Reproductive Biology
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2022
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IF 2.089
Jing Xia,Shujuan Wu,Gengxiang Wu,Jing Yang
It has been reported that oxidative stress and chronic inflammation may be involved in the pathogenesis of polycystic ovary syndrome (PCOS). 8-oxoguanine DNA glycosylase (OGG1) is the main glycosylase that catalyzes the excision of DNA oxidation products. In this study, we investigated the role and potential mechanisms of OGG1 in the development of PCOS. We first analyzed OGG1 levels in serum and follicular fluid (FF) of PCOS patients , and significantly elevated OGG1 levels were noted in PCOS patients. We similarly observed a significant upregulation of OGG1 expression levels in ovarian tissue of the dehydroepiandrosterone (DHEA)-induced PCOS rat model. In addition, increased apoptosis and increased production of reactive oxygen species (ROS) were observed after the addition of OGG1-specific inhibitor (TH5487) in human granulosa-like tumor cell line (KGN) cells following a concentration gradient, along with a significant decrease in mRNA levels of inflammatory factors such as CXCL2 , IL-6, MCP1, IL-1β, and IL-18. Significant decreases in protein phosphorylation levels of P65 and IκBα were also observed in cells. In addition, we found a significant positive correlation between OGG1 and IL-6 expression levels in human and DHEA-induced PCOS rat models. In conclusion, our results suggest that OGG1 might be involved in the pathogenesis of PCOS by regulating the secretion of IL-6 through NF-κB signaling pathway , and there might be a balance between the inhibition of oxidative stress and the promotion of chronic inflammation by OGG1 on KGN cells.
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CHEMICO-BIOLOGICAL INTERACTIONS
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2022
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IF 5.168
Jiwen Liu,Yuting Wu,Shuhui Liu,Zhangshan Gao,Wentao Fan,Chenchen Ding,Zhihui Tang,Shuo Zhang,Xizhi Shi,Lei Tan,Yan Luo,Suquan Song
The bromoacetic acid (BAA) is one of the most teratogenic and neurotoxic disinfection byproducts . Birds take environmental water as their habitat and are inevitably affected by BAA in the environment. However, the neurotoxicity caused by BAA in birds has not been reported and the mechanism remains unclear. In this study, we chose chickens as the avian model to explore the effects of different concentrations of BAA on the brain tissues. Here, we selected the 3 μg/L dose of BAA detected in Tai Lake basin as a reference, and designed 1-, 100-, and 1000-fold of the environmental exposure dose as the experimental doses to explore the neurotoxicity of BAA in birds. Results showed that BAA increased the number of pyknotic nuclear neurons, deformed vascular sheaths, and glial cells in the brain. BAA inhibited the activity of antioxidant enzymes and the expression of antioxidant genes. With the increase of BAA concentration, the oxidative stress-responsive transcription factor NF-κB was activated. Furthermore, BAA remarkably changed the expression of lipid metabolism related genes (i.e., acc , gpat , hmgr , pparα , cpt1 , and ampkα ). Importantly, BAA decreased the mRNA and protein expression levels of autophagy-related genes (i.e., atg5 , ulk1 , beclin1 , and lc3 ). Meantime, BAA increased the mRNA and protein levels of apoptotic and pro-apoptotic genes, such as p53 , bax , cytochrome c , caspase-9 , and caspase-3 . Overall, our study provided new insights into the potential neurotoxic effects of BAA in birds, which was important for the clinical monitoring and prevention of BAA.
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Frontiers in Pharmacology
·
2022
·
IF 5.988
Lei Jin,Xiang Peng,Zeng Shengmei,Chen Le,Zhang Lei,Yuan Zhiyi,Zhang Jun,Wang Tingting,Yu Ruihong,Zhang Wanping,Ibrahim Issa Issoufou,Ma Limei,Yu Chao
Tetramethylpyrazine (TMP), a Chinese traditional herbal extraction widely used in treating cardiovascular diseases, could attenuate vascular endothelial injuries, but the underlying mechanism remains incomprehensive. Vascular glycocalyx coating on the endothelium would be damaged and caused endothelial dysfunction in the inflammatory microenvironment, which was the initial factor of morbidity of many vascular diseases, such as atherosclerosis (AS). Here, we thoroughly investigated the molecular mechanism of TMP on vascular endothelial glycocalyx in the LPS-induced inflammatory model both in vitro and in vivo. Results showed that pretreatment with TMP significantly inhibited glycocalyx degradation and monocytes adhesion to the endothelial process. Moreover, TMP pretreatment inhibited the expression of HPSE1 (a major degrading enzyme of endothelial glycocalyx), Toll-like receptor 4 (TLR4), and the translocation of nuclear factor kappa B p65 (NF-κB p65). We were utilized withTLR4 siRNA, NF-κB inhibitor, and HPSE1 overexpression analysis confirmed TMP’s protection on endothelial glycocalyx injury, which further contributed to the monocyte-endothelial adhesion process. It was indicated that TMP might suppress glycocalyx degradation through TLR4/NF-κB/HPSE1 signaling pathway. Taken together, our results enriched the occurrence molecular mechanism of glycocalyx shedding and molecular regulation mechanism of TMP in protecting integrity of the glycocalyx structure during inflammation. As TMP is currently used in clinical applications, it may be considered a novel strategy against atherosclerosis through its ability to protect endothelial glycocalyx.
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CELL CYCLE
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2021
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IF 4.534
Limei Yan,Zeping He,Wei Li,Ning Liu,Song Gao
Rhophilin Rho GTPase binding protein 2 (P76RBE) belongs to rhophilin family of Rho-GTPase-binding proteins and is found to contribute to the development of diverse cancers. Data in Oncomine and Kaplan–Meier Plotter databases showed that P76RBE was upregulated in ovarian cancer tissues compared with normal tissues, and patients with high P76RBE expression had worse overall survival, which indicated P76RBE may be associated with the pathogenesis of ovarian cancer. This study aimed to investigate the role of P76RBE in ovarian cancer and to reveal the possible underlying mechanisms. The results demonstrated that P76RBE was highly expressed in ovarian cancer tissues and ovarian cancer cell lines. Functionally, silencing of P76RBE suppressed the proliferation, induced cell cycle arrest, and inhibited migration and invasion in OVCAR-3 and OV-90 cells, while overexpression of P76RBE showed opposite effects on A2780 cells. Mechanically, P76RBE silencing resulted in downregulation of integrin β1, accompanying the reduced NF-κB p65 phosphorylation and nuclear translocation. Importantly, integrin β1 knockdown effectively rescued the effects of P76RBE overexpression on ovarian cancer cells with suppressed proliferation, migration, and invasion. Additionally, in the xenograft tumors derived from OVCAR-3 and OV-90 cell lines, P76RBE knockdown inhibited tumor growth. Meanwhile, the expression of integrin β1 and NF-κB p65 phosphorylation was decreased. In summary, our findings indicate that P76RBE contributes to the progression of ovarian cancer through regulating the integrin β1/NF-κB signaling, and it may be a promising target for ovarian cancer therapy.
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IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
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2021
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IF 2.73
Jinhui Dong,Ou Xu,Jianxing Wang,Chunguang Shan,Xiumin Ren
Objective Luteolin has an anti-allergic effect but its mechanism is not clear. This study attempted to determine the mechanisms of luteolin in rhinitis.Methods Allergic rhinitis rat model was established by ovalbumin (OVA) stimulation. Then, the rats were treated with normal saline, luteolin, or lipopolysaccharide (LPS) for 14 days. Nasal symptoms were scored; the histopathological changes of nasal mucosa were detected by hematoxylin–eosin staining. Serum levels of Th1 type cytokines (IFN-γ, IL-2), Th2 type cytokines (IL-4, IL-5, IL-13), and OVA-specific IgE (sIgE) were determined by ELISA. The expressions of Toll-like receptor 4 (TLR4) and p65 in nasal mucosa were detected by Western blot or immunohistochemistry.Results Luteolin decreased symptom scores, specifically, the scores in control group, model group, model + 0.1 mg/kg luteolin, model + 1 mg/kg luteolin, and model + 10 mg/kg luteolin groups were 0.63 ± 0.52, 7.88 ± 0.83, 1.38 ± 0.52, 2.75 ± 0.46, and 5.00 ± 0.53, respectively. Luteolin ameliorated nasal mucosa inflammation by promoting the down-regulated levels of Th1 type cytokines, and suppressing the up-regulated levels of Th2 type cytokines, OVE-sIgE, TLR4, and p65. LPS further increased symptom scores, aggravated nasal mucosa inflammation, improved the unbalance of Th1/Th2 type cytokines, and lowered the expressions of OVE-sIgE, TLR4, and p65. Moreover, LPS reversed the effect of luteolin on allergic rhinitis rats.Conclusion Luteolin ameliorated inflammation and Th1/Th2 imbalance via regulating the TLR4/NF-κB pathway in allergic rhinitis rats. This study provided novel evidence that luteolin could be used as a candidate drug in allergic rhinitis treatment.
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BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
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2021
·Vol. 85
·期 7
·1665-1674
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IF 2.043
Feng Wei
This study aims to explore the effect of Tectorigenin in chronic cerebral ischemia (CCI)-induced cognitive impairment mice model. Cognitive impairment, hippocampal tissue histopathology, and myelin density in CCI mice were detected. HT22 cells were used to induce oxygen–glucose deprivation/reperfusion (OGD/R) injury. Cell viability and apoptosis of transfected HT22 cells and toll-like receptor-4 (TLR4)/nuclear factor-kappaB (NF-κB) pathway–related factor levels in hippocampal tissue and OGD/R models were detected. CCI caused cognitive impairment, hippocampal damage, and decreased myelin density in mice while promoting interleukin-1β, tumor necrosis factor-alpha, TLR4, myeloid differentiation primary response gene 88, p-p65, NLRP3, and ASC levels. Tectorigenin reversed the effects of CCI in mice and reversed the promoting effects of OGD/R on apoptosis and TLR4/NF-κB pathway–related factors levels, while overexpressed TLR4 reversed the effects of Tectorigenin in OGD/R-induced HT-22 cells. Tectorigenin alleviated cognitive impairment in CCI mice by inhibiting the TLR4/NF-κB signaling pathway.
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Applied Materials Today
·
2020
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IF 8.352
Qiongcong Xu,Liying Wang,Tong Tong,Xitai Huang,Chensong Huang,Fuxi Li,Qiao Su,Yichih Tien,Jun Wu,Wei Zhao,Xiaoyu Yin
Gallbladder cancer (GBC) is one of the most common and aggressive biliary tract diseases with limited therapeutic strategies and poor prognosis. Various therapeutic agents have been demonstrated effective in preclinical models, but high dose requirement and toxicity to normal cells limit their clinical applications. Considering the high concentration of glutathione (GSH) in GBC, we developed a GSH-responsive nanoparticle (NP) system based on biodegradable poly(disulfide amide) (Cys-8E Polymer) for targeted delivery of a BRD4 inhibitor (JQ1), which is known as a promising therapeutic agent for GBC treatment. JQ1-loaded Cys-8E nanoparticles ( [email protected] NPs) possessed a high JQ1 loading, preferable stability and redox-responsive release behavior. Additionally, the NPs showed good targeted delivery into GBC tumor spheroids and GBC patient-derived xenograft (PDX) tumors. Specifically, the intracellular GSH in tumors could trigger the release of JQ1, which induced the cell cycle arrest and apoptosis of GBC cells. RNA-sequencing analysis revealed that [email protected] NPs enhanced the effect of JQ1 through inhibiting NF-κB pathway. Importantly, [email protected] NPs significantly suppressed GBC tumor growth in the PDX model of early recurrence. No obvious systemic toxicity and organ damages were observed after treatment with [email protected] NPs. Our results demonstrate the promising therapeutic applications of [email protected] NPs for adjuvant therapy in GBC treatment.
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INFLAMMATION
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2020
·Vol. 44
·期 2
·746-757
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IF 3.212
Gao Yang,Kang Kai,Liu Yan-song,Li Na-na,Han Qiu-yuan,Liu Hai-tao,Kong Wei-lan,Zhang Xing,Huang Rui,Yang Zhen-yu,Qi Zhi-dong,Zheng Jun-bo,Li Ming,Wang Hong-liang,Li Jia-yu,Liu Rui-jin,Wang Si-cong,Zhang Wei-hua,Zhao Ming-yan,Yu Kai-jiang
This study aimed to investigate the effect of splenectomy on dexmedetomidine-activated cholinergic anti-inflammatory pathway-mediated alleviation of LPS-induced AKI. A mouse model of septic kidney injury was established in C57BL/6 mice. A total of 30 C57BL/6 mice were randomly divided into the control group, LPS group, dexmedetomidine + LPS group, splenectomy group, splenectomy + LPS group, and splenectomy + dexmedetomidine + LPS group. The pathological effects in kidney tissues in each group were analyzed by HE staining. Apoptosis in each group was examined by the TUNEL method. Cr and Cys-C levels in each group were measured by ELISA. The expression levels of IL-6, NF-κB p65, Caspase-3, the antiapoptotic protein Bcl-2, the proapoptotic protein Bax, and α7nAChR in each group were measured by qRT-PCR and Western blotting. Dexmedetomidine alone reduced apoptosis in kidney tissue; however, apoptosis was increased after splenectomy in mice treated with dexmedetomidine. Splenectomy reduced the production of proinflammatory cytokines in circulation and had a protective effect on the kidney. Splenectomy inhibited dexmedetomidine-mediated activation of the α7nAChR pathway. Dexmedetomidine effectively alleviated LPS-induced kidney injury, and splenectomy inhibited the anti-inflammatory, antiapoptotic, and renoprotective effects of dexmedetomidine. The kidney-spleen axis is mediated by the α7nAChR-NF-κB signaling pathway and is involved in the development of AKI.
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Cancer Management and Research
·
2020
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IF 2.886
Weixu Luo,Yuanshan Han,Pan Meng,Qin Yang,Hongqing Zhao,Jia Ling,Yuhong Wang
Background Breast cancer is one of the most common cancer with high risk in females all over the world. It is usually complicated with depression, which can further accelerate the development and progression of breast tumors. We aim to identify a new drug and identify its functional mechanism in the regulation of hippocampal microglia (MG) in breast cancer complicated with depression (BCCD). Methods The activation model of MG was established by treatments from corticosterone (CORT) or lipopolysaccharides (LPS). The inhibitory effects of resatorvid on MG were investigated by CCK-8, ROS, immunofluorescence, TUNEL, scratch test, ELISA, RT-qPCR and Western blot. BCCD animal model was established using 4T1 inflammatory breast cancer cells and CORT treatment in vitro. Open field experiment (OFE), tail suspension test (TST), ELISA, RT-qPCR and Western blot experiments were utilized to examine the effects of resatorvid on the animal model in vivo. Results The cell viability and migration ability of the BCCD model group were suppressed. The expressions of inflammatory factors, ROS, and the apoptotic rate of the BCCD model group were up-regulated, in contrast to the control group. The expressions related to the TLR4/NF-κB/NLRP3 signaling in the BCCD model group were also elevated. Resatorvid reversed the above changes, which showed good therapeutic effects in depression-related behavioral changes, tumor treatment, and blood–brain barrier function. Conclusion In summary, resatorvid inhibited the activation of hippocampal MG in BCCD by regulating TLR4/NF-κB/NLRP3 signaling pathway.
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npj Science of Food
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2026
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IF 9.7
Jin Hongchen,Bai Huasong,Liu Tong,Wang Hengyan,Yin Yulong,Ruan Siyu,Li Yunliang,Wang Zhanzhong
Anti-aging bioproducts from natural active ingredients represent a core future direction in food research. Cardiovascular aging drives most age-related disorders. This study investigated the anti-aging effects of a postbiotic preparations derived from brown algae extract fermented by Bifidobacterium adolescentis Life Age 20 (LA20FM). Multi-model were used, including doxorubicin (DOX)-induced senescent canine (CVECs) and feline vascular endothelial cells (FVECs), senescence-accelerated mouse prone 8 (SAMP8) mice, Caenorhabditis elegans , and naturally aged dogs and cats. In vitro, LA20FM markedly attenuated DOX-induced endothelial senescence, reduced the secretion of senescence-associated secretory phenotype factors, and restored endothelial function-related markers. In aged SAMP8 mice, LA20FM alleviated vascular remodeling, reduced circulating senescence- and inflammation-related biomarkers, and improved physiological performance. In C. elegans , LA20FM extended lifespan by approximately 30%, enhanced reproductive capacity, and significantly reduced intracellular reactive oxygen species levels. Comparable improvements in physiological parameters were also observed in aged dogs and cats. Transcriptomic analyses of CVECs and SAMP8 vascular tissues revealed that LA20FM treatment was accompanied by downregulation of NF-κB-related inflammatory signaling. Phorbol 12-myristate 13-acetate rescue experiments and early time-point analyses further supported NF-κB signaling as an early and functionally important mediator of its protective effects. Metabolomic analysis further revealed metabolic remodeling characterized by reduced lipid-associated metabolic activity and enhanced amino acid biosynthesis and antioxidant-related metabolism. Collectively, these findings indicate that LA20FM alleviates canine and feline vascular endothelial senescence and improves aging-associated phenotypes across multiple experimental models, supporting its potential as a postbiotic preparation for canine and feline nutritional intervention against vascular functional decline and further aging.
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EXPERIMENTAL BIOLOGY AND MEDICINE
·
2023
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IF 3.2
Jinhong Tian,Shuaishuai Zhang,Lu Li,Xueman Lin,Yongmei Li,Kunlu Zhao,Fengxin Zheng,Yongjun Chen,Yang Yang,Ting Wu,Jianxin Pang
Excessive acetaminophen (APAP) application is a major cause of drug-induced liver injury (DILI). Febuxostat (Feb), a drug for reducing uric acid (UA) levels, was demonstrated to relieve hepatic inflammation and reverse organ functions. However, the effect of Feb on APAP-induced DILI and its mechanisms have not been fully explored. In this study, Feb (10 mg/kg) was given to mice by gavage 1 h after APAP (300 mg/kg, i.g.) induction. Serum and liver samples were collected 12 or 3 h after APAP challenge. Feb treatment was found to remarkably improve APAP-induced DILI, as evidenced by reduced serum ALT, AST and UA levels, pathomorphology, inflammatory, and oxidative responses. Consistently, treatment with Feb also reduced the cell injury induced by APAP in LO2 cells. Mechanistically, Feb induced GPX4 expression, activated the Keap1/Nrf2 pathway, and inhibited the TLR4/NF-κB p65 pathway. Feb also inhibited glutathione (GSH) depletion and Jun N-terminal kinase (JNK) activation in the early injury phase. Notably, pretreatment with Feb for 3 days also revealed preventive effects against APAP-induced DILI in mice. Overall, our data revealed a potential health impact of Feb on APAP-mediated DILI in vivo and in vitro, suggesting that Feb might be a potential candidate for treating DILI.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2023
·Vol. 24
·期 19
·14771
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IF 5.6
Pan Lei,Zhiyang Li,Qiuwei Hua,Ping Song,Lun Gao,Long Zhou,Qiang Cai
The neuroinflammatory response after intracerebral hemorrhage (ICH) causes a large amount of neuronal loss, and inhibiting the inflammatory response can improve the prognosis. In previous laboratory studies and clinical trials, ursolic acid (UA) inhibited the inflammatory response, but whether it can be administered to inhibit the neuroinflammatory response after cerebral hemorrhage is unknown. The aim of this study was to investigate the effects of ursolic acid after cerebral hemorrhage. Online databases were used to obtain potential therapeutic targets of ursolic acid for the treatment of cerebral hemorrhage, and possible mechanisms were analyzed by KEGG, GO, and molecular docking. A rat model of cerebral hemorrhage was established using collagenase, and an in vitro cerebral hemorrhage model was constructed by adding hemin to BV2 cell culture medium. Enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), immunofluorescence, TUNEL staining, and calcein/PI staining were used to investigate the degree of microglial M1 polarization, changes in the levels of inflammatory factors, activation of the NF-κB pathway, and changes in the indicators of cellular death after ursolic acid treatment. In addition, phorbol 12-myristate 13-acetate (PMA) was used to activate the NF-κB pathway to verify that ursolic acid exerts its anti-neuroinflammatory effects by regulating the NF-κB/NLRP3/GSDMD pathway. Network pharmacology and bioinformatics analyses revealed that ursolic acid may exert its therapeutic effects on cerebral hemorrhage through multiple pathways. Together, in vivo and in vitro experiments showed that ursolic acid inhibited microglial M1 polarization and significantly reduced the levels of p-NF-κB, GSDMD-N, cleaved caspase-1, TNF-α, IL-6, and IL-1β, which were significantly inhibited by the use of PMA. Ursolic acid inhibits microglial pyroptosis via the NF-κB/NLRP3/GSDMD pathway to alleviate neuroinflammatory responses after cerebral hemorrhage.Keywords:ursolic acid;neuroinflammation;cerebral hemorrhage;microglial;pyroptosis
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