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Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan (Trp)-kynurenine (KYN)-kynurenic acid (KA) axis metabolism. Mechanistically, chemotherapy-induced intestinal damage triggered the formation of an interleukin-6 (IL-6)-indoleamine 2,3-dioxygenase 1 (IDO1)-aryl hydrocarbon receptor (AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35 (GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity
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Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors. This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination, and most importantly its influence on tumorigenesis, to provide new directions and strategies for tumor therapy.
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Introdução: A interação da pele com poluentes atmosféricos tem demonstrado efeitos na barreira cutânea, assim como o desencadeamento de processos oxidativos relacionados ao envelhecimento prematuro da pele. O receptor de aril hidrocarbonetos (ArH) é proteína de transcrição que interage com os xenobióticos, regulando a transcrição de genes envolvidos com estresse oxidativo, inflamação, imunossupressão e pigmentação, além de levar a processos relacionados ao envelhecimento e carcinogênese. Objetivo: Avaliar a eficácia antipoluente de uma associação antioxidante na prevenção da translocação nuclear do receptor AhR Métodos: Um modelo in vitro (cultura de queratinócitos) foi exposto à fumaça de cigarro, e a presença de AhR foi medida por ensaio Elisa-sanduíche. Resultados: A cultura tratada demonstrou inibição da translocação nuclear do AhR em todas as concentrações avaliadas: aumentos de ArH de 75,38%; 59,88% e 117,79% são observados nas concentrações de 0,316; 0,100 e 0,0316mg/ml, respectivamente. Conclusão: Os resultados sugerem a capacidade da formulação avaliada em prevenir a ativação de genes responsáveis pelos efeitos nocivos da fumaça de cigarro.
Introduction: The interaction between the skin and air pollutants has demonstrated effects in the cutaneous barrier, as well as triggering oxidative processes related to premature ageing of the skin. The aryl hydrocarbon receptor (ArH) is a transcription protein that interacts with xenobiotics, regulating the transcription of genes involved with oxidative stress, inflammation, immunosuppression and pigmentation, besides leading to processes related to ageing and carcinogenesis. Objective: Evaluate the anti-pollution efficacy of an antioxidant association for the prevention of the nuclear translocation of the AhR receptor. Methods: A in vitro model (keratinocyte culture) was exposed to cigarette smoke and the presence of AhR was measured through sanduwich ELISA assay. Results: The treated culture demonstrated inhibition of the nuclear translocation of AhR in all concentrations evaluated: ArH increase of 75.38%; 59.88% and 117.79% are seen with the concentrations of 0.316; 0.100 and 0.0316mg / mL, respectively. Conclusion: The results suggest the ability of the formulation analyzed in preventing the activation of genes responsible for the damaging effects of cigarette smoke.
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Methods , In Vitro Techniques , Keratinocytes , Air PollutantsABSTRACT
Objective To explore the relationship between aryl hydrocar-bon receptor (AhR),aryl hydrocarbon receptor nuclear translocator (ARNT),estradiol (E2),estrogen receptor (ER) and recurrent spontaneous abortion (RSA) through observing the level of serum AhR,ARNT,E2,and AhR,ARNT,ER in decidua and chorionic tissues of the patients with recurrent spontaneous abortion.Methods 64 cases of RSA patients who induced abortion at the Shanxi Dayi hospital from May 2015 to September2017 were chosen as RSA group,and 30 cases of healthy abortion women of the same period who had born full-term normal fetus were choosen as the normal group.The serum,villi and decidua of each case were collected during abortion.The level of AhR,ARNT,ER of both groupswere detected by enzyme-linked immunoscrbent assay (ELISA) method.The Serum E2 lever were detected by the method of chemical luminescence.The data of all the patients were analyzed.Results (1) The level of ARNT in peripheral blood of RSA group was significantly higher than that of normal group (P ＜ 0.05),and the levels of AhR and E2 in peripheral blood were not statistically significant between the two groups (P ＞ 0.05).The levels of AhR and ARNT in villi and decidua were significantly higher in RSA group than in normal group (P ＜ 0.05),while the expression of ER in villi and decidua was significantly lower in RSA group than in normal group (P ＜ 0.05).(2) There was no significant difference in the ratio of AhR/ARNT between the two groups (P ＞ 0.05);the ratio of AhR/ER and ARNT/ER in the villi and decidua of the RSA group was higher than that of the normal group (P ＜ 0.05).Conclusions Overexpression of AhR and ARNT and low expression of ER in villi and decidua tissues may be related to the occurrence of RSA.
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Objective To investigate the effects and the mechanism of sorafenib on hepatocellular car-cinoma growth and vasculogenic mimicry (VM)in mice.Methods A subcutaneous implantation mouse model of human hepatocellular carcinoma (HCC)HepG2 cells were established.Mice inoculated with HepG2 cells were randomly divided into the treatment group (sorafenib 30 mg·kg -1 ·d -1 )and the control group by using of paired comparison method.Growth of established tumor xenografts was monitored at least twice weekly by vernier caliper measurements.VMwas assessed by immunohistochemical assay and periodic acid schiff reaction (PAS)histochemical double-staining.The expressions of HIF-1 α,VEGFA,VEGFR-1 and MMP-2 in tumor tissues were also assessed by immunohistochemical assay,Western blotting and real-time quantitative PCR. Results The tumor volume in the sorafenib group was obviously decreased compared with the control group (809.69 mm3 ±208.71 mm3 vs 1 678.00 mm3 ±31 3.29 mm3 ),with a statistically significant difference (t =6.1 03,P =0.030).Haematoxylin and eosin (HE)staining showed that tumor tissues treated with sorafenib were characterized by obvious necrosis,but there were not the same cases in the control group.Sorafenib group significantly reduced the number of tumor functional vessel in HepG2 xenografts compared with the control group,as assessed by tumor vasculature uptake of DiOC7 (4.77 ±0.1 5 vs 8.44 ±0.68,t =9.1 92,P =0.01 3).The number of VMwas significantly decreased by sorafenib (1 .04 ±0.46 vs 2.66 ±0.42,t =4.51 0, P =0.041 ).Relative to controls,CD31 -positive vessels decreased after treatments (3.42 ±0.1 0 vs 1 .26 ± 0.1 4),with a statistically significant difference (t =21 .580,P =0.002).Compared with the control group, the protein levels of HIF-1 α(0.65 ±0.03 vs 1 .00 ±0.00),VEGFA (0.51 ±0.02 vs 1 .00 ±0.00), VEGFR-1 (0.45 ±0.04 vs 1 .00 ±0.00)and MMP-2 (0.69 ±0.02 vs 1 .00 ±0.00)were significantly decreased in the sorafenib group (t =1 9.650,P =0.003;t =40.493,P =0.000;t =23.429,P =0.002;t =26.071 ,P =0.002).Compared with the control group,the mRNA levels of HIF-1 α(0.78 ±0.05 vs 1 .00 ±0.00),VEGFA (0.52 ±0.05 vs 1 .00 ±0.00),VEGFR-1 (0.45 ±0.02 vs 1 .00 ±0.00)and MMP-2 (0.71 ±0.02 vs 1 .00 ±0.00)were also significantly decreased in sorafenib group (t =6.840,P =0.021 ;t =27.71 0,P =0.001 ;t =62.740,P =0.000;t =23.850,P =0.002).Conclusion Sorafenib can inhibit the tumor growth and VMchannels formation,which may be related with the HIF-1 αand VEGFA /VEGFR-1 signa-ling pathway.
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Objective To observe the changes of ischemic preconditioning on the expression of hypoxia inducible fac?tor (HIF)-1αand vascular endothelial growth factor (VEGF) in ischemia hippocampus CA1 region after focal cerebral isch?emia/reperfusion (I/R) in rats, and the mechanisms of brain protection from brain ischemia preconditioning (BIP) thereof. Methods The male SD rats were randomly divided into three groups:sham operation (SO) group,middle cerebral artery oc?clusion (MCAO) group and brain ischemia preconditioning (BIP) group. The MCAO group and BIP group were further divid?ed into six subgroups according to perfusion time after I/R including 2 h, 6 h, 12 h, 24 h, 48 h and 72 h. The ischemia pre?conditioning model rats were established. Immunohistochemistry and Western blot assay were used to observe the expres?sions of HIF-1αand VEGF in ischemia hippocampal CA1 region. Results Neurological function deficit was not observed in SO group. Compared with MCAO group, there was a lower neurological function deficit score in BIP group. In MCAO group and BIP group, the expressions of HIF-1αand VEGF positive cells and protein increased at 2 h after I/R, then gradu?ally increased from 6 h to12 h and reached the maximum level at 24 h, then gradually decreased. The levels were still higher at 72 h than those of SO group. The number of HIF-1αand VEGF positive cells and protein were significantly increased in MCAO group and BIP group than that of SO group (P<0.05). The number of HIF-1αpositive cells was higher in BIP group than that in MCAO group except 2 h and 6 h reperfusion groups. The expression of VEGF positive cells, HIF-1αand VEGF protein were significantly higher in BIP group than those in MCAO group at different time points (P < 0.05). Conclusion Ischemic preconditioning plays a protective role in brain, which may be related to up-regulation of HIF-1αand VEGF.