Background: Recent studies indicate that C-X-C motif chemokine receptor 4(CXCR4) and its ligand, C-X-C motif chemokine ligand 12(CXCL12), stimulate expression of the cell cycle regulatory protein Cyclin D1 in neurofib...Background: Recent studies indicate that C-X-C motif chemokine receptor 4(CXCR4) and its ligand, C-X-C motif chemokine ligand 12(CXCL12), stimulate expression of the cell cycle regulatory protein Cyclin D1 in neurofibromatosis 1-associated malignant peripheral nerve sheath tumor(MPNST) cells and promote their proliferation. In this study, we measured the expression of CXCR4, CXCL12, and Cyclin D1 proteins in sporadic MPNST tissues from Chinese patients and investigated their prognostic values.Methods: CXCR4, CXCL12, and Cyclin D1 protein expression in samples from 58 Chinese patients with sporadic MPNST was assessed with immunohistochemical staining.Their prognostic values were evaluated with Kaplan-Meier analysis and a log-rank test. Multivariate Cox regression analysis was used to identify independent prognostic factors.Results: High expression of CXCR4, CXCL12, and Cyclin D1 was observed in 19(32.8%), 32(55.2%), and 16(27.6%)samples, respectively. CXCR4 expression was positively correlated with CXCL12 expression(r = 0.334, P = 0.010) and Cyclin D1 expression(r = 0.309, P = 0.018). Patients with high CXCR4 expression showed longer overall survival than those with low CXCR4 expression(χ~2 = 4.642, P = 0.031).Conclusion: High CXCR4 expression may define a specific subtype of sporadic MPNST with favorable prognosis.展开更多
Epstein-Barr virus (EBV) infects over 90% of the global population, establishing latent infections in most individuals. Under specific conditions like inflammation and immune suppression, EBV can be reactivated, leadi...Epstein-Barr virus (EBV) infects over 90% of the global population, establishing latent infections in most individuals. Under specific conditions like inflammation and immune suppression, EBV can be reactivated, leading to the initiation and progression of related diseases. While inflammation is known to induce EBV reactivation, the precise mechanisms underlying this phenomenon remain unclear. Chemokine (C-X-C motif) ligand (CXCL10), a key inflammatory factor, plays a significant role in various infectious diseases. In this study, we investigated how CXCL10 levels regulate the transition between the latent and lytic replication phases of the EBV lifecycle using cell culture, Western blot, fluorescent quantitative PCR, immunofluorescence, and flow cytometric apoptosis assays. Our findings indicate that CXCL10 induces EBV transition from latency to lytic replication through its receptor CXCR3 by regulating the downstream effector, exostosis-like glycosyltransferase 1. Additionally, CXCL10 activates the JAK2/STAT3 pathway. This study confirms the role of CXCL10 in promoting EBV lytic replication, providing crucial insights into the pathogenic mechanisms of inflammation-triggered EBV reactivation.展开更多
Chemokine(C-X-C motif)receptor 7(CXCR7),recently termed ACKR3,belongs to the G protein-coupled cell surface receptor family,binds to stromal cellderived factor-1[SDF-1,or chemokine(C-X-C motif)ligand 12]or chemokine(C...Chemokine(C-X-C motif)receptor 7(CXCR7),recently termed ACKR3,belongs to the G protein-coupled cell surface receptor family,binds to stromal cellderived factor-1[SDF-1,or chemokine(C-X-C motif)ligand 12]or chemokine(CX-C motif)ligand 11,and is the most common chemokine receptor expressed in a variety of cancer cells.SDF-1 binds to its receptor chemokine(C-X-C motif)receptor 4(CXCR4)and regulates cell proliferation,survival,angiogenesis and migration.In recent years,another new receptor for SDF-1,CXCR7,has been discovered,and CXCR7 has also been found to be expressed in a variety of tumor cells and tumor-related vascular endothelial cells.Many studies have shown that CXCR7 can promote the growth and metastasis of a variety of malignant tumor cells.Unlike CXCR4,CXCR7 exhibits a slight modification in the DRYLAIV motif and does not induce intracellular Ca^2+release following ligand binding,which is essential for recruiting and activating G proteins.CXCR7 is generally thought to work in three ways:(1)Recruitingβ-arrestin 2;(2)Heterodimerizing with CXCR4;and(3)Acting as a“scavenger”of SDF-1,thus lowering the level of SDF-1 to weaken the activity of CXCR4.In the present review,the expression and role of CXCR7,as well as its prognosis in cancers of the digestive system,were investigated.展开更多
We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation r...We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation remains unclear.In this study,we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine,a H2S precursor,attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionineβsynthase(a major H2S synthetase in the brain)in the prefrontal cortex.We also found that an miR-9-5p inhibitor blocked the expression of cystathionineβsynthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia.Furthermore,miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury.L-cysteine decreased the expression of CXCL11,an miR-9-5p target gene,in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3,FSTL1,SOCS2 and SOCS5,while treatment with an miR-9-5p inhibitor reversed these changes.These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoringβ-synthase expression,thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.展开更多
目的:观察趋化因子配体5(chemokine C-C motif ligand 5,CCL5)、趋化因子CXC配体[chemokine(C-X-C motif)ligand,CXCL]10、CXCL13在创伤性脑损伤(traumatic brain injury,TBI)患者外周血液中的表达变化,分析这些趋化因子对损伤程度和预...目的:观察趋化因子配体5(chemokine C-C motif ligand 5,CCL5)、趋化因子CXC配体[chemokine(C-X-C motif)ligand,CXCL]10、CXCL13在创伤性脑损伤(traumatic brain injury,TBI)患者外周血液中的表达变化,分析这些趋化因子对损伤程度和预后的影响。方法:选取39例重度TBI患者[格拉斯哥昏迷评分(Glasgow coma scale,GCS)3~8分]与13例健康对照者。酶联免疫吸附测定法检测TBI患者术后1、3、7 d和对照组外周血中CCL5、CXCL10、CXCL13蛋白含量;Spearman相关分析对不同时间点外周血中CCL5、CXCL10、CXCL13和入院GCS、术后30 d GCS和格拉斯哥结局量表评分(Glasgow outcome scale,GOS)进行相关性分析。结果:与对照组相比,重度TBI患者外周血液中CCL5、CXCL10、CXCL13的表达量均明显升高(均P<0.05)。重度TBI患者术后1 d血液中CCL5、CXCL13的蛋白浓度与入院GCS评分呈负相关(P<0.05),术后3 d CXCL10的浓度与术后30 d GCS评分呈负相关(P<0.05)。重度TBI患者术后1 d CCL5的蛋白含量、术后1 d和3 d CXCL10蛋白含量及术后7 d CXCL13的蛋白含量与术后30 d GOS评分呈负相关(P<0.05)。结论:趋化因子CCL5、CXCL10、CXCL13在TBI早期表达量迅速增加,且表达量越高,损伤程度越重,预后可能越差。展开更多
Objective Proprionibacterium acnes(P.acnes)-induced inflammatory responses,proliferation and differentiation of keratinocytes contribute to the progression of acne vulgaris(AV).P.acnes was found to enhance the product...Objective Proprionibacterium acnes(P.acnes)-induced inflammatory responses,proliferation and differentiation of keratinocytes contribute to the progression of acne vulgaris(AV).P.acnes was found to enhance the production of interleukin-8(IL-8)by keratinocytes.This study aimed to investigate the role of IL-8 in P.acnes-induced proliferation and differentiation of keratinocytes and the underlying mechanism.Methods The P.acnes-stimulated HaCaT cell(a human keratinocyte cell line)model was established.Western blotting and immunofluorescence were performed to detect the expression of the IL-8 receptors C-X-C motif chemokine receptor 1(CXCR1)and C-X-C motif chemokine receptor 2(CXCR2)on HaCaT cells.Cell counting kit-8(CCK-8)assay,5-ethynyl-20-deoxyuridine(EdU)assay and Western blotting were performed to examine the effects of IL-8/CXCR2 axis on the proliferation and differentiation of HaCaT cells treated with P.acnes,the IL-8 neutralizing antibody,the CXCR2 antagonist(SB225002),or the CXCR1/CXCR2 antagonist(G31P).Western blotting,nuclear and cytoplasmic separation,CCK-8 assay,and EdU assay were employed to determine the downstream pathway of CXCR2 after P.acnes-stimulated HaCaT cells were treated with the CXCR2 antagonist,the protein kinase B(AKT)antagonist(AZD5363),or the constitutively active forkhead box O1(FOXO1)mutant.Finally,autophagy markers were measured in HaCaT cells following the transfection of the FOXO1 mutant or treatment with the autophagy inhibitor 3-methyladenine(3-MA).Results The expression levels of CXCR1 and CXCR2 were significantly increased on the membrane of HaCaT cells following P.acnes stimulation.The IL-8/CXCR2 axis predominantly promoted the proliferation and differentiation of P.acnes-induced HaCaT cells by activating AKT/FOXO1/autophagy signaling.In brief,IL-8 bound to its receptor CXCR2 on the membrane of keratinocytes to activate the AKT/FOXO1 axis.Subsequently,phosphorylated FOXO1 facilitated autophagy to promote the proliferation and differentiation of P.acnes-induced keratinocytes.Conclusion This study demonstrated the novel autocrine effect of IL-8 on the proliferation and differentiation of P.acnes-induced keratinocytes,suggesting a potential therapeutic target for AV.展开更多
Aflatoxin B_(1)(AFB_(1))is a naturally-occurring mycotoxin and recognized as the most toxic foodborne toxin,particularly causing damages to kidney.Glomerular podocytes are terminally differentiated epithelial cells.AF...Aflatoxin B_(1)(AFB_(1))is a naturally-occurring mycotoxin and recognized as the most toxic foodborne toxin,particularly causing damages to kidney.Glomerular podocytes are terminally differentiated epithelial cells.AFB_(1)induces podocyte inflammation,proteinuria and renal dysfunction.Studying the mechanism of AFB_(1)-induced podocyte inflammation and murine kidney dysfunction,we detected that AFB_(1)increased ubiquitindependent degradation of the transcription factor RelA through enhanced interaction of RelA with E3 ubiquitin ligase tripartite motif containing 7(TRIM7)in mouse podocyte clone-5(MPC-5)and mouse glomeruli.Reduction of RelA resulted in decreasing microRNA-9(miR-9)and activating the chemokine receptor 4(CXCR4),thioredoxin interacting protein(TXNIP),and NOD-like receptor pyrin domain-containing 3(NLRP3)signaling axis(CXCR4/TXNIP/NLRP3 pathway),leading to podocyte inflammation.We also determined that downregulation of miR-9 led to CXCR4 expression and the downstream TXNIP/NLRP3 pathway activation.Overexpression of miR-9 or deletion of CXCR4 suppressed AFB_(1)-induced CXCR4/TXNIP/NLRP3 pathway,resulting in alleviating podocyte inflammation and kidney dysfunction.Our findings indicated that ubiquitin-dependent proteolysis of RelA,downregulation of miR-9,and activation of CXCR4/TXNIP/NLRP3 pathway played an essential role in AFB_(1)-induced glomerular podocyte inflammation.Our study revealed a novel mechanism,via RelA,for the control of AFB_(1)’s nephrotoxicity,leading to an effective protection of food safety and public health.展开更多
Background:We previously found that overexpression of the gene known as amplified in breast cancer 1(AIB1)was associated with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma.However,the r...Background:We previously found that overexpression of the gene known as amplified in breast cancer 1(AIB1)was associated with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma.However,the role of AIB1 in that malignancy remains unknown.The present study aimed to investigate the function of AIB1 in the process of lung adenocarcinoma cell metastasis.Methods:A series of in vivo and in vitro assays were performed to elucidate the function of AIB1,while real-time PCR and Western blotting were utilized to identify the potential downstream targets of AIB1 in the process of lung adenocarcinoma metastasis.Rescue experiments and in vitro assays were performed to investigate whether the invasive-ness of AIB1-induced lung adenocarcinoma was mediated by C-X-C motif chemokine receptor 4(CXCR4).Results:The ectopic overexpression of AIB1 in lung adenocarcinoma cells substantially enhanced cell migration and invasive abilities in vitro and tumor metastasis in vivo,whereas the depletion of AIB1 expression substantially inhibited lung adenocarcinoma cell migration and invasion.CXCR4 was identified as a potential downstream target of AIB1 in lung adenocarcinoma.The knockdown of AIB1 greatly reduced CXCR4 gene expression at both the transcription and protein levels,whereas the knockdown of CXCR4 in cells with AIB1 ectopic overexpression diminished AIB1-induced migration and invasion in vitro and tumor metastasis in vivo.Furthermore,we found a significant positive association between the expression of AIB1 and CXCR4 in lung adenocarcinoma patients(183 cases),and the co-overexpression of AIB1 and CXCR4 predicted the poorest prognosis.Conclusions:These findings suggest that AIB1 promotes the aggressiveness of lung adenocarcinoma in vitro and in vivo by upregulating CXCR4 and that it might be usable as a novel prognostic marker and/or therapeutic target for this disease.展开更多
Objective: Since acute rejection remains one of the major complications which necessitate periodic surveillance, noninvasive diagnostic/prognostic methods are preferred by renal transplant recipients. Here, we explore...Objective: Since acute rejection remains one of the major complications which necessitate periodic surveillance, noninvasive diagnostic/prognostic methods are preferred by renal transplant recipients. Here, we explored whether urinary C-X-C motif chemokines 13(CXCL13) could be a potential candidate to reflect ongoing immune processes within the renal graft. Methods: We investigated urinary CXCL13 levels by a cross-sectional analysis of 146 renal allograft recipients and 40 healthy controls. Besides, a subset of patients(n=57) were followed-up for kinetic monitoring of immune status.Results: Urinary CXCL13/Cr was lower in normal transplants compared to those with acute tubular necrosis(ATN, P=0.001), chronic allograft nephropathy(CAN, P=0.01) and acute rejection(AR, P<0.0001), which yielded a good diagnosis performance of urinary CXCL13 for AR(AUC=0.818, P<0.0001). Interestingly, urinary CXCL13 further distinguished acute antibody mediated rejection(ABMR) from acute cellular rejection,with an AUC of 0.856. Besides, patients with steroid-resistant acute rejection had distinctly greater urinary CXCL13/Cr levels than patients with reversible acute rejection,P=0.001. Follow-up data revealed that urinary CXCL13/Cr varied in line with the occurrence of ABMR. Furthermore, elevated levels of urinary CXCL13/Cr within the first month was predictive of graft function at 3, 6 months, P=0.044 and 0.4. Conclusion: This study demonstrates that monitoring of urinary CXCL13/Cr might be a valuable noninvasive approach for the detection of AR, especially ABMR. Additionally, high urinary CXCL13/Cr levels related to the poor response to steroid treatment and predicted a compromised graft function after AR.展开更多
基金supported by the National Nature Science Foundation of China(81372872 to Jilong Yang,81672650 to Ze Zhu,and 81402215 to Xiaoling Du)funds from the University Cancer Foundation via the Sister Institution Network Fund(to Jilong Yang)
文摘Background: Recent studies indicate that C-X-C motif chemokine receptor 4(CXCR4) and its ligand, C-X-C motif chemokine ligand 12(CXCL12), stimulate expression of the cell cycle regulatory protein Cyclin D1 in neurofibromatosis 1-associated malignant peripheral nerve sheath tumor(MPNST) cells and promote their proliferation. In this study, we measured the expression of CXCR4, CXCL12, and Cyclin D1 proteins in sporadic MPNST tissues from Chinese patients and investigated their prognostic values.Methods: CXCR4, CXCL12, and Cyclin D1 protein expression in samples from 58 Chinese patients with sporadic MPNST was assessed with immunohistochemical staining.Their prognostic values were evaluated with Kaplan-Meier analysis and a log-rank test. Multivariate Cox regression analysis was used to identify independent prognostic factors.Results: High expression of CXCR4, CXCL12, and Cyclin D1 was observed in 19(32.8%), 32(55.2%), and 16(27.6%)samples, respectively. CXCR4 expression was positively correlated with CXCL12 expression(r = 0.334, P = 0.010) and Cyclin D1 expression(r = 0.309, P = 0.018). Patients with high CXCR4 expression showed longer overall survival than those with low CXCR4 expression(χ~2 = 4.642, P = 0.031).Conclusion: High CXCR4 expression may define a specific subtype of sporadic MPNST with favorable prognosis.
文摘Epstein-Barr virus (EBV) infects over 90% of the global population, establishing latent infections in most individuals. Under specific conditions like inflammation and immune suppression, EBV can be reactivated, leading to the initiation and progression of related diseases. While inflammation is known to induce EBV reactivation, the precise mechanisms underlying this phenomenon remain unclear. Chemokine (C-X-C motif) ligand (CXCL10), a key inflammatory factor, plays a significant role in various infectious diseases. In this study, we investigated how CXCL10 levels regulate the transition between the latent and lytic replication phases of the EBV lifecycle using cell culture, Western blot, fluorescent quantitative PCR, immunofluorescence, and flow cytometric apoptosis assays. Our findings indicate that CXCL10 induces EBV transition from latency to lytic replication through its receptor CXCR3 by regulating the downstream effector, exostosis-like glycosyltransferase 1. Additionally, CXCL10 activates the JAK2/STAT3 pathway. This study confirms the role of CXCL10 in promoting EBV lytic replication, providing crucial insights into the pathogenic mechanisms of inflammation-triggered EBV reactivation.
基金Supported by Key Projects of Tianjin Natural Science Foundation,No.19JCZDJC36100General Project of Natural Science Fund of Tianjin Education Commission,No.2018KJ047+1 种基金Subject in the Third Affiliated Central Hospital of Nankai University,No.2017YNY3Tianjin Key Special Projects,No.15KG115。
文摘Chemokine(C-X-C motif)receptor 7(CXCR7),recently termed ACKR3,belongs to the G protein-coupled cell surface receptor family,binds to stromal cellderived factor-1[SDF-1,or chemokine(C-X-C motif)ligand 12]or chemokine(CX-C motif)ligand 11,and is the most common chemokine receptor expressed in a variety of cancer cells.SDF-1 binds to its receptor chemokine(C-X-C motif)receptor 4(CXCR4)and regulates cell proliferation,survival,angiogenesis and migration.In recent years,another new receptor for SDF-1,CXCR7,has been discovered,and CXCR7 has also been found to be expressed in a variety of tumor cells and tumor-related vascular endothelial cells.Many studies have shown that CXCR7 can promote the growth and metastasis of a variety of malignant tumor cells.Unlike CXCR4,CXCR7 exhibits a slight modification in the DRYLAIV motif and does not induce intracellular Ca^2+release following ligand binding,which is essential for recruiting and activating G proteins.CXCR7 is generally thought to work in three ways:(1)Recruitingβ-arrestin 2;(2)Heterodimerizing with CXCR4;and(3)Acting as a“scavenger”of SDF-1,thus lowering the level of SDF-1 to weaken the activity of CXCR4.In the present review,the expression and role of CXCR7,as well as its prognosis in cancers of the digestive system,were investigated.
基金supported by the National Natural Science Foundation of China,Nos.82271327(to ZW),82072535(to ZW),81873768(to ZW),and 82001253(to TL).
文摘We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation remains unclear.In this study,we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine,a H2S precursor,attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionineβsynthase(a major H2S synthetase in the brain)in the prefrontal cortex.We also found that an miR-9-5p inhibitor blocked the expression of cystathionineβsynthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia.Furthermore,miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury.L-cysteine decreased the expression of CXCL11,an miR-9-5p target gene,in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3,FSTL1,SOCS2 and SOCS5,while treatment with an miR-9-5p inhibitor reversed these changes.These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoringβ-synthase expression,thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.
文摘目的:观察趋化因子配体5(chemokine C-C motif ligand 5,CCL5)、趋化因子CXC配体[chemokine(C-X-C motif)ligand,CXCL]10、CXCL13在创伤性脑损伤(traumatic brain injury,TBI)患者外周血液中的表达变化,分析这些趋化因子对损伤程度和预后的影响。方法:选取39例重度TBI患者[格拉斯哥昏迷评分(Glasgow coma scale,GCS)3~8分]与13例健康对照者。酶联免疫吸附测定法检测TBI患者术后1、3、7 d和对照组外周血中CCL5、CXCL10、CXCL13蛋白含量;Spearman相关分析对不同时间点外周血中CCL5、CXCL10、CXCL13和入院GCS、术后30 d GCS和格拉斯哥结局量表评分(Glasgow outcome scale,GOS)进行相关性分析。结果:与对照组相比,重度TBI患者外周血液中CCL5、CXCL10、CXCL13的表达量均明显升高(均P<0.05)。重度TBI患者术后1 d血液中CCL5、CXCL13的蛋白浓度与入院GCS评分呈负相关(P<0.05),术后3 d CXCL10的浓度与术后30 d GCS评分呈负相关(P<0.05)。重度TBI患者术后1 d CCL5的蛋白含量、术后1 d和3 d CXCL10蛋白含量及术后7 d CXCL13的蛋白含量与术后30 d GOS评分呈负相关(P<0.05)。结论:趋化因子CCL5、CXCL10、CXCL13在TBI早期表达量迅速增加,且表达量越高,损伤程度越重,预后可能越差。
基金supported by the National Natural Science Foundation of China(No.82103756).
文摘Objective Proprionibacterium acnes(P.acnes)-induced inflammatory responses,proliferation and differentiation of keratinocytes contribute to the progression of acne vulgaris(AV).P.acnes was found to enhance the production of interleukin-8(IL-8)by keratinocytes.This study aimed to investigate the role of IL-8 in P.acnes-induced proliferation and differentiation of keratinocytes and the underlying mechanism.Methods The P.acnes-stimulated HaCaT cell(a human keratinocyte cell line)model was established.Western blotting and immunofluorescence were performed to detect the expression of the IL-8 receptors C-X-C motif chemokine receptor 1(CXCR1)and C-X-C motif chemokine receptor 2(CXCR2)on HaCaT cells.Cell counting kit-8(CCK-8)assay,5-ethynyl-20-deoxyuridine(EdU)assay and Western blotting were performed to examine the effects of IL-8/CXCR2 axis on the proliferation and differentiation of HaCaT cells treated with P.acnes,the IL-8 neutralizing antibody,the CXCR2 antagonist(SB225002),or the CXCR1/CXCR2 antagonist(G31P).Western blotting,nuclear and cytoplasmic separation,CCK-8 assay,and EdU assay were employed to determine the downstream pathway of CXCR2 after P.acnes-stimulated HaCaT cells were treated with the CXCR2 antagonist,the protein kinase B(AKT)antagonist(AZD5363),or the constitutively active forkhead box O1(FOXO1)mutant.Finally,autophagy markers were measured in HaCaT cells following the transfection of the FOXO1 mutant or treatment with the autophagy inhibitor 3-methyladenine(3-MA).Results The expression levels of CXCR1 and CXCR2 were significantly increased on the membrane of HaCaT cells following P.acnes stimulation.The IL-8/CXCR2 axis predominantly promoted the proliferation and differentiation of P.acnes-induced HaCaT cells by activating AKT/FOXO1/autophagy signaling.In brief,IL-8 bound to its receptor CXCR2 on the membrane of keratinocytes to activate the AKT/FOXO1 axis.Subsequently,phosphorylated FOXO1 facilitated autophagy to promote the proliferation and differentiation of P.acnes-induced keratinocytes.Conclusion This study demonstrated the novel autocrine effect of IL-8 on the proliferation and differentiation of P.acnes-induced keratinocytes,suggesting a potential therapeutic target for AV.
基金funded by Suzhou Science and Technology Council(SNG201907)Universities Natural Science Foundation of Jiangsu Province(20KJB330002)+6 种基金General Program of China Postdoctoral Science Foundation(2022M711369)the Startup Funding of Soochow University,Jiangsu Province-Suzhou Science and Technology Planning Project(SL T201917)National Natural Science Foundation of China(32172922,31972741)Natural Science Foundation of Jiangsu Province of China(BK20211216,BK20221091)the Startup Funding of Hefei University of Technology(1302003712022058)China-CEEC Joint University Education Project(202010)the Excellence Project PrF UHK(2217/2022-2023)。
文摘Aflatoxin B_(1)(AFB_(1))is a naturally-occurring mycotoxin and recognized as the most toxic foodborne toxin,particularly causing damages to kidney.Glomerular podocytes are terminally differentiated epithelial cells.AFB_(1)induces podocyte inflammation,proteinuria and renal dysfunction.Studying the mechanism of AFB_(1)-induced podocyte inflammation and murine kidney dysfunction,we detected that AFB_(1)increased ubiquitindependent degradation of the transcription factor RelA through enhanced interaction of RelA with E3 ubiquitin ligase tripartite motif containing 7(TRIM7)in mouse podocyte clone-5(MPC-5)and mouse glomeruli.Reduction of RelA resulted in decreasing microRNA-9(miR-9)and activating the chemokine receptor 4(CXCR4),thioredoxin interacting protein(TXNIP),and NOD-like receptor pyrin domain-containing 3(NLRP3)signaling axis(CXCR4/TXNIP/NLRP3 pathway),leading to podocyte inflammation.We also determined that downregulation of miR-9 led to CXCR4 expression and the downstream TXNIP/NLRP3 pathway activation.Overexpression of miR-9 or deletion of CXCR4 suppressed AFB_(1)-induced CXCR4/TXNIP/NLRP3 pathway,resulting in alleviating podocyte inflammation and kidney dysfunction.Our findings indicated that ubiquitin-dependent proteolysis of RelA,downregulation of miR-9,and activation of CXCR4/TXNIP/NLRP3 pathway played an essential role in AFB_(1)-induced glomerular podocyte inflammation.Our study revealed a novel mechanism,via RelA,for the control of AFB_(1)’s nephrotoxicity,leading to an effective protection of food safety and public health.
基金supported by grants from National Key R&D Program of China(No.2017YFC1309001)Nature Science Foundation of China(No.81201842 and No.81772483)Open Project of State Key Laboratory of Respiratory Disease of China(No.SKLRD2016OP004 and No.2007DA80154F1108).
文摘Background:We previously found that overexpression of the gene known as amplified in breast cancer 1(AIB1)was associated with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma.However,the role of AIB1 in that malignancy remains unknown.The present study aimed to investigate the function of AIB1 in the process of lung adenocarcinoma cell metastasis.Methods:A series of in vivo and in vitro assays were performed to elucidate the function of AIB1,while real-time PCR and Western blotting were utilized to identify the potential downstream targets of AIB1 in the process of lung adenocarcinoma metastasis.Rescue experiments and in vitro assays were performed to investigate whether the invasive-ness of AIB1-induced lung adenocarcinoma was mediated by C-X-C motif chemokine receptor 4(CXCR4).Results:The ectopic overexpression of AIB1 in lung adenocarcinoma cells substantially enhanced cell migration and invasive abilities in vitro and tumor metastasis in vivo,whereas the depletion of AIB1 expression substantially inhibited lung adenocarcinoma cell migration and invasion.CXCR4 was identified as a potential downstream target of AIB1 in lung adenocarcinoma.The knockdown of AIB1 greatly reduced CXCR4 gene expression at both the transcription and protein levels,whereas the knockdown of CXCR4 in cells with AIB1 ectopic overexpression diminished AIB1-induced migration and invasion in vitro and tumor metastasis in vivo.Furthermore,we found a significant positive association between the expression of AIB1 and CXCR4 in lung adenocarcinoma patients(183 cases),and the co-overexpression of AIB1 and CXCR4 predicted the poorest prognosis.Conclusions:These findings suggest that AIB1 promotes the aggressiveness of lung adenocarcinoma in vitro and in vivo by upregulating CXCR4 and that it might be usable as a novel prognostic marker and/or therapeutic target for this disease.
基金the Projects of Medical and Health Technology Development Program in Zhejiang Provincegrant number:2014KYA057+1 种基金Foundation of Zhejiang Provincial Natural Science Foundation of Chinagrant number:LQ16H050003
文摘Objective: Since acute rejection remains one of the major complications which necessitate periodic surveillance, noninvasive diagnostic/prognostic methods are preferred by renal transplant recipients. Here, we explored whether urinary C-X-C motif chemokines 13(CXCL13) could be a potential candidate to reflect ongoing immune processes within the renal graft. Methods: We investigated urinary CXCL13 levels by a cross-sectional analysis of 146 renal allograft recipients and 40 healthy controls. Besides, a subset of patients(n=57) were followed-up for kinetic monitoring of immune status.Results: Urinary CXCL13/Cr was lower in normal transplants compared to those with acute tubular necrosis(ATN, P=0.001), chronic allograft nephropathy(CAN, P=0.01) and acute rejection(AR, P<0.0001), which yielded a good diagnosis performance of urinary CXCL13 for AR(AUC=0.818, P<0.0001). Interestingly, urinary CXCL13 further distinguished acute antibody mediated rejection(ABMR) from acute cellular rejection,with an AUC of 0.856. Besides, patients with steroid-resistant acute rejection had distinctly greater urinary CXCL13/Cr levels than patients with reversible acute rejection,P=0.001. Follow-up data revealed that urinary CXCL13/Cr varied in line with the occurrence of ABMR. Furthermore, elevated levels of urinary CXCL13/Cr within the first month was predictive of graft function at 3, 6 months, P=0.044 and 0.4. Conclusion: This study demonstrates that monitoring of urinary CXCL13/Cr might be a valuable noninvasive approach for the detection of AR, especially ABMR. Additionally, high urinary CXCL13/Cr levels related to the poor response to steroid treatment and predicted a compromised graft function after AR.
