provided a new approach to develop TNFR1 antagonist and S1B2 should be a promising lead molecule of TNFR1 antagonist for further development.
研究领域:
生物化学
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免疫学
·
药物开发
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产品关联
DOI
PubMed
高影响因子
PLoS Pathogens
·
2024
·Vol. 20
·期 1
·e1011926
·
IF 5.5
Zihao Wang,Ziming Jiang,Yu Zhang,Congwei Wang,Zhaoyang Liu,Zhankui Jia,Sudhanshu Bhushan,Jinjian Yang,Zhengguo Zhang
Uropathogenic Escherichia coli (UPEC) is the primary causative agent of urinary tract infections (UTIs) in humans. Moreover, as one of the most common bacterial pathogens, UPEC imposes a substantial burden on healthcare systems worldwide. Epithelial cells and macrophages are two major components of the innate immune system, which play critical roles in defending the bladder against UPEC invasion. Yet, the routes of communication between these cells during UTI pathogenesis are still not fully understood. In the present study, we investigated the role of membrane-bound nanovesicles (exosomes) in the communication between bladder epithelial cells and macrophages during UPEC infection, using an array of techniques such as flow cytometry, miRNA profiling, RNA sequencing, and western blotting. Moreover, our in vitro findings were validated in a mouse model of UPEC-induced cystitis. We found that UPEC infection induced the bladder epithelial MB49 cell line to secrete large numbers of exosomes (MB49-U-Exo), which were efficiently absorbed by macrophages both in vivo and in vitro. Assimilation of MB49-U-Exo induced macrophages to produce proinflammatory cytokines, including tumor necrosis factor (TNF)α. Exposure of macrophages to MB49-U-Exo reduced their phagocytic activity (by downregulating the expression of phagocytosis-related genes) and increased their rate of apoptosis. Mechanistically, we showed that MB49-U-Exo were enriched in miR-18a-5p, which induced TNFα expression in macrophages by targeting PTEN and activating the MAPK/JNK signaling pathway. Moreover, administration of the exosome secretion inhibitor GW4869 or a TNFα-neutralizing antibody alleviated UPEC-mediated tissue damage in mice with UPEC-induced cystitis by reducing the bacterial burden of the bladder and dampening the associated inflammatory response. Collectively, these findings suggest that MB49-U-Exo regulate macrophage function in a way that exacerbates UPEC-mediated tissue impairment. Thus, targeting exosomal -release or TNFα signaling during UPEC infection may represent promising non-antibiotic strategies for treating UTIs.
Urinary tract infections, which are typically caused by uropathogenic Escherichia coli (UPEC), affect over 150 million people each year, worldwide. Because the incidence of antibiotic resistance among UPEC strains is on the rise, urinary tract infections are becoming increasingly challenging to treat using this standard treatment method. Moreover, although the host immune response against UPEC has been intensively studied, the mechanism of communication between bladder epithelial cells and macrophages during UPEC infection remains largely unexplored. Here, we characterized the exosomes released from bladder epithelial cells following UPEC infection and evaluated their impact on macrophages. We demonstrated that bladder tissue destruction following excessive innate immune cell activation during UPEC infection may be driven by exosomes secreted from bladder epithelial cells. We further showed that pharmacologically inhibiting exosomal release from epithelial cells limited macrophage-associated inflammation, innate immune cell infiltration, and histopathological injuries in a mouse model of UPEC-induced cystitis. Collectively, our findings suggest that modulating exosome release represents a promising non-antibiotic therapy for UTIs.
研究领域:
微生物学
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免疫学
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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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMAZIE
·
2018
·Vol. 73
·期 8
·465-468
·
IF 1.016
Ma Wenxue,Yao Yawen,Gu Yuyan,Li Fang,Cai Jiaxuan,He Baozhu,Chen Qiuyan,Fang Jian,Ouyang Zizhang
Acute phase protein pentraxin 3 (PTX3) is increased in patients with atherosclerotic cardiovascular diseases, such as acute coronary syndrome and coronary artery vulnerability, thereby serving as an important biomarker for the prognosis of cardiovascular diseases. This study was designed
to evaluate the effects of statins on the expression of PTX3 in human endothelial cells. We observed that PTX3 is a TNFα inducible protein in human endothelial cells. In contrast, treatment with simvastatin reduces basal as well as TNFα induced gene and protein expression of PTX3
in a dose- and time-dependent manner. Our study suggests that reducing PTX3 expression by statins could contribute to its protective effects against endothelial dysfunction and coronary artery plaque destabilization.
研究领域:
心血管疾病
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药理学
·
分子生物学
✓ 已验证
DOI
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2019
·
IF 3.743
Yanke Lin,Shuai Wang,Zemin Yang,Lu Gao,Ziyue Zhou,Pei Yu,Baojian Wu
Bilirubin is an endogenous substance derived from heme catabolism. In this study, we aimed to assess the anti-inflammatory activity of bilirubin, and to determine the mechanism thereof. The anti-inflammatory activity of bilirubin was evaluated using lipopolysaccharide (LPS)-treated peritoneal macrophages (PMs) and Raw264.7 cells, and mice with alum-induced peritonitis. The mRNA and proteins of NOD-like receptor family pyrin domain containing 3 (Nlrp3) and inflammatory cytokines were determined using qPCR and Western blotting, respectively. Distribution of phosphorylated (p) p65 [a NF-κB (nuclear factor-κB) subunit] in the cytoplasm and nucleus were evaluated by immunofluorescence analysis and electrophoretic mobility shift assay. Bilirubin prior to LPS treatment decreased protein expressions of Nlrp3, pro-interleukin (IL)-1β and mature IL-1β in PMs, whereas bilirubin post LPS treatment showed no effects. Bilirubin prior to LPS treatment dose-dependently repressed expressions of Nlrp3 and IL-1β, and inhibited translocation of p-p65 to nucleus in Raw264.7 cells. Bilirubin treatment decreased myeloperoxidase activity and reduced the levels of inflammatory cytokines (i.e., IL-1β, TNFα and IL-6) in lavage fluid in mice with alum-induced peritonitis. This was accompanied by a lower mortality rate. In addition, the mRNAs of Nlr p3 and IL-1β in peritoneal exudates cells were decreased, and the levels of p-p65 and mature IL-1β proteins were reduced. In conclusion, bilirubin acted on inflammation and alleviated alum–induced peritonitis through inactivation of Nlrp3 inflammasome.
研究领域:
免疫学
·
炎症
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2022
·Vol. 38
·期 1
·136-145
·
IF 4.109
Dandan Wang,Peng Li,Lixiang Liu,Peng Liu,Zheng Zhou,Meihui Jin,Baoxiang Li,Fan Li,Yao Chen,Hongmei Shen
Iodine excess (IE) can cause thyroid dysfunction, thyroid diseases can adversely affect cardiovascular function. Accordingly, this study was to explore the direct and indirect effects of IE on endothelial function. Nthy-ori 3-1 and HUVECs cells were treated with potassium iodide (KI). CCK-8, LDH leakage, Elisa, RT-PCR and Western blotting were used to detect relevant indicators. Results showed that a certain level of KI can directly and indirectly reduce the viability of HUVECs and increase cytotoxicity. KI decreased the expression of ET-1 and VWF in HUVECs, inhibited the secretion of ET-1 in culture medium, and increased the expression of IL-6 and TNFα in HUVECs or Nthy-ori 3-1 cells alone. In the co-culture system, KI decreased the expression of ET-1 and THBD and increased the expression of TNFα and IL-6. Collectively, IE can directly and indirectly inhibit endothelial function of endothelial cells, which may be related to its induced inflammatory response.
研究领域:
内分泌学
·
心血管科学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2020
·
IF 2.985
Peng Ma,Rongrong Huang,Jingyao Jiang,Yuan Ding,Tingting Li,Yu Ou
C-phycocyanin (C-PC) is a kind of photosynthetically assisted pigment, which is ubiquitous in cyanobacteria cells. We investigated the effect of C-PC on non-alcoholic fatty liver disease (NAFLD) and its mechanism. Through oil red O staining, TC/TG detection, liver SOD/MDA detection and liver H&E staining, we found that C-PC could significantly reduce the lipid accumulation in the steatosis L02 cells and the liver of non-alcoholic steatohepatitis (NASH) mice, and improve the antioxidant capacity of liver. The results of Western Blotting showed that C-PC upregulated the expression of AMPK phosphorylation and downregulated SREBP-1c and its target genes ACC and FAS expression levels. Furthermore, C-PC also upregulated the expression of transcription factor PPARα , which was regulated by AMPK, and its target genes CPT1 level. In addition, C-PC could promote AMPK phosphorylation in hepatocytes while increasing the phosphorylation level of ACC in vivo and in vitro. Besides, C-PC could also improve the liver inflammatory infiltration by upregulated the expression of PPARγ and downregulated the expression of CD36 , IL6 and TNFα . These results indicate that C-PC may improve hepatic lipid accumulation and inflammation in the non-alcoholic fatty liver mice by activating AMPK pathway of hepatocytes. The finding provides important help for the research and development of C-PC in the nutraceuticals and therapeutics of NAFLD.
研究领域:
药理学
·
肝病学
·
营养保健品
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHOTOCHEMISTRY AND PHOTOBIOLOGY
·
2024
·
IF 2.6
Yu Li,Miao Guo,Li Li,Fan Yang,Lidan Xiong
Photoaging, caused by ultraviolet (UV) radiation, is characterized by the senescence of skin cells and reduction of collagens. Although rice fermentation is widely used in the cosmetics, its impact on skin photoaging is still not well understood. Herein, we investigated the possible effectiveness of Maifuyin, a fermented rice product, and its components, succinic acid (SA), and choline, for safeguarding UVA-exposed human dermal fibroblasts (HDFs) against photoaging. In this study, the effects of Maifuyin, SA, and choline on UVA-induced cell death and senescence in fibroblasts were evaluated in cell counting kit-8 (CCK-8), expression of β-galactosidase (β-GAL), and matrix metalloproteinases (MMP)-1. To identify oxidative stress, the investigation focused on reactive oxygen species, glutathione, superoxide dismutase, and malondialdehyde. Additionally, a mRNA sequencing technology (RNA-seq) was applied to study the underlying mechanisms of these components on UVA-induced photoaging. Meanwhile, the level of C–X–C motif chemokine ligand 2 (CXCL2) in the cell supernatant was confirmed to assess the autocrine chemokine level. To reassess the involvement of CXCL2, the expression of β-GAL was evaluated in fibroblasts treated with or without CXCL2. The results indicated that 1 mg/mL Maifuyin and SA inhibited UVA-induced senescence in fibroblasts, MMP-1 expression, and oxidative damage. The RNA-seq revealed 1 mg/mL Maifuyin and SA might be recruited chemokine CXCLs to inhibit MMPs production and fibroblast senescence via TNFα, MAPK, and NF-κB pathways. ELISA results showed a significant reduction of autocrine CXCL2 in UVA-irradiated HDFs by pretreating Maifuyin and SA. The β-GAL staining assay revealed that CXCL2 treatment increased β-GAL activity, while the administration of Maifuyin and SA counteracted this effect in HDFs. These results highlighted the potential use of Maifuyin and SA as promising candidates for anti-photoaging applications.
研究领域:
美容学
·
细胞生物学
·
药理学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2022
·
IF 6.1
Min Chen,Yifei Xiao,Fugui Zhang,Jianhao Du,Li Zhang,Yifang Li,Danyi Lu,Zhigang Wang,Baojian Wu
Delirium is a common and serious neuropsychiatric syndrome characterized with acute cognitive and attentional deficits, however, the effective therapies are lacking. Here, using mouse models of delirium, we investigated the effects of tangeretin (TAN, a natural flavonoid) on cognitive impairment by assessing object preference with novel object recognition (NOR) test and spontaneous alternation with Y maze test. We found that TAN, as a RORα/γ agonist, prevented cognitive decline in delirious mice as evidenced by a normal novel object preference and increased spontaneous alternation. This was accompanied by decreased expression of ERK1/2, TNFα and IL-1β as well as diminished microglial activation in delirious mice. The protective effect of TAN on delirium was mainly attributed to increased hippocampal E4BP4 expression (a known target of RORs and a regulator of cognition in delirium through modulating the ERK1/2 cascade and microglial activation) via activation of RORα/γ. In addition, TAN treatment modulated the expression of RORα/γ target genes (such as E4bp4 and Bmal1 ) and inhibited the expression of TNFα and IL-1β in lipopolysaccharide (LPS)-stimulated cells, supporting a beneficial effect of TAN on delirium. In conclusion, TAN is identified as a RORα/γ agonist which promotes E4BP4 expression to prevent cognitive decline in delirious mice. Our findings may have implications for drug development of TAN for prevention and treatment of various diseases associated with cognitive deficiency.
研究领域:
神经科学
·
药理学
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
·
2017
·
IF 1.916
Xin Yang,Qian Wang,Zeng-run Pang,Meng-ran Pan,Wen Zhang
Context: Flavonoid-enriched extract from Hippophae rhamnoides L. (Elaeagnaceae) seed (FSH) has shown beneficial effects in anti-hypertension and lowering cholesterol level. However, evidence for its efficacy in treating obesity is limited.Objective: We sought to determine if FSH can reduce body weight and regulate lipid metabolism disorder in high fat diet (HFD)-induced obese mouse model, and to investigate potential molecular targets involved.Materials and methods: C57BL/6 mice were fed with HFD for 8 weeks to induce obesity. The modeled mice were divided into four groups and treated with vehicle, rosiglitazone (2 mg/kg), low (100 mg/kg) and high (300 mg/kg) dose of FSH, respectively. Normal control was also used. The treatments were administered orally for 9 weeks. We measured the effect of FSH on regulating body weight, various liver and serum parameters, and molecular targets that are key to lipid metabolism.Results: FSH administration at 100 and 300 mg/kg significantly reduced body weight gain by 33.06 and 43.51%, respectively. Additionally, triglyceride concentration in serum and liver were decreased by 15.67 and 49.56%, individually, after FSH (300 mg/kg) treatment. Upon FSH (100 and 300 mg/kg) treatment, PPARα mRNA expression was upregulated in liver (1.24- and 1.42-fold) and in adipose tissue (1.66- and 1.72-fold). Furthermore, FSH downregulated PPARγ protein level both in liver and adipose tissue. Moreover, FSH inhibited macrophage infiltration into adipose tissues, and downregulated TNFα mRNA expression in adipose tissue (38.01–47.70%).Conclusion: This effect was mediated via regulation of PPARγ and PPARα gene expression, and suppression of adipose tissue inflammation.
研究领域:
药理学
·
营养学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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