scholarly journals The Extract of Sonneratia apetala Leaves and Branches Ameliorates Hyperuricemia in Mice by Regulating Renal Uric Acid Transporters and Suppressing the Activation of the JAK/STAT Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yu-Lin Wu ◽  
Jin-Fen Chen ◽  
Lin-Yun Jiang ◽  
Xiao-Li Wu ◽  
Yu-Hong Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Uric Acid ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Organic Anion ◽  
Janus Kinase ◽  
Vehicle Group ◽  
Cytokine Signaling ◽  
Sonneratia Apetala ◽  
Stat Signaling

Sonneratia apetala Buch-Ham., an exotic mangrove species with antidiabetic, antibacterial, and antioxidant capacities, mainly distributes in the southeast coastal areas in China. The present work investigated the protective effects of Sonneratia apetala leaves and branches extraction (SAL) on hyperuricemia (HUA) in mice. Potassium oxonate (PO) and hypoxanthine (HX) were used to establish the HUA model by challenge for consecutive 7 days. Results revealed that SAL inhibited the increases in kidney weight and index compared to the vehicle group. Meanwhile, SAL significantly decreased the levels of uric acid (UA), creatinine (CRE), and blood urea nitrogen (BUN) in serum. Additionally, SAL inhibited the activity of xanthine oxidase (XOD) in the liver. SAL ameliorated PO- and HX-induced histopathological changes. Moreover, it regulated oxidative stress markers including malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD) activity, and glutathione (GSH) content. Also, SAL inhibited the increases in renal levels of interleukin-6 (IL-6), interleukin-18 (IL-18), interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), monocyte chemotactic protein 1 (MCP-1), and transforming growth factor-β (TGF-β). SAL remarkably reduced suppressor of cytokine signaling 3 (SOCS3), Janus kinase 2 (JAK2), and subsequent phosphorylation of signal transducer and activator of transcription 3 (STAT3) expression. In addition, SAL inhibited the activation of nuclear factor kappa-B (NF-κB) in the kidney. Furthermore, SAL protected against HUA by regulating renal UA transporters of organic anion transporter (OAT1), urate reabsorption transporter 1 (URAT1), and glucose transporter 9 (GLUT9). These findings suggested that SAL ameliorated HUA by inhibiting the production of uric acid and enhancing renal urate excretion, which are related to oxidative stress and inflammation, and the possible molecular mechanisms include its ability to inhibit the JAK/STAT signaling pathway. Thus, SAL might be developed into a promising agent for HUA treatments.

Atomistic insight into the inhibition mechanisms of suppressors of cytokine signaling on Janus kinase

2019 ◽  
Vol 21 (24) ◽  
pp. 12905-12915 ◽  
Author(s):  
Yaru Wei ◽  
Zhiyang Zhang ◽  
Nai She ◽  
Xin Chen ◽  
Yuan Zhao ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Negative Feedback ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Jak Kinase ◽  
Stat Signaling ◽  
Suppressors Of Cytokine Signaling ◽  
Insight Into

Suppressors of cytokine signaling (SOCS) act as negative feedback regulators of the Janus kinase/signal transducer (JAK–STAT) signaling pathway by inhibiting the activity of JAK kinase.

scholarly journals Ventilator-induced diaphragm dysfunction in critical illness

2018 ◽  
Vol 243 (17-18) ◽  
pp. 1331-1339 ◽  
Author(s):  
Yung-Yang Liu ◽  
Li-Fu Li
Keyword(s):  
Oxidative Stress ◽  
Mechanical Ventilation ◽  
Muscle Atrophy ◽  
Structural Damage ◽  
Molecular Mechanisms ◽  
Substantial Reduction ◽  
Mechanical Stretch ◽  
Janus Kinase ◽  
Diaphragm Muscle ◽  
Diaphragm Dysfunction

Mechanical ventilation is an essential intervention for intensive care unit patients with acute lung injury. However, the use of controlled mechanical ventilation in both animal and human models causes ventilator-induced diaphragm dysfunction, wherein a substantial reduction in diaphragmatic force-generating capacity occurs, along with structural injury and atrophy of diaphragm muscle fibers. Although diaphragm dysfunction, noted in most mechanically ventilated patients, is correlated with poor clinical outcome, the specific pathophysiology underlying ventilator-induced diaphragm dysfunction requires further elucidation. Numerous factors may underlie this condition in humans as well as animals, such as increased oxidative stress, calcium-activated calpain and caspase-3, the ubiquitin–proteasome system, autophagy–lysosomal pathway, and proapoptotic proteins. All these alter protein synthesis and degradation, thus resulting in muscle atrophy and impaired contractility and compromising oxidative phosphorylation and upregulating glycolysis associated with impaired mitochondrial function. Furthermore, infection combined with mechanical stretch may induce multisystem organ failure and render the diaphragm more sensitive to ventilator-induced diaphragm dysfunction. Herein, several major cellular mechanisms associated with autophagy, apoptosis, and mitochondrial biogenesis—including toll-like receptor 4, nuclear factor-κB, Src, class O of forkhead box, signal transducer and activator of transcription 3, and Janus kinase—are reviewed. In addition, we discuss the potential therapeutic strategies used to ameliorate ventilator-induced diaphragm dysfunction and thus prevent delay in the management of patients under prolonged duration of mechanical ventilation. Impact statement Mechanical ventilation (MV) is life-saving for patients with acute respiratory failure but also causes difficult liberation of patients from ventilator due to rapid decrease of diaphragm muscle endurance and strength, which is termed ventilator-induced diaphragmatic damage (VIDD). Numerous studies have revealed that VIDD could increase extubation failure, ICU stay, ICU mortality, and healthcare expenditures. However, the mechanisms of VIDD, potentially involving a multistep process including muscle atrophy, oxidative loads, structural damage, and muscle fiber remodeling, are not fully elucidated. Further research is necessary to unravel mechanistic framework for understanding the molecular mechanisms underlying VIDD, especially mitochondrial dysfunction and increased mitochondrial oxidative stress, and develop better MV strategies, rehabilitative programs, and pharmacologic agents to translate this knowledge into clinical benefits.

Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy

2001 ◽  
Vol 281 (6) ◽  
pp. R2048-R2058 ◽  
Author(s):  
Abram M. Madiehe ◽  
Ling Lin ◽  
Christy White ◽  
H. Doug Braymer ◽  
George A. Bray ◽  
...  
Keyword(s):  
Dna Binding ◽  
Signaling Pathway ◽  
Leptin Receptor ◽  
Binding Activity ◽  
Janus Kinase ◽  
Adrenal Steroids ◽  
Western Blots ◽  
Protein Levels ◽  
Dna Binding Activity ◽  
Stat Signaling

Removal of adrenal steroids by adrenalectomy (ADX) slows or reverses the development of many forms of obesity in rodents, including those that are leptin or leptin receptor deficient. Obesity is associated with hyperleptinemia and leptin resistance. We hypothesized that glucocorticoids impair leptin receptor signaling and that removal thereof would activate the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway. The inhibitory effect of leptin (2.5 μg icv) on food intake was enhanced in ADX rats. A combination of ribonuclease protection assays, RT-PCR, Western blots, and mobility shift assays was used to evaluate the leptin signaling pathway in whole hypothalami from sham-operated, ADX and corticosterone-replaced ADX (ADX-R) Sprague-Dawley rats that were treated acutely with either saline vehicle or leptin intracerebroventricularly. ADX increased the expression of leptin receptor mRNA, increased STAT-3 mRNA and protein levels, induced constitutive STAT-3 phosphorylation and DNA binding activity, and also reduced suppressor of cytokine signaling-3 (SOCS-3) mRNA and protein levels. ADX and leptin treatment increased STAT-3 phosphorylation, but with no concomitant increase in DNA binding activity. Leptin and ADX decreased NPY mRNA expression, but their combination did not further decrease NPY mRNA. Corticosterone supplementation of ADX rats partially reversed many of these effects. In conclusion, ADX through activation of STAT-3 and inhibition of SOCS-3 activates the JAK-STAT signaling pathway. These effects most probably explain the ability to prevent the development of obesity by removal of adrenal steroids.

scholarly journals Luteolin Inhibits Respiratory Syncytial Virus Replication by Regulating the MiR-155/SOCS1/STAT1 Signaling Pathway

2020 ◽  
Author(s):  
Saisai Wang ◽  
Yiting Ling ◽  
Yuanyuan Yao ◽  
Gang Zheng ◽  
Wenbin Chen
Keyword(s):  
Respiratory Syncytial Virus ◽  
Signaling Pathway ◽  
Western Blotting ◽  
Virus Replication ◽  
Janus Kinase ◽  
Luciferase Assay ◽  
Luciferase Reporter ◽  
Cytokine Signaling ◽  
Stat1 Signaling ◽  
Syncytial Virus

Abstract Background: Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infection in infants, children, immunocompromised adults, and elderly individuals. Currently, there are few therapeutic options available to prevent RSV infection. The present study aimed to investigate the effects of luteolin on RSV replication and the related mechanisms. Material and methods: We pretreated cells and mice with luteolin before infection with RSV, the virus titer, expressions of RSV-F, interferon (IFN)-stimulated genes (ISGs), and production of IFN-α and IFN-β were determined by plaque assay, RT-qPCR, and ELISA, respectively. The activation of Janus kinase (JAK)-signal transducer and activator of transcription 1 (STAT1) signaling pathway was detected by Western blotting and luciferase assay. Proteins which negatively regulates STAT1 was determined by Western blotting. Then cells were transfected with suppressor of cytokine signaling 1 (SOCS1) plasmid and virus replication and ISGs expression was determined. Luciferase reporter assay and Western blotting was performed to detect the relationship between SOCS1 and miR-155. Results: Luteolin inhibited RSV replication, as shown by the decreased viral titer and RSV-F mRNA expression both in vitro and in vivo. The antiviral activity of luteolin was attributed to the enhanced phosphorylation of STAT1, resulting in the increased production of ISGs. Further study showed that SOCS1 was downregulated by luteolin and SOCS1 is a direct target of microRNA-155 (miR-155). Inhibition of miR-155 rescued luteolin-mediated SOCS1 downregulation, whereas upregulation of miR-155 enhanced the inhibitory effect of luteolin. Conclusion: Luteolin inhibits RSV replication by regulating the miR-155/SOCS1/STAT1 signaling pathway.

scholarly journals SOCS1/SOCS3 Immune Axis Modulates Synthetic Perturbations in IL6 Biological Circuit for Dynamical Cellular Response

2020 ◽  
Author(s):  
Bhavnita Soni ◽  
Shailza Singh
Keyword(s):  
Signaling Pathway ◽  
Cellular Response ◽  
Inflammatory Cytokine ◽  
Cytokine Expression ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Macrophage Phenotype ◽  
Regulatory Circuit ◽  
Stat Pathway

AbstractMacrophage phenotype plays a crucial role in the pathogenesis of Leishmanial infection. Pro-inflammatory cytokines are the key regulators that eliminate the infection induced by Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Suppressor of cytokine signaling (SOCS) is a well-known negative feedback regulator of JAK/STAT pathway. However, change in expression levels of SOCS in correlation with the establishment of infection is not well understood. Mathematical modeling of IL6 signaling pathway have helped identified the role of SOCS1 in establishment of infection. Furthermore, the ratio of SOCS1 and SOCS3 has been quantified both in silico as well as in vitro, indicating an immune axis which governs the macrophage phenotype during L. major infection. The ability of SOCS1 protein to inhibit the JAK/STAT1 signaling pathway and thereby decreasing pro-inflammatory cytokine expression makes it a strong candidate for therapeutic intervention. Using synthetic biology approaches, peptide based immuno-regulatory circuit have been designed to target the activity of SOCS1 which can restore pro-inflammatory cytokine expression during infection.

scholarly journals JAK/STAT Activation: A General Mechanism for Bone Development, Homeostasis, and Regeneration

2020 ◽  
Vol 21 (23) ◽  
pp. 9004
Author(s):  
Alexandra Damerau ◽  
Timo Gaber ◽  
Sarah Ohrndorf ◽  
Paula Hoff
Keyword(s):  
Signaling Pathway ◽  
Bone Development ◽  
Gene Knockout ◽  
Selective Inhibition ◽  
Janus Kinase ◽  
General Mechanism ◽  
Stat Signaling ◽  
Skeletal Phenotype ◽  
Pro Inflammatory Cytokines

The Janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling pathway serves as an important downstream mediator for a variety of cytokines, hormones, and growth factors. Emerging evidence suggests JAK/STAT signaling pathway plays an important role in bone development, metabolism, and healing. In this light, pro-inflammatory cytokines are now clearly implicated in these processes as they can perturb normal bone remodeling through their action on osteoclasts and osteoblasts at both intra- and extra-articular skeletal sites. Here, we summarize the role of JAK/STAT pathway on development, homeostasis, and regeneration based on skeletal phenotype of individual JAK and STAT gene knockout models and selective inhibition of components of the JAK/STAT signaling including influences of JAK inhibition in osteoclasts, osteoblasts, and osteocytes.

A Janus Kinase in the JAK/STAT signaling pathway from Litopenaeus vannamei is involved in antiviral immune response

2015 ◽  
Vol 44 (2) ◽  
pp. 662-673 ◽  
Author(s):  
Xuan Song ◽  
Zijian Zhang ◽  
Sheng Wang ◽  
Haoyang Li ◽  
Hongliang Zuo ◽  
...  
Keyword(s):  
Immune Response ◽  
Signaling Pathway ◽  
Litopenaeus Vannamei ◽  
Janus Kinase ◽  
Antiviral Immune Response ◽  
Stat Signaling

scholarly journals Emodin Alleviates Hydrogen Peroxide-Induced Inflammation and Oxidative Stress via Mitochondrial Dysfunction by Inhibiting the PI3K/mTOR/GSK3β Pathway in Neuroblastoma SH-SY5Y Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Rui Li ◽  
Wenzhou Liu ◽  
Li Ou ◽  
Feng Gao ◽  
Min Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Cell Damage ◽  
Neuroblastoma Cells ◽  
Inflammatory Factors ◽  
Protective Mechanism ◽  
Human Neuroblastoma ◽  
Induced Apoptosis

Emodin is an active monomer extracted from rhubarb root, which has many biological functions, including anti-inflammation, antioxidation, anticancer, and neuroprotection. However, the protective effect of emodin on nerve injury needs to be further elucidated. The purpose of this study is to investigate the effect of emodin on the neuroprotection and the special molecular mechanism. Here, the protective activity of emodin inhibiting H2O2-induced apoptosis and neuroinflammation as well as its molecular mechanisms was examined using human neuroblastoma cells (SH-SY5Y cells). The results showed that emodin significantly enhanced cell viability, reduced cell apoptosis and LDH release. Simultaneously, emodin downregulated H2O2-induced inflammatory factors, including IL-6, NO, and TNF-α, and alleviated H2O2-induced oxidative stress and mitochondrial dysfunction in SH-SY5Y cells. In addition, emodin inhibited the activation of the PI3K/mTOR/GSK3β signaling pathway. What is more, the PI3K/mTOR/GSK3β pathway participated in the protective mechanism of emodin on H2O2-induced cell damage. Collectively, it suggests that emodin alleviates H2O2-induced apoptosis and neuroinflammation potentially by regulating the PI3K/mTOR/GSK3β signaling pathway.

scholarly journals Long non-coding RNA RP11-468E2.5 curtails colorectal cancer cell proliferation and stimulates apoptosis via the JAK/STAT signaling pathway by targeting STAT5 and STAT6

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Li Jiang ◽  
Xu-Hai Zhao ◽  
Yin-Ling Mao ◽  
Jun-Feng Wang ◽  
Hui-Jun Zheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Target Genes ◽  
Biological Activities ◽  
Janus Kinase ◽  
Normal Tissues ◽  
Stat Signaling

Abstract Background Long non-coding RNAs (lncRNAs) are tumor-associated biological molecules and have been found to be implicated in the progression of colorectal cancer (CRC). This study aims to examine the effects of lncRNA RP11-468E2.5 and its target genes (STAT5 and STAT6) on the biological activities of CRC cells via the Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway. Methods We initially screened the GEO database for differentially expressed lncRNAs related to CRC and then made a prediction of the implicated target genes. Then we collected CRC tissues and adjacent normal tissues from 169 CRC patients. Human CRC HCT116 and SW480 cells were treated with small interference RNA (siRNA) against RP11-468E2.5, AG490 (an inhibitor of the JAK/STAT signaling pathway), or both in combination. Next, we measured the effects of RP11-468E2.5 treatment on cellular activities such as cell viability, cycle distribution and cell apoptosis, and studied interactions among RP11-468E2.5, STAT5/STAT6, and the JAK/STAT signaling pathway. Finally, an in vivo tumor formation assay was performed to observe the effect of RP11-468E2.5 on tumor growth. Results The CRC-related gene microarray data showed low expression of RP11-468E2.5 in CRC surgical specimens. However, RP11-468E2.5 was confirmed to target STAT5 and STAT6, which participate in the JAK/STAT signaling pathway. CRC tissues showed lower expression of RP11-468E2.5, higher expression of STAT5, STAT6 and of the cell cycle marker Cyclin D1 (CCND1), compared to the findings in adjacent normal tissues. The treatment of siRNA against RP11-468E2.5 increased expression of JAK2, STAT3, STAT5, STAT6, CCND1 and Bcl-2 along with the extent of STAT3, STAT5 and STAT6 phosphorylation, while lowering expression of P21 and P27. Treatment with AG490 exhibited approximately opposite effects, whereas siRNA against RP11-468E2.5 treatment stimulated CRC cell proliferation and reduced cell apoptosis, while promoting cell cycle entry; AG490 treatment reversed these results. Conclusions Altogether, we conclude that up-regulation of RP11-468E2.5 inhibits the JAK/STAT signaling pathway by targeting STAT5 and STAT6, thereby suppressing cell proliferation and promoting cell apoptosis in CRC.

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