共查询到20条相似文献,搜索用时 15 毫秒
1.
Song Li Lihua Luo Yan He Ruohan Li Yangfan Xiang Zhenjie Xing Yejian Li Abdullkhaleg Ali Albashari Xiangyan Liao Keke Zhang Liang Gao Qingsong Ye 《Cell proliferation》2021,54(8)
ObjectivesThe study aimed to determine whether dental pulp stem cell‐derived exosomes (DPSC‐Exos) exert protective effects against cerebral ischaemia‐reperfusion (I/R) injury and explore its underlying mechanism.Materials and MethodsExosomes were isolated from the culture medium of human DPSC. Adult male C57BL/6 mice were subjected to 2 hours transient middle cerebral artery occlusion (tMCAO) injury followed by 2 hours reperfusion, after which singular injection of DPSC‐Exos via tail vein was administrated. Brain oedema, cerebral infarction and neurological impairment were measured on day 7 after exosomes injection. Then, oxygen‐glucose deprivation–reperfusion (OGD/R) induced BV2 cells were studied to analyse the therapeutic effects of DPSC‐Exos on I/R injury in vitro. Protein levels of TLR4, MyD88, NF‐κB p65, HMGB1, IL‐6, IL‐1β and TNF‐α were determined by western blot or enzyme‐linked immunosorbent assay. The cytoplasmic translocation of HMGB1 was detected by immunofluorescence staining.ResultsDPSC‐Exos alleviated brain oedema, cerebral infarction and neurological impairment in I/R mice. DPSC‐Exos inhibited the I/R‐mediated expression of TLR4, MyD88 and NF‐κB significantly. DPSC‐Exos also reduced the protein expression of IL‐6, IL‐1β and TNF‐α compared with those of the control both in vitro and in vivo. Meanwhile, DPSC‐Exos markedly decreased the HMGB1 cytoplasmic translocation induced by I/R damage.ConclusionsDPSC‐Exos can ameliorate I/R‐induced cerebral injury in mice. Its anti‐inflammatory mechanism might be related with the inhibition of the HMGB1/TLR4/MyD88/NF‐κB pathway. 相似文献
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Xueqing Hu Wenqian Zhou Shun Wu Rui Wang Zhiyong Luan Xin Geng Na Xu Zhaoyong Zhang Zhenmin Ruan Zenghui Wang Furong Li Chen Yu Hongqi Ren 《Journal of cellular and molecular medicine》2022,26(2):507
Lipopolysaccharide (LPS)‐induced sepsis‐associated acute kidney injury (SA‐AKI) is a model of clinical serious care syndrome, with high morbidity and mortality. Tacrolimus (TAC), a novel immunosuppressant that inhibits inflammatory response, plays a pivotal role in kidney diseases. In this study, LPS treated mice and cultured podocytes were used as the models of SA‐AKI in vivo and in vitro, respectively. Medium‐ and high‐dose TAC administration significantly attenuated renal function and renal pathological manifestations at 12, 24 and 48 h after LPS treatment in mice. Moreover, the Toll‐like receptor 4 (TLR4)/myeloid differential protein‐88 (MyD88)/nuclear factor‐kappa (NF‐κB) signalling pathway was also dramatically inhibited by medium‐ and high‐dose TAC administration at 12, 24 and 48 h of LPS treatment mice. In addition, TAC reversed LPS‐induced podocyte cytoskeletal injury and podocyte migratory capability. Our findings indicate that TAC has protective effects against LPS‐induced AKI by inhibiting TLR4/MyD88/NF‐κB signalling pathway and podocyte dysfunction, providing another potential therapeutic effects for the LPS‐induced SA‐AKI. 相似文献
3.
XiaoYan Zhou ChangJiang Ying Bin Hu YuSheng Zhang Tian Gan YanDong Zhu Nan Wang AnAn Li YuanJian Song 《Aging cell》2022,21(2)
In this study, we explored the precise mechanisms underlying the receptor for advanced glycation end products (RAGE)‐mediated neuronal loss and behavioral dysfunction induced by hyperglycemia. We used immunoprecipitation (IP) and GST pull‐down assays to assess the interaction between RAGE and mitogen‐activated protein kinase kinase 3 (MKK3). Then, we investigated the effect of specific mutation of RAGE on plasticity at hippocampal synapses and behavioral deficits in db/db mice through electrophysiological recordings, morphological assays, and behavioral tests. We discovered that RAGE binds MKK3 and that this binding is required for assembly of the MEKK3‐MKK3‐p38 signaling module. Mechanistically, we found that activation of p38 mitogen‐activated protein kinase (MAPK)/NF‐κB signaling depends on mediation of the RAGE‐MKK3 interaction by C‐terminal RAGE (ctRAGE) amino acids (AAs) 2‐5. We found that ctRAGE R2A‐K3A‐R4A‐Q5A mutation suppressed neuronal damage, improved synaptic plasticity, and alleviated behavioral deficits in diabetic mice by disrupting the RAGE‐MKK3 conjugation. High glucose induces direct binding of RAGE and MKK3 via ctRAGE AAs 2‐5, which leads to assembly of the MEKK3‐MKK3‐p38 signaling module and subsequent activation of the p38MAPK/NF‐κB pathway, and ultimately results in diabetic encephalopathy (DE). 相似文献
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Stefania Raimondo Ornella Urzì Serena Meraviglia Marta Di Simone Anna Maria Corsale Nima Rabienezhad Ganji Antonio Palumbo Piccionello Giulia Polito Elena Lo Presti Francesco Dieli Alice Conigliaro Riccardo Alessandro 《Journal of cellular and molecular medicine》2022,26(15):4195
Chronic inflammation is associated with the occurrence of several diseases. However, the side effects of anti‐inflammatory drugs prompt the identification of new therapeutic strategies. Plant‐derived extracellular vesicles (PDEVs) are gaining increasing interest in the scientific community for their biological properties. We isolated PDEVs from the juice of Citrus limon L. (LEVs) and characterized their flavonoid, limonoid and lipid contents through reversed‐phase high‐performance liquid chromatography coupled to electrospray ionization quadrupole time‐of‐flight mass spectrometry (RP‐HPLC–ESI‐Q‐TOF‐MS). To investigate whether LEVs have a protective role on the inflammatory process, murine and primary human macrophages were pre‐treated with LEVs for 24 h and then were stimulated with lipopolysaccharide (LPS). We found that pre‐treatment with LEVs decreased gene and protein expression of pro‐inflammatory cytokines, such as IL‐6, IL1‐β and TNF‐α, and reduced the nuclear translocation and phosphorylation of NF‐κB in LPS‐stimulated murine macrophages. The inhibition of NF‐κB activation was associated with the reduction in ERK1‐2 phosphorylation. Furthermore, the ability of LEVs to decrease pro‐inflammatory cytokines and increase anti‐inflammatory molecules was confirmed ex vivo in human primary T lymphocytes. In conclusion, we demonstrated that LEVs exert anti‐inflammatory effects both in vitro and ex vivo by inhibiting the ERK1‐2/NF‐κB signalling pathway. 相似文献
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Gunter Maubach Michelle C C Lim Olga Sokolova Steffen Backert Thomas F Meyer Michael Naumann 《EMBO reports》2021,22(9)
Helicobacter pylori infection constitutes one of the major risk factors for the development of gastric diseases including gastric cancer. The activation of nuclear factor‐kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) via classical and alternative pathways is a hallmark of H. pylori infection leading to inflammation in gastric epithelial cells. Tumor necrosis factor receptor‐associated factor (TRAF)‐interacting protein with forkhead‐associated domain (TIFA) was previously suggested to trigger classical NF‐κB activation, but its role in alternative NF‐κB activation remains unexplored. Here, we identify TRAF6 and TRAF2 as binding partners of TIFA, contributing to the formation of TIFAsomes upon H. pylori infection. Importantly, the TIFA/TRAF6 interaction enables binding of TGFβ‐activated kinase 1 (TAK1), leading to the activation of classical NF‐κB signaling, while the TIFA/TRAF2 interaction causes the transient displacement of cellular inhibitor of apoptosis 1 (cIAP1) from TRAF2, and proteasomal degradation of cIAP1, to facilitate the activation of the alternative NF‐κB pathway. Our findings therefore establish a dual function of TIFA in the activation of classical and alternative NF‐κB signaling in H. pylori‐infected gastric epithelial cells. 相似文献
6.
Kangfeng Jiang Jing Yang Chunlian Song Fengping He Liangyu Yang Xiaobing Li 《International journal of biological sciences》2021,17(5):1289
Endometritis is a reproductive disorder characterized by an inflammatory response in the endometrium, which causes significant economic losses to the dairy farming industry. MicroRNAs (miRNAs) are implicated in the inflammatory response and immune regulation following infection by pathogenic bacteria. Recent miRNA microarray analysis showed an altered expression of miR-92b in cows with endometritis. In the present study, we set out to investigate the regulatory mechanism of miR-92b in endometritis. Here, qPCR results first validated that miR-92b was down-regulated during endometritis. And then, bovine endometrial epithelial cells (BEND cells) stimulated by high concentration of lipopolysaccharide (LPS) were employed as an in vitro inflammatory injury model. Our data showed that overexpression of miR-92b significantly suppressed the activation of Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF‐κB) in LPS-stimulated BEND cells, thereby reducing pro-inflammatory cytokines release and inhibiting cell apoptosis. Looking into the molecular mechanisms of regulation of inflammatory injury by miR-92b, we observed that overexpression of miR-92b restrained TLR4/NF‐κB by activating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT)/β-catenin pathway. Furthermore, the luciferase reporter assay suggested that miR-92b targeted inhibition of phosphatase and tensin homolog (PTEN), an inhibitor of the PI3K/AKT/β-catenin pathway. Importantly, in vivo experiments confirmed that up-regulation of miR-92b attenuated the pathological injury in an experimental murine model of LPS-induced endometritis. Collectively, these findings show that enforced expression of miR-92b alleviates LPS-induced inflammatory injury by activating the PI3K/AKT/β-catenin pathway via targeting PTEN, suggesting a potential application for miR-92b-based therapy to treat endometritis or other inflammatory diseases. 相似文献
7.
Marina Kolesnichenko Nadine Mikuda Uta E Hpken Eva Krgel Bora Uyar Ahmet Bugra Tufan Maja Milanovic Wei Sun Inge Krahn Kolja Schleich Linda von Hoff Michael Hinz Michael Willenbrock Sabine Jungmann Altuna Akalin Soyoung Lee Ruth SchmidtUllrich Clemens A Schmitt Claus Scheidereit 《The EMBO journal》2021,40(6)
8.
Marie Oliver Metzig Ying Tang Simon Mitchell Brooks Taylor Robert Foreman Roy Wollman Alexander Hoffmann 《Molecular systems biology》2020,16(12)
Balancing cell death is essential to maintain healthy tissue homeostasis and prevent disease. Tumor necrosis factor (TNF) not only activates nuclear factor κB (NFκB), which coordinates the cellular response to inflammation, but may also trigger necroptosis, a pro‐inflammatory form of cell death. Whether TNF‐induced NFκB affects the fate decision to undergo TNF‐induced necroptosis is unclear. Live‐cell microscopy and model‐aided analysis of death kinetics identified a molecular circuit that interprets TNF‐induced NFκB/RelA dynamics to control necroptosis decisions. Inducible expression of TNFAIP3/A20 forms an incoherent feedforward loop to interfere with the RIPK3‐containing necrosome complex and protect a fraction of cells from transient, but not long‐term TNF exposure. Furthermore, dysregulated NFκB dynamics often associated with disease diminish TNF‐induced necroptosis. Our results suggest that TNF''s dual roles in either coordinating cellular responses to inflammation, or further amplifying inflammation are determined by a dynamic NFκB‐A20‐RIPK3 circuit, that could be targeted to treat inflammation and cancer. 相似文献
9.
Jiansen Lu Hong Guan Dan Wu Zhiqiang Hu Hongbo Zhang Huaji Jiang Jingyao Yu Ke Zeng Hongyu Li Haiyan Zhang Chenglong Pan Daozhang Cai Xiao Yu 《Journal of cellular and molecular medicine》2021,25(14):6664
Synovial macrophage polarization and inflammation are essential for osteoarthritis (OA) development, yet the molecular mechanisms and regulation responsible for the pathogenesis are still poorly understood. Here, we report that pseudolaric acid B (PAB) attenuated articular cartilage degeneration and synovitis during OA. PAB, a diterpene acid, specifically inhibited NF‐κB signalling and reduced the production of pro‐inflammatory cytokines, which further decreased M1 polarization and vessel formation. We further provide in vivo and in vitro evidences that PAB suppressed NF‐κB signalling by stabilizing PPARγ. Using PPARγ antagonist could abolish anti‐inflammatory effect of PAB and rescue the activation of NF‐κB signalling during OA. Our findings identify a previously unrecognized role of PAB in the regulation of OA and provide mechanisms by which PAB regulates NF‐κB signalling through PPARγ, which further suggest targeting synovial inflammation or inhibiting vessel formation at early stage could be an effective preventive strategy for OA. 相似文献
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13.
Mengyuan Li Yu Yan Xinxin Zhang Yidan Zhang Xiaohan Xu Lei Zhang Liangliang Lu Jie Wang Yazhuo Zhang Qiaoling Song Chenyang Zhao 《Journal of cellular and molecular medicine》2021,25(13):6333
JAK/STAT and NFκB signalling pathways play essential roles in regulating inflammatory responses, which are important pathogenic factors of various serious immune‐related diseases, and function individually or synergistically. To find prodrugs that can treat inflammation, we performed a preliminary high‐throughput screening of 18 840 small molecular compounds and identified scaffold compound L971 which significantly inhibited JAK/STAT and NFκB driven luciferase activities. L971 could inhibit the constitutive and stimuli‐dependent activation of STAT1, STAT3 and IκBα and could significantly down‐regulate the proinflammatory gene expression in mouse peritoneal macrophages stimulated by LPS. Gene expression profiles upon L971 treatment were determined using high‐throughput RNA sequencing, and significant differentially up‐regulated and down‐regulated genes were identified by DESeq analysis. The bioinformatic studies confirmed the anti‐inflammatory effects of L971. Finally, L971 anti‐inflammatory character was further verified in LPS‐induced sepsis shock mouse model in vivo. Taken together, these data indicated that L971 could down‐regulate both JAK/STAT and NFκB signalling activities and has the potential to treat inflammatory diseases such as sepsis shock. 相似文献
14.
Zhixiao Wu Lena A Berlemann Verian Bader Dominik A Sehr Eva Dawin Alberto Covallero Jens Meschede Lena Angersbach Cathrin Showkat Jonas B Michaelis Christian Münch Bettina Rieger Dmitry Namgaladze Maria Georgina Herrera Fabienne C Fiesel Wolfdieter Springer Marta Mendes Jennifer Stepien Katalin Barkovits Katrin Marcus Albert Sickmann Gunnar Dittmar Karin B Busch Dietmar Riedel Marisa Brini Jrg Tatzelt Tito Cali Konstanze F Winklhofer 《The EMBO journal》2022,41(24)
Mitochondria are increasingly recognized as cellular hubs to orchestrate signaling pathways that regulate metabolism, redox homeostasis, and cell fate decisions. Recent research revealed a role of mitochondria also in innate immune signaling; however, the mechanisms of how mitochondria affect signal transduction are poorly understood. Here, we show that the NF‐κB pathway activated by TNF employs mitochondria as a platform for signal amplification and shuttling of activated NF‐κB to the nucleus. TNF treatment induces the recruitment of HOIP, the catalytic component of the linear ubiquitin chain assembly complex (LUBAC), and its substrate NEMO to the outer mitochondrial membrane, where M1‐ and K63‐linked ubiquitin chains are generated. NF‐κB is locally activated and transported to the nucleus by mitochondria, leading to an increase in mitochondria‐nucleus contact sites in a HOIP‐dependent manner. Notably, TNF‐induced stabilization of the mitochondrial kinase PINK1 furthermore contributes to signal amplification by antagonizing the M1‐ubiquitin‐specific deubiquitinase OTULIN. Overall, our study reveals a role for mitochondria in amplifying TNF‐mediated NF‐κB activation, both serving as a signaling platform, as well as a transport mode for activated NF‐κB to the nuclear. 相似文献
15.
Huanlian Tian Feng Chen Yingfang Wang Yixuan Liu Guojing Ma Yuhong Zhao Yanan Ma Tingting Tian Ruze Ma Yang Yu Difei Wang 《Journal of cellular and molecular medicine》2022,26(8):2163
Inflammation is a major risk factor for osteoporosis, and reducing inflammatory levels is important for the prevention of osteoporosis. Although nuclear receptor 77 (Nur77) protects against inflammation in a variety of diseases, its role in osteoporosis is unknown. Therefore, the main purpose of this study was to investigate the osteoprotective and anti‐inflammatory effects of Nur77. The microCT and haematoxylin and eosin staining results indicated that knockout of Nur77 accelerated femoral bone loss in mice. The enzyme‐linked immunosorbent assay (ELISA) results showed that knockout of Nur77 increased the serum levels of hsCRP and IL‐6. The expression levels of NF‐κB, IL‐6, TNF‐α and osteoclastogenesis factors (TRAP, NFATC1, Car2, Ctsk) in the femurs of Nur77 knockout mice were increased significantly. Furthermore, in vitro, shNur77 promoted the differentiation of RAW264.7 cells into osteoclasts by activating NF‐κB, which was confirmed by PDTC treatment. Mechanistically, Nur77 inhibited osteoclast differentiation by inducing IκB‐α and suppressing IKK‐β. In RAW264.7 cells, overexpression of Nur77 alleviated inflammation induced by siIκB‐α, while siIKK‐β alleviated inflammation induced by shNur77. Consistent with the in vivo studies, we found that compared with control group, older adults with high serum hsCRP levels were more likely to suffer from osteoporosis (OR = 1.76, p < 0.001). Our data suggest that Nur77 suppresses osteoclast differentiation by inhibiting the NF‐κB signalling pathway, strongly supporting the notion that Nur77 has the potential to prevent and treat osteoporosis. 相似文献
16.
Lei Zhang Jing Zhao Xiaodong Mu Sara J. McGowan Luise Angelini Ryan D. O'Kelly Matthew J. Yousefzadeh Ayumi Sakamoto Zaira Aversa Nathan K. LeBrasseur Yousin Suh Johnny Huard Theodore M. Kamenecka Laura J. Niedernhofer Paul D. Robbins 《Aging cell》2021,20(12)
Constitutive NF‐κB activation is associated with cellular senescence and stem cell dysfunction and rare variants in NF‐κB family members are enriched in centenarians. We recently identified a novel small molecule (SR12343) that inhibits IKK/NF‐κB activation by disrupting the association between IKKβ and NEMO. Here we investigated the therapeutic effects of SR12343 on senescence and aging in three different mouse models. SR12343 reduced senescence‐associated beta‐galactosidase (SA‐β‐gal) activity in oxidative stress‐induced senescent mouse embryonic fibroblasts as well as in etoposide‐induced senescent human IMR90 cells. Chronic administration of SR12343 to the Ercc1 −/ ∆ and Zmpste24 −/− mouse models of accelerated aging reduced markers of cellular senescence and SASP and improved multiple parameters of aging. SR12343 also reduced markers of senescence and increased muscle fiber size in 2‐year‐old WT mice. Taken together, these results demonstrate that IKK/NF‐κB signaling pathway represents a promising target for reducing markers of cellular senescence, extending healthspan and treating age‐related diseases. 相似文献
17.
Yanfei Jia Yanyan Liu Jingyu Zhu Liang Liu Xiaoli Ma Duanrui Liu Shuyi Han Lulu Zhang ZhiQiang Ling Yunshan Wang 《Journal of cellular and molecular medicine》2022,26(7):1943
Helicobacter pylori (H. pylori) infection plays a crucial role in the initiation and progression of gastric cancer (GC). Differentiated embryo‐chondrocyte expressed gene 1 (DEC1) is dysregulated in some cancers and may regulate cell proliferation in specific contexts. Of note, DEC1 is emerging as one of the important factors regulating cellular responses in microenvironment. However, the triggers and precise regulation mechanism for DEC1 during inflammatory carcinoma transformation of GC are unclear. In this study, we identified DEC1 was upregulated in both H. pylori‐infected gastric tissues and GC cells. DEC1 expression was positively associated with H. pylori infection status and GC progression. DEC1‐positive expression indicated a poorer prognosis in H. pylori‐positive GC. DEC1 was required for H. pylori‐induced GC cells proliferation. Mechanistically, H. pylori infection significantly activated Akt/NF‐κB signal pathway and this induction depend on DEC1 expression level in GC cells. Importantly, their interaction pathway was further verified by H. pylori‐positive gastritis mice model. Taken together, our findings identified a novel function of DEC1 in GC. H. pylori infection induce DEC1 expression, and which leading to the progression of GC through activating Akt/ NF‐κB signalling pathway. Blocking DEC1/Akt/NF‐κB, therefore, presents a promising novel therapeutic strategy for H. pylori‐positive GC. 相似文献
18.
Lei Qi Hui Hu Ye Wang Hesheng Hu Kang Wang Pingjiang Li Jie Yin Yugen Shi Yu Wang Yuepeng Zhao Hangji Lyu Meng Feng Mei Xue Xinran Li Yan Li Suhua Yan 《Journal of cellular and molecular medicine》2022,26(4):1264
Ventricular arrhythmias (VAs) triggers by sympathetic nerve hyperactivity contribute to sudden cardiac death in myocardial infarction (MI) patients. Microglia‐mediated inflammation in the paraventricular nucleus (PVN) is involved in sympathetic hyperactivity after MI. N6‐methyladenosine (m6A), the most prevalent mRNA and epigenetic modification, is critical for mediating cell inflammation. We aimed to explore whether METTL3‐mediated m6A modification is involved in microglia‐mediated sympathetic hyperactivity after MI in the PVN. MI model was established by left coronary artery ligation. METTL3‐mediated m6A modification was markedly increased in the PVN at 3 days after MI, and METTL3 was primarily located in microglia by immunofluorescence. RNA‐seq, MeRIP‐seq, MeRIP‐qPCR, immunohistochemistry, ELISA, heart rate variability measurements, renal sympathetic nerve activity recording and programmed electrical stimulation confirmed that the elevated toll‐like receptor 4 (TLR4) expression by m6A modification on TLR4 mRNA 3''‐UTR region combined with activated NF‐κB signalling led to the overwhelming production of pro‐inflammatory cytokines IL‐1β and TNF‐α in the PVN, thus inducing the sympathetic hyperactivity and increasing the incidence of VAs post‐MI. Targeting METTL3 attenuated the inflammatory response and sympathetic hyperactivity and reduced the incidence of VAs post‐MI. 相似文献
19.
Pu Chen Jun Zhou Anmin Ruan Hua Guan Jiewei Xie Lingfeng Zeng Jun Liu Qingfu Wang 《Journal of cellular and molecular medicine》2022,26(7):2038
Osteoarthritis (OA) is a whole‐joint disease characterized by synovial inflammation and cartilage degeneration. However, the relationship between synovial inflammation and cartilage degeneration remains unclear. The modified Hulth''s method was adopted to establish a knee OA (KOA) rabbit model. Synovial tissue was collected after 8 weeks, and synovial tissue‐derived extracellular vesicles (ST‐EVs) were extracted by filtration combined with size exclusion chromatography (SECF), followed by identification through transmission electron microscopy (TEM), nanoparticle tracer analysis (NTA) and Western blot (WB). The collagenase digestion method was used to extract normal rabbit chondrocytes, which were then treated with the SF‐EVs to observe the effect and mechanism of SF‐EVs on chondrocytes. The morphology, particle size and labelled protein marker detection confirmed that SECF successfully extract ST‐EVs. The ST‐EVs in the KOA state significantly inhibited chondrocyte proliferation and promoted chondrocytes apoptosis. Moreover, the ST‐EVs also promoted the expression of pro‐inflammatory cytokines (IL‐1β, IL‐6, TNF‐α and COX‐2) and cartilage degradation‐related enzymes (MMP13, MMP9 and ADAMTS5) in the chondrocytes. Mechanistically, the ST‐EVs significantly promoted the activation of NF‐κB signalling pathway in chondrocytes. Inhibition the activation of the NF‐κB signalling pathway significantly rescued the expression of inflammatory cytokines and cartilage degradation‐related enzymes in the ST‐EVs–induced chondrocytes. In conclusion, the ST‐EVs promote chondrocytes inflammation and degradation by activating the NF‐κB signalling pathway, providing novel insights into the occurrence and development of OA. 相似文献
20.
Moein Ala Razieh Mohammad Jafari Mahan Ala Sedigheh Marjaneh Hejazi Seyed Mohammad Tavangar Seied Rabi Mahdavi Ahmad Reza Dehpour 《Journal of cellular and molecular medicine》2022,26(16):4556
Radiation‐induced oral mucositis is a common and dose‐limiting complication of head and neck radiotherapy with no effective treatment. Previous studies revealed that sildenafil, a phosphodiesterase 5 inhibitor, has anti‐inflammatory and anti‐cancer effects. In this study, we investigated the effect of sildenafil on radiation‐induced mucositis in rats. Two doses of radiation (8 and 26 Gy X‐ray) were used to induce low‐grade and high‐grade oral mucositis, separately. A control group and three groups of sildenafil citrate‐treated rats (5, 10, and 40 mg/kg/day) were used for each dose of radiation. Radiation increased MDA and activated NF‐κB, ERK and JNK signalling pathways. Sildenafil significantly decreased MDA level, nitric oxide (NO) level, IL1β, IL6 and TNF‐α. The most effective dose of sildenafil was 40 mg/kg/day in this study. Sildenafil also significantly inhibited NF‐κB, ERK and JNK signalling pathways and increased bcl2/bax ratio. In addition, high‐dose radiation severely destructed the mucosal layer in histopathology and led to mucosal cell apoptosis in the TUNEL assay. Sildenafil significantly improved mucosal structure and decreased inflammatory cell infiltration after exposure to high‐dose radiation and reduced apoptosis in the TUNEL assay. These findings show that sildenafil can improve radiation‐induced oral mucositis and decrease the apoptosis of mucosal cells via attenuation of inflammation and oxidative stress. 相似文献