Erythropoietin Ameliorates Lung Injury by Accelerating Pulmonary Endothelium Cell Proliferation via Janus Kinase-Signal Transducer and Activator of Transcription 3 Pathway After Kidney Ischemia and Reperfusion Injury
Minyan ZhuL. WangJielai YangKeliang XieMinyan ZhuS. LiuChenqi XuJ. WangLijie GuZhaohui NiGaolian XuMiaolin Che
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Kidney ischemia and reperfusion injury could cause microvascular barrier dysfunction, lung inflammatory cascades activation, and programmed cell death of pulmonary endothelium, leading to acute lung injury. Our study aimed at determining whether erythropoietin (EPO) can ameliorate lung dysfunction following renal ischemia and reperfusion (IR) injury and explored the underlying mechanisms. In vivo, C57BL/6 mice received EPO (6000 U/kg) before right renal vascular pedicles clamping for 30 minutes, followed by 24 hours of reperfusion. The lung histopathologic changes and inflammatory cytokines expression were assessed. In vitro, cultured human umbilical vein endothelial cells were treated with EPO, and apoptosis rate, proliferation capacity, and phosphorylation status of the Janus kinase-signal transducer and activator of transcription 3 (Jak-STAT3) pathway were measured respectively in the presence or absence of lipopolysaccharide stimulation. In vivo, EPO remarkably attenuated pulmonary interstitial and alveolar epithelial edema caused by renal IR injury. In vitro, the proliferation capacity of human umbilical vein endothelial cells was significantly increased under EPO stimulation, which correlated with changes in Jak-STAT3 signaling. Our data indicated that EPO is able to ameliorate acute lung tissue damage induced by renal IR, and at least in part, via the Jak-STAT3 pathway.Keywords:
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Read the full review for this Faculty Opinions recommended article: Sustained Src inhibition results in signal transducer and activator of transcription 3 (STAT3) activation and cancer cell survival via altered Janus-activated kinase-STAT3 binding.
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Abstract Hepatocellular carcinoma (HCC) remains the most common malignant tumor worldwide. Long noncoding RNAs can modulate various tumorigenic processes. In addition, growing evidence has indicated tha the Janus kinase–signal transducer and activator of transcription (JAK‐STAT) pathway is activated in multiple cancers, including HCC. Recently, it was found that LINC00346 can participate in several cancers. Nevertheless, the biological roles of LINC00346 in HCC have been barely investigated. In this study, the function of LINC00346 was specifically concentrated upon. We observed that LINC00346 was obviously elevated in HCC cells (Bel7404, Huh‐6, HepG2, and QGY‐7703 cells). Then, Bel7404 and HepG2 cells were overexpressed with LINC00346. Overexpression of LINC00346 repressed HCC cell survival and cell proliferation. In addition, apoptosis of Bel7404 and HepG2 cells was triggered by LINC00346 upregulation. Bel7404 and HepG2 cell cycle was arrested in the G1 phase by LINC00346. Meanwhile, we conducted wound‐healing assay and Transwell invasion assays. As shown, we observed that the migratory and invasive capacities of Bel7404 and HepG2 cells were remarkably restrained by the increase of LINC00346. Moreover, we showed that LINC00346 overexpression activated the JAK‐STAT3 pathway, which is involved in many cancers. Afterward, in vivo experiments were utilized and we proved that LINC00346 was able to induce HCC tumor growth via activating the JAK‐STAT3 pathway. To conclude, we revealed the potential possibility of developing LINC00346 as an indicator for HCC.
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To investigate the role of Janus kinase-signal transducer and transcription activator (JAK-STAT) pathway in the regulation of synthesis and release of lipopolysaccharide-induced high mobility group box-1 protein (HMGB1).Peritoneal macrophages harvested from male Wistar rats were incubated for 3 days before the experiment. The activation of Janus kinase-2 (JAK2), signal transducer and activator of transcription-1 (STAT1) and STAT3 was observed before and 10, 30, 60 and 120 mins after LPS stimulation (4 determinations at each time point) and it was expressed as A value (absorption). In addition, the cells were divided into normal control, LPS stimulation, JAK2 inhibition (with AG490 treatment 2 hours before LPS stimulation), STAT1 inhibition (with fludarabine treatment 2 hours before LPS stimulation) and STAT3 inhibition (with rapamycin treatment 2 hours before LPS stimulation) groups. The cells in all groups except control group were stimulated with LPS 3 days after culture. The expression of HMGB1 gene and its protein release in each group were determined for 4 times and were expressed as A value.LPS could activate JAK2, STAT1 and STAT3 within 2 hours, especially the activation of STAT3 appeared more quickly, peaking at 10 minutes after LPS stimulation (7.47 +/- 0.56). Pretreatment with the inhibitors of JAK-STAT pathway could markedly reduce the expression of HMGB1 mRNA (P < 0.01), but exerted no effect on HMGB1 release.JAK-STAT pathway can be activated early during endotoxin challenge, and it may play a role in the regulation of HMGB1 synthesis.
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Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) axis is fundamental to the molecular pathogenesis of a host of hematological disorders, including acute leukemias and myeloproliferative neoplasms (MPN). We demonstrate here that the major JAK2 mutation observed in these diseases (JAK2V617F) enforces Mcl-1 transcription via STAT3 signaling. Targeting this lesion with JAK inhibitor I (JAKi-I) attenuates STAT3 binding to the Mcl-1 promoter and suppresses Mcl-1 transcript and protein expression. The neutralization of Mcl-1 in JAK2V617F-harboring myelodyssplastic syndrome cell lines sensitizes them to apoptosis induced by the BH3-mimetic and Bcl-xL/Bcl-2 inhibitor, ABT-263. Moreover, simultaneously targeting JAK and Bcl-xL/-2 is synergistic in the presence of the JAK2V617F mutation. These findings suggest that JAK/Bcl-xL/-2 inhibitor combination therapy may have applicability in a range of hematological disorders characterized by activating JAK2 mutations.
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The pathogenesis of severe acute pancreatitis (SAP) remains unclear. The Janus kinase and signal transducer and activator of transcription (JAK/STAT) pathway is important for various cytokines and growth factors. This study investigated the effect of the late inflammatory factor high mobility group box 1 (HMGB1) on the activation of JAK2/STAT3 in pancreatic acinar cells and the inhibitory effects of AG490 (a JAK2 inhibitor) and rapamycin (a STAT3 inhibitor) on this pathway. Rat pancreatic acinar cells were randomly divided into the control, HMGB1, AG490, and rapamycin groups. The mRNA levels of JAK2 and STAT3 at 10, 30, 60, and 120 minutes were detected using reverse transcription polymerase chain reaction (RT-PCR). The protein levels of JAK2 and STAT3 at 60 and 120 minutes were observed using Western blotting. Compared with the control group, the HMGB1 group exhibited significantly increased levels of JAK2 mRNA at each time point; STAT3 mRNA at 30, 60, and 120 minutes; and JAK2 and STAT3 proteins at 60 and 120 minutes (p < 0.01). Compared with the HMGB1 group, the AG490 and rapamycin groups both exhibited significantly decreased levels of JAK2 mRNA at each time point (p < 0.05); STAT3 mRNA at 30, 60, and 120 minutes (p < 0.01); and JAK2 and STAT3 proteins at 60 and 120 minutes (p < 0.01). HMGB1 induces the activation of the JAK2/STAT3 signaling pathway in rat pancreatic acinar cells, and this activation can be inhibited by AG490 and rapamycin. The results of this study may provide new insights for the treatment of SAP.
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Dexmedetomidine (Dex) works as a crucial agent for the treatment of intestinal ischemia/reperfusion (I/R), but its mechanism remains unclear. Recent articles demonstrated the pivotal role of Janus kinase/signal transducer and activator of transcription (JAK2/STAT3) signalling in I/R. Therefore, it is reasonable to explore the associated mechanism of JAK2/STAT3 signalling in Dex treatment. The study purpose was to evaluate the JAK2/STAT3 signalling regulatory mechanisms of Dex in preventing I/R. Anaesthetized rats were subjected to superior mesenteric artery occlusion consisting of 1 h of ischemia and 2 h of reperfusion while served as controls. Animals received subcutaneous administration of 50 μg/kg Dex, JAK1 and JAK2 inhibitor, Ruxolitinib, selective JAK2 inhibitor, 10 mg/kg AG490 or STAT inhibitor and 0.4 mg/kg rapamycin; or Dex-treatment in the presence of α2-adrenoceptor antagonists Atip or Dex-treatment alone after I/R. Injury was scored histologically, apoptosis was detected via the apoptotic mediators caspase-3 and Bcl-2/Bax and the degree of activation of the JAK/STAT pathway was evaluated. Dex inhibited I/R injury by decreasing apoptosis significantly with rescue of cleaved caspase-3 and the Bcl-2/Bax ratio. Furthermore, phosphorylation of JAK2, STAT1 and STAT3 was affected, suggesting the involvement of activated JAK/STAT in response to Dex. Meanwhile, the JAK2 or STAT inhibitors AG490 and rapamycin, but not Ruxolitinib, exhibited a similar but even greater JAK2 and STAT3 regulatory effect, thus leading to a greater benefit. JAK2/STAT3 activation is crucial to the diminishing effect of Dex on mesenteric I/R injury; however, the efficacy and timing of Dex administration should be considered in clinical practice.
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Psoriasis is a chronic inflammatory skin disease. Its pathogenesis remains unclear, and is currently considered to be co-mediated by heredity, environment and immunity. Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor, which is associated with cancer and autoimmune diseases. STAT3 plays a crucial role in the occurrence of psoriasis by participating in the differentiation of T helper 17 cells, hyperproliferation and abnormal differentiation of keratinocytes, interaction with inflammatory cells, hyperplasia of dermal vessels and other important pathological processes. In recent studies, therapies targeting STAT3 and its upstream Janus kinases (JAK) have shown good efficacy and safety in the management of psoriasis. This review summarizes the association between psoriasis and STAT3, so as to provide evidence for the feasibility of the treatment of psoriasis with targeted inhibition of STAT3.
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Psoriasis; STAT3 transcription factor; Janus kinases; Keratinocytes; Pathogenesis; Therapy
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