Frontiers in Pharmacology
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2023
·
IF 5.6
Niuben Cao,Xiaomeng Liu,Yubo Hou,Yu Deng,Yu Xin,Xirui Xin,Xinchen Xiang,Xinchan Liu,Weixian Yu
Objective: Periodontitis is a common chronic inflammatory disease in which oxidative stress is one of the key pathogenic factors. Connexin43 (Cx43) is the most critical and widely distributed connexin isoform. When the organism undergoes a severe and sustained stress response, Cx43-mediated gap junctions (GJs) are believed to underlie the biology of tissue injury exacerbation and amplification. Notably, 18-α-glycyrrhetinic acid (GA) is a classical pharmacological inhibitor of GJs and has antioxidant potential. However, the regulatory role of GA in the redox signaling of periodontal tissues and the potential mechanisms of Cx43 in the pathogenesis of periodontitis remain uncertain. Methods: In this study, we evaluated the effects and mechanisms of GA in alleviating oxidative damage of periodontal tissues and cells by constructing an H 2 O 2 -induced oxidative stress model in human periodontal ligament cells (hPDLCs) and a periodontitis model in rats. Results: Cellular experiments showed that GA effectively attenuated H 2 O 2 -induced oxidative damage in hPDLCs by inhibiting the expression and function of Cx43. In addition, pretreatment of hPDLCs with either GA or SP600125 (a JNK inhibitor) inhibited the Cx43/JNK/NF-κB pathway, restored cell viability, and reduced apoptosis. Animal experiment results showed that GA intervention reduced alveolar bone resorption and periodontal tissue destruction, inhibited osteoclast differentiation, improved mitochondrial structural abnormalities and dysfunction in periodontal tissue, and decreased oxidative stress levels and apoptosis in rats with periodontitis. Conclusion: Overall, our findings suggest that the Cx43/JNK/NF-κB pathway may play a vital role to promote periodontitis progression, while GA reduces oxidative stress and apoptosis by inhibiting the interaction of Cx43 and JNK/NF-κB pathways, thus alleviating oxidative damage in the periodontal tissues.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2023
·
IF 3.8
Hao Zhao,Xin Lin,Qingfeng Chen,Xiaoyue Wang,Yongya Wu,Xiaoxia Zhao
Sepsis-induced cardiomyopathy (SIC) has high morbidity and mortality. Quercetin (QUE) has been used to treat many inflammatory diseases related to pyroptosis . However, its effect on SIC has not been reported before. We aimed to explore the therapeutic mechanism of QUE on SIC. We found that the expression levels of NOX2, markers of myocardial injury and inflammatory factors related to pyroptosis were upregulated in the serum of SIC patients. QUE improved the viability and reduced the death rate of LPS-treated H9C2 cells. It could downregulate the expression level of NOX2 and alleviate NOX2-induced mitochondrial damage to inhibit the ROS-mediated NF-κB/TXNIP pathway thus ameliorating cell pyroptosis. Overexpression of NOX2 partially attenuated the anti-pyroptotic effects of QUE on LPS-treated H9C2 cells in vitro. Besides, the results of animal experiments reported that the mitochondrial damage was reduced by QUE treatment, which subsequently inhibited the ROS-mediated NF-κB/TXNIP pathway to ameliorate cell pyroptosis to further alleviate myocardial injury in CLP-induced rats in vivo. To conclude, QUE suppressed the NOX2/ROS-mediated NF-κB/TXNIP signaling pathway to ameliorate pyroptosis of cardiomyocytes to relieve SIC.
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Neural Regeneration Research
·
2023
·
IF 6.1
Jingwen Jiang,Hong Pan,Fanxia Shen,Yuyan Tan,Shengdi Chen
Alzheimer’s disease is a progressive neurological disorder characterized by cognitive decline and chronic inflammation within the brain. The ketogenic diet, a widely recognized therapeutic intervention for refractory epilepsy, has recently been proposed as a potential treatment for a variety of neurological diseases, including Alzheimer’s disease. However, the efficacy of ketogenic diet in treating Alzheimer’s disease and the underlying mechanism remains unclear. The current investigation aimed to explore the effect of ketogenic diet on cognitive function and the underlying biological mechanisms in a mouse model of Alzheimer’s disease. Male amyloid precursor protein/presenilin 1 (APP/PS1) mice were randomly assigned to either a ketogenic diet or control diet group, and received their respective diets for a duration of 3 months. The findings show that ketogenic diet administration enhanced cognitive function, attenuated amyloid plaque formation and proinflammatory cytokine levels in APP/PS1 mice, and augmented the nuclear factor-erythroid 2-p45 derived factor 2/heme oxygenase-1 signaling pathway while suppressing the nuclear factor-kappa B pathway. Collectively, these data suggest that ketogenic diet may have a therapeutic potential in treating Alzheimer’s disease by ameliorating the neurotoxicity associated with Aβ-induced inflammation. This study highlights the urgent need for further research into the use of ketogenic diet as a potential therapy for Alzheimer’s disease.
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Food & Function
·
2023
·Vol. 14
·期 14
·6678-6689
·
IF 6.1
Ziqian He,Na Deng,Bisheng Zheng,Yingjie Gu,Jian Chen,Tong Li,Rui Hai Liu,Ling Yuan,Wenzhi Li
The intestine and its flora have established a strong link with each other and co-evolved to become a micro-ecological system that plays an important role in human health. Plant polyphenols have attracted a great deal of attention as potential interventions to regulate the intestinal microecology. In this study, we investigated the effects of apple peel polyphenol (APP) on the intestinal ecology by establishing an intestinal ecological dysregulation model using lincomycin hydrochloride-induced Balb/c mice. The results showed that APP enhanced the mechanical barrier function of mice by upregulating the expression of the tight junction proteins at the transcriptional and translational levels. In terms of the immune barrier, APP downregulated the protein and mRNA expression of TLR4 and NF-κB. As for the biological barrier, APP promoted the growth of beneficial bacteria as well as increasing the diversity of intestinal flora. In addition, APP treatment significantly increased the contents of short-chain fatty acids in mice. In conclusion, APP can alleviate intestinal inflammation and epithelial damage as well as inducing potentially beneficial changes in the intestinal microbiota, which helps to reveal the potential mechanisms of host–microbial interactions and polyphenol regulation of intestinal ecology.
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Experimental and Therapeutic Medicine
·
2023
·Vol. 25
·期 5
·1-16
·
IF 2.7
Yijuan Wu,Zhiyu Wang,Shengmian Li,Xianliang Chen,Shengyun Zhou
Excessive proliferation, metastasis and immune escape are considered to be hallmarks of cancer contributing to tumor progression. Split hand and foot malformation 1 (SHFM1) is highly expressed in various cancers and has been reported to increase malignant behaviors. However, the biological functions of SHFM1 in esophageal squamous cell carcinomas (ESCC) progression remain to be elucidated. An integrated bioinformatics analysis was performed to identify candidate genes in ESCC progression based on GSE microarrays. SHFM1 was found to be profoundly upregulated in ESCC tissues compared with normal tissues and SHFM1 expression was positively associated with poor prognosis. The biological effects of SHFM1 on cell growth, metastasis and immune escape were investigated following depletion or overexpression of SHFM1 in vitro. A xenograft mouse model was established to investigate the effect of SHFM1 on ESCC progression in vivo. SHFM1 overexpression promoted ESCC cell proliferation and migration in vitro as well as tumorigenesis in vivo, while SHFM1 knockdown restored those phenotype changes. Additionally, the present study demonstrated that the effects of SHFM1 on malignant behaviors of ESCC cells were achieved by activating the NF‑κB signaling accompanied by increased P65 phosphorylation and nuclear translocation. Furthermore, SHFM1 was also found to regulate the sensitivity of cancer cells to natural killer (NK) cells. Specifically, inhibition of SHFM1 enhanced cell‑mediated cell apoptosis and increased NK toxicity, which might involve the downregulation of c‑Myc and programmed death‑ligand 1, key targets in cancer immunotherapy. In conclusion, these findings suggested that SHFM1 probably promoted ESCC progression by activating the NF‑κB pathway and enhancing the resistance of ESCC cells to NK cell cytotoxicity, indicating that SHFM1 may be a promising target for ESCC treatment.
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TROPICAL JOURNAL OF PHARMACEUTICAL RESEARCH
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2023
·Vol. 22
·期 1
·15-22
·
IF 0.6
Jingwen Gong,Yu Xie,Yinfen Tan,Hailong Li,Junqing Zhang
Purpose: To investigate the mechanism of action of galangin (GAL) against indomethacin (Indo)-induced gastric injury.
Methods: Ten micromolar GAL with 2 mM Indo or 0.5 mM L-NAME or 2 mM propargylglycine were co-administered to human gastric mucosal epithelial cells GES-1 for 24 h. Cell viability assay and reactive oxygen species (ROS) test were conducted with commercial kits. Protein expressions of constitutive and inducible nitric oxide synthase (cNOS and iNOS, respectively), and cystathionine-γ-lyase (CSE) in GSE-1 cells were investigated by western blot. After 100 - 300 mg/kg, GAL was daily administered to rats for 5 days, and 30 mg/kg Indo was administered to induce gastric injury. Protein expressions of endothelial NOS (eNOS), iNOS, CSE, nuclear factor (NF)-κB, PKC, Akt, phospho-eNOS (Ser-1177), and phospho-eNOS (Thr-495) were investigated by western blot.
Results: Galangin ameliorated the proliferative inhibitions of Indo, propargylglycine, and L-NAME on GSE-1 cells (p < 0.05), rapidly scavenged ROS, and increased cNOS protein expressions (p < 0.05). Galangin (300 mg/kg) inhibited protein expressions of iNOS (p < 0.01), NF-κB, Akt, and PKC (p < 0.05), inhibited the Ser-1177 and Thr 495 phosphorylation of eNOS, elevated eNOS and CSE protein expressions (p < 0.001).
Conclusion: Galangin protects gastric mucosa from Indo by scavenging ROS and inhibiting protein expressions of Akt and PKC. The inhibition leads to Ser-1177 and Thr 495 dephosphorylation of eNOS, thereby prolonging eNOS activity. Besides, GAL inhibits iNOS-produced NO by inhibiting NF-κB to ameliorate the inflammatory reaction induced by Indo.
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JOURNAL OF CELLULAR BIOCHEMISTRY
·
2019
·Vol. 120
·期 10
·18509-18523
·
IF 3.448
Yujie Yao,Xueyuan Hu,Xiujing Feng,Yuan Zhao,Manyu Song,Chaoran Wang,Honggang Fan
Dexmedetomidine (DEX) prevents kidney damage caused by sepsis, but the mechanism of this effect remains unclear. In this study, the protective molecular mechanism of DEX in lipopolysaccharide (LPS)-induced acute kidney injury was investigated and its potential pharmacological targets from the perspective of inhibiting oxidative stress damage and the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation. Intraperitoneal injection of DEX (30 μg/kg) significantly improved LPS (10 mg/kg) induced renal pathological damage and renal dysfunction. DEX also ameliorated oxidative stress damage by reducing the contents of reactive oxygen species, malondialdehyde and hydrogen peroxide, and increasing the level of glutathione, as well as the activity of superoxide dismutase and catalase. In addition, DEX prevented nuclear factor-kappa B (NF-κB) activation and I-kappa B (IκB) phosphorylation, as well as the expressions of NLRP3 inflammasome-associated protein and downstream IL-18 and IL-1β. The messengerRNA (mRNA) and protein expressions of toll-like receptor 4 (TLR4), NADPH oxidase-4 (NOX4), NF-κB, and NLRP3 were also significantly reduced by DEX. Their expressions were further evaluated by immunohistochemistry, yielding results were consistent with the results of mRNA and protein detection. Interestingly, the protective effects of DEX were reversed by atipamezole-an alpha 2 adrenal receptor (α 2 AR) inhibitor, whereas idazoxan-an imidazoline receptor (IR) inhibitor failed to reverse this change. In conclusion, DEX attenuated LPS-induced AKI by inhibiting oxidative stress damage and NLRP3 inflammasome activation via regulating the TLR4/NOX4/NF-κB pathway, mainly acting on the α 2 AR rather than IR.
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CNS Neuroscience & Therapeutics
·
2019
·Vol. 25
·期 5
·575-590
·
IF 3.394
Xin Jin,Ming-Yan Liu,Dong-Fang Zhang,Xin Zhong,Ke Du,Ping Qian,Wei-Fan Yao,Hua Gao,Min-Jie Wei
Summary Aims Baicalin (BAI), a flavonoid compound isolated from the root of Scutellaria baicalensis Georgi, has been established to have potent anti-inflammation and neuroprotective properties; however, its effects during Alzheimer's disease (AD) treatment have not been well studied. This study aimed to investigate the effects of BAI pretreatment on cognitive impairment and neuronal protection against microglia-induced neuroinflammation and to explore the mechanisms underlying its anti-inflammation effects. Methods To determine whether BAI plays a positive role in ameliorating the memory and cognition deficits in APP (amyloid beta precursor protein)/PS1 (presenilin-1) mice, behavioral experiments were conducted. We assessed the effects of BAI on microglial activation, the production of proinflammatory cytokines, and neuroinflammation-mediated neuron apoptosis in vivo and in vitro using Western blot, RT-PCR, ELISA, immunohistochemistry, and immunofluorescence. Finally, to elucidate the anti-inflammation mechanisms underlying the effects of BAI, the protein expression of NLRP3 inflammasomes and the expression of proteins involved in the TLR4/NF-κB signaling pathway were measured using Western blot and immunofluorescence. Results The results indicated that BAI treatment attenuated spatial memory dysfunction in APP/PS1 mice, as assessed by the passive avoidance test and the Morris water maze test. Additionally, BAI administration effectively decreased the number of activated microglia and proinflammatory cytokines, as well as neuroinflammation-mediated neuron apoptosis, in APP/PS1 mice and LPS (lipopolysaccharides)/Aβ-stimulated BV2 microglial cells. Lastly, the molecular mechanistic study revealed that BAI inhibited microglia-induced neuroinflammation via suppression of the activation of NLRP3 inflammasomes and the TLR4/NF-κB signaling pathway. Conclusion Overall, the results of the present study indicated that BAI is a promising neuroprotective compound for use in the prevention and treatment of microglia-mediated neuroinflammation during AD progression.
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MOLECULES
·
2018
·Vol. 23
·期 7
·1788
·
IF 3.098
Hong-Xin Cui,Ji-Hong Chen,Jing-Wan Li,Fang-Rong Cheng,Ke Yuan
Myrica rubra(MR) is rich in anthocyanins, and it has good anti-cancer, anti-aging, antioxidant, and antiviral effects. The proportion of disability and death caused by ischemic stroke gradually increased, becoming a major disease that is harmful to human health. However, research on effects of anthocyanin from MR on cerebral ischemia-reperfusion (I/R) injury is rare. In this study, we prepared eight purified anthocyanin extracts (PAEs) from different types of MR, and examined the amounts of total anthocyanin (TA) and cyanidin-3-O-glucoside (C-3-G). After one week of PAE treatment, the cerebral infarction volume, disease damage, and contents of nitric oxide and malondialdehyde were reduced, while the level of superoxide dismutase was increased in I/R mice. Altogether, our results show that Boqi1MR contained the most TA (22.07%) and C-3-G (21.28%), and that PAE isolated from Dongkui MR can protect the brain from I/R injury in mice, with the mechanism possibly related to the Toll-like receptor 4 (TLR4)/ nuclear factor-κB (NF-κB) and NOD-like receptor pyrin domain-containing 3 protein (NLRP3) pathways.Keywords:Myrica rubra;anthocyanins;cyanidin-3-O-glucoside;cerebral ischemia-reperfusion;TLR4/NF-κB;NLRP3
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CHEMOSPHERE
·
2018
·
IF 4.427
Feibo Xu,Qiang Ji,Jian Zhang,Wanyue Huang,Zheng Cao,Yanfei Li
Aluminum (Al), a common environmental pollutant, has been reported to inhibit the immune functions of macrophage. However, the mechanisms involved remain unclear. In this study, murine peritoneal macrophages were exposed to 0, 0.27, 0.54, and 1.08 mg/mL of aluminium chloride (AlCl 3 ) for 24 h, and then treated with 1 μg/mL lipopolysaccharide (LPS) for another 6 h. No addition of both AlCl 3 and LPS serviced as control group. We observed that AlCl 3 has cytotoxicity in murine peritoneal macrophages, showing a decrease in cell viability and an increase in lactate dehydrogenase release. Besides, AlCl 3 exposure restrained the LPS-induced NLR pyrin domain containing 3 (NLRP3) inflammasome activation presented as NLRP3 expressions reduction, caspase-1 cleavage inhibition and interleukin 1 beta (IL-1β) maturation lessened. Meanwhile, AlCl 3 exposure decreased LPS-induced IKKβ activity, IκBα phosphorylation, the phosphorylation and mRNA expression of NF-κB p65, as well the genes expression and concentration in medium supernatant of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). The results suggested that AlCl 3 inhibited the activation of NF-κB signaling pathway induced by LPS, which maybe one of the upstream signals involved in the inhibition of NLRP3 inflammasome activation by AlCl 3 . This research can provide theoretical basis for understanding the immune toxicity of Al, and deepening the cognition of Al exposure hazards to immune response.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2016
·
IF 2.73
Kegang Linghu,Dan Lin,Hong Yang,Yini Xu,Yanyan Zhang,Ling Tao,Yan Chen,Xiangchun Shen
1,8-Cineole (also known as eucalyptol) is a monoterpene that occurs naturally in many aromatic plants, 1,8-cineole has been reported to ameliorate dysfunction of endothelial cells. However, the mechanism of action of 1,8-cineole is incompletely understood. We investigated the protective effect of 1,8-cineole on lipopolysaccharide (LPS)-induced human umbilical vein endothelial cell (HUVEC) injury and the underlying mechanisms. HUVECs were preincubated with 1,8-cineole for 1.5 h, then exposed to LPS for 12 h. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase leakage assays showed 1,8-cineole reduced LPS-induced HUVEC injury significantly. Results from enzyme linked immunosorbent assays revealed that 1,8-cineole suppressed LPS-induced secretion of interleukin-6 and interleukin-8, and recovered nitric oxide to normal levels. 1,8-Cineole decreased phosphorylation of nuclear factor-kappa B (NF-κB) p65 and expression of inducible nitric oxide synthase , and simultaneously improved protein levels of endothelial nitric oxide synthase . Immunofluorescence confirmed 1,8-cineole moderates nuclear translocation of NF-κB. These results suggest that 1,8-cineole ameliorates HUVEC dysfunction significantly, and that this effect at least involves NF-κB suppression.
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NEUROTOXICITY RESEARCH
·
2016
·Vol. 31
·期 2
·259-268
·
IF 3.14
Zhang Yaqiong,Gao Lingyue,Cheng Zhihua,Cai Jiayi,Niu Yixuan,Meng Weihong,Zhao Qingchun
Impaired hippocampal neurogenesis and neuroinflammation are involved in the pathogenesis of radiation-induced brain injury. Kukoamine A (KuA) was demonstrated to have neuroprotective effects through inhibiting oxidative stress and apoptosis after whole-brain irradiation (WBI) in rats. The aim of this study was to investigate whether administration of KuA would prevent radiation-induced neuroinflammation and the detrimental effect on hippocampal neurogenesis. For this study, male Wistar rats received either sham irradiation or WBI (30 Gy single dose of X-rays) followed by the immediate injection of either KuA or vehicle intravenously. The dose of KuA was 5, 10, and 20 mg/kg, respectively. The levels of pro-inflammatory cytokines were assayed by ELISA kits. The newborn neurons were detected by 5-bromo-2-deoxyuridine (BrdU)/neuronal nuclei (NeuN) double immunofluorescence. Microglial activation was measured by Iba-1 immunofluorescence. The expression of Cox-2 and the activation of nuclear factor κB (NF-κB), activating protein 1(AP-1), and PPARδ were evaluated by western blot. WBI led to a significant increase in the level of TNF-α, IL-1β, and Cox-2, and it was alleviated by KuA administration. KuA attenuated microglial activation in rat hippocampus after WBI. Neurogenesis impairment induced by WBI was ameliorated by KuA. Additionally, KuA alleviated the increased translocation of NF-κB p65 subunit and phosphorylation of c-jun induced by WBI and elevated the expression of PPARδ. These data indicate that KuA could ameliorate the neuroinflammatory response and protect neurogenesis after WBI, partially through regulating the activation of NF-κB, AP-1, and PPARδ.
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