Urolithin A Inactivation of TLR3/TRIF Signaling to Block the NF-κB/STAT1 Axis Reduces Inflammation and Enhances Antioxidant Defense in Poly(I:C)-Induced RAW264.7 Cells.

Urolithin A is an active compound of gut-microbiota-derived metabolites of polyphenol ellagic acid that has anti-aging, antioxidative, and anti-inflammatory effects. However, the effects of urolithin A on polyinosinic acid-polycytidylic acid (poly(I:C))-induced inflammation remain unclear. Poly(I:C) is a double-stranded RNA (dsRNA) similar to a virus and is recognized by Toll-like receptor-3 (TLR3), inducing an inflammatory response in immune cells, such as macrophages. Inflammation is a natural defense process of the innate immune system. Therefore, we used poly(I:C)-induced RAW264.7 cells and attenuated the inflammation induced by urolithin A. First, our data suggested that 1-30 µM urolithin A does not reduce RAW264.7 cell viability, whereas 1 µM urolithin A is sufficient for antioxidation and the decreased production of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and C-C chemokine ligand 5. The inflammation-related proteins cyclooxygenase-2 and inducible nitric oxide synthase were also downregulated by urolithin A. Next, 1 µM urolithin A inhibited the levels of interferon (INF)-α and INF-ß. Urolithin A was applied to investigate the blockade of the TLR3 signaling pathway in poly(I:C)-induced RAW264.7 cells. Moreover, the TLR3 signaling pathway, subsequent inflammatory-related pathways, and antioxidation pathways showed changes in nuclear factor-κB (NF-κB) signaling and blocked ERK/mitogen-activated protein kinase (MAPK) signaling. Urolithin A enhanced catalase (CAT) and superoxide dismutase (SOD) activities, but decreased malondialdehyde (MDA) levels in poly(I:C)-induced RAW264.7 cells. Thus, our results suggest that urolithin A inhibits TLR3-activated inflammatory and oxidative-associated pathways in macrophages, and that this inhibition is induced by poly(I:C). Therefore, urolithin A may have antiviral effects and could be used to treat viral-infection-related diseases.

Chitosan oligosaccharide regulates AMPK and STAT1 pathways synergistically to mediate PD-L1 expression for cancer chemoimmunotherapy.

After regular chemotherapy, the expression of programmed cell death ligand 1 (PD-L1) in almost all kinds of cancers is significantly increased, leading to reduced efficacy of T cell mediated immune killing in tumors. To solve this, a lot of PD-L1 antibodies were produced and used, but their high cost and serious toxic side effects still limit its usage. Recently, small molecule compounds that could effectively regulate PD-L1 expression possess the edges to solve the problems of PD-L1 antibodies. Chitosan oligosaccharide (COS), a biomaterial derived from the N-deacetylation product of chitin, has a broad spectrum of biological activities in treating tumors. However, the mechanism of its anti-cancer effect is still not well understood. Here, for the first time, we clearly identified that COS could inhibit the upregulated PD-L1 expression induced by interferon γ (IFN-γ) in various tumors via the AMPK activation and STAT1 inhibition. Besides, COS itself significantly restricted the growth of CT26 tumors by enhancing the T cell infiltration in tumors. Furthermore, we observed that combining COS with Gemcitabine (GEM), one of the typical chemotherapeutic drugs, leaded to a more remarkable tumor remission. Therefore, it was demonstrated that COS could be used as a useful way to improve the efficacy of existing chemotherapies by effective PD-L1 downregulation.

SARS-CoV-2 inhibits induction of the MHC class I pathway by targeting the STAT1-IRF1-NLRC5 axis.

The MHC class I-mediated antigen presentation pathway plays a critical role in antiviral immunity. Here we show that the MHC class I pathway is targeted by SARS-CoV-2. Analysis of the gene expression profile from COVID-19 patients as well as SARS-CoV-2 infected epithelial cell lines reveals that the induction of the MHC class I pathway is inhibited by SARS-CoV-2 infection. We show that NLRC5, an MHC class I transactivator, is suppressed both transcriptionally and functionally by the SARS-CoV-2 ORF6 protein, providing a mechanistic link. SARS-CoV-2 ORF6 hampers type II interferon-mediated STAT1 signaling, resulting in diminished upregulation of NLRC5 and IRF1 gene expression. Moreover, SARS-CoV-2 ORF6 inhibits NLRC5 function via blocking karyopherin complex-dependent nuclear import of NLRC5. Collectively, our study uncovers an immune evasion mechanism of SARS-CoV-2 that targets the function of key MHC class I transcriptional regulators, STAT1-IRF1-NLRC5.

Complement factor B in high glucose-induced podocyte injury and diabetic kidney disease.

The role and mechanisms for upregulating complement factor B (CFB) expression in podocyte dysfunction in diabetic kidney disease (DKD) are not fully understood. Here, analyzing Gene Expression Omnibus GSE30528 data, we identified genes enriched in mTORC1 signaling, CFB, and complement alternative pathways in podocytes from patients with DKD. In mouse models, podocyte mTOR complex 1 (mTORC1) signaling activation was induced, while blockade of mTORC1 signaling reduced CFB upregulation, alternative complement pathway activation, and podocyte injury in the glomeruli. Knocking down CFB remarkably alleviated alternative complement pathway activation and DKD in diabetic mice. In cultured podocytes, high glucose treatment activated mTORC1 signaling, stimulated STAT1 phosphorylation, and upregulated CFB expression, while blockade of mTORC1 or STAT1 signaling abolished high glucose-upregulated CFB expression. Additionally, high glucose levels downregulated protein phosphatase 2Acα (PP2Acα) expression, while PP2Acα deficiency enhanced high glucose-induced mTORC1/STAT1 activation, CFB induction, and podocyte injury. Taken together, these findings uncover a mechanism by which CFB mediates podocyte injury in DKD.

Baricitinib, a JAK-STAT Inhibitor, Reduces the Cellular Toxicity of the Farnesyltransferase Inhibitor Lonafarnib in Progeria Cells.

Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare multisystem premature aging disorder that leads to early death (mean age of 14.7 years) due to myocardial infarction or stroke. Most cases have a de novo point mutation at position G608G within exon 11 of the LMNA gene. This mutation leads to the production of a permanently farnesylated truncated prelamin A protein called "progerin" that is toxic to the cells. Recently, farnesyltransferase inhibitor (FTI) lonafarnib has been approved by the FDA for the treatment of patients with HGPS. While lonafarnib treatment irrefutably ameliorates HGPS disease, it is however not a cure. FTI has been shown to cause several cellular side effects, including genomic instability as well as binucleated and donut-shaped nuclei. We report that, in addition to these cellular stresses, FTI caused an increased frequency of cytosolic DNA fragment formation. These extranuclear DNA fragments colocalized with cGAs and activated the cGAS-STING-STAT1 signaling axis, upregulating the expression of proinflammatory cytokines in FTI-treated human HGPS fibroblasts. Treatment with lonafarnib and baricitinib, a JAK-STAT inhibitor, not only prevented the activation of the cGAS STING-STAT1 pathway, but also improved the overall HGPS cellular homeostasis. These ameliorations included progerin levels, nuclear shape, proteostasis, cellular ATP, proliferation, and the reduction of cellular inflammation and senescence. Thus, we suggest that combining lonafarnib with baricitinib might provide an opportunity to reduce FTI cellular toxicity and ameliorate HGPS symptoms further than lonafarnib alone.

Esculetin protects against early sepsis via attenuating inflammation by inhibiting NF-κB and STAT1/STAT3 signaling.

Esculetin, a natural derivative from the traditional and widely-used Chinese medicinal herb Cortex Fraxini, has a variety of pharmacological effects, especially in anti-inflammation. However, it is not clear whether esculetin has a therapeutic effect on sepsis. This study aimed to investigate the anti-inflammatory and protective effects of esculetin on early sepsis. The results showed that the lung injury was significantly relieved with the treatment of esculetin, accompanied with the restrained production of inflammatory factors including IL-1ß, IL-6, TNF-α, CCL2 and iNOS during the early phase of E.coli-induced sepsis. Of note, activation of NF-κB and STAT1/STAT3 signals, the main upstream signals of many inflammatory factors, were attenuated by esculetin in both lung tissues from septic mice and LPS-stimulated macrophage. These findings suggested that the protection of esculetin against early sepsis should be related to its anti-inflammatory effect, which was at least partly due to its inhibition on NF-κB and STAT1/STAT3 signaling pathway in macrophage. Thus, esculetin could serve as a potential therapeutic agent by rebalancing innate immune response in macrophage for the treatment of early sepsis.

Vitamin D protects glomerular mesangial cells from high glucose-induced injury by repressing JAK/STAT signaling.

AIM: High glucose (HG) induces the production of transforming growth factor (TGF)-ß and reactive oxygen species, which further activates JAK/STAT signaling and promotes the synthesis of matrix proteins, contributes to the pathophysiological processes of diabetic nephropathy. This study aims to investigate the protection role of vitamin D (VD) in the kidney in high glucose condition. METHODS: Rat glomerular mesangial cells were cultured in high glucose medium, with or without VD or VD receptor (VDR) siRNAs treatment. The levels of TGF-ß and fibronectin were detected by qRT-PCR, immunoblotting and enzyme-linked immunosorbent assay (ELISA). The levels of phosphorylated JAK2, STAT1 and STAT3, and JAK/STAT signaling downstream genes were examined by immunoblotting and qRT-PCR. RESULTS: In rat glomerular mesangial cells, VD treatment can repress the tyrosine phosphorylation of JAK2, STAT1 and STAT3. VD inhibited TGF-ß and fibronectin expression which was rescued by vitamin d receptor (VDR) siRNA and STATs inhibitor perficitinib. The JAK/STAT signaling downstream protein coding genes including SOCS1, SOCS3 and type IV collagen were repressed by VD. Meanwhile, the expression of non-coding RNAs such as miR-181a, miR-181b, was repressed by VD, and the expression of miR-34a and Let-7b was upregulated by VD. CONCLUSION: Vitamin D (VD) treatment inhibits the function of HG on fibronectin production through regulating JAK/STAT pathway. These results provide direct evidences that VD protects glomerular mesangial cells from high glucose-induced injury through repressing JAK/STAT signaling, which has the potential for clinical DN treatment.

JAK/STAT inhibitor therapy partially rescues the lipodystrophic autoimmune phenotype in Clec16a KO mice.

CLEC16A is implicated in multiple autoimmune diseases. We generated an inducible whole-body knockout (KO), Clec16aΔUBC mice to address the role of CLEC16A loss of function. KO mice exhibited loss of adipose tissue and severe weight loss in response to defective autophagic flux and exaggerated endoplasmic reticulum (ER) stress and robust cytokine storm. KO mice were glucose tolerant and displayed a state of systemic inflammation with elevated antibody levels, including IgM, IgA, Ig2b and IgG3, significantly reduced circulating insulin levels in the presence of normal food consumption. Metabolic analysis revealed disturbances in the lipid profile, white adipose decreasing concomitantly with enhanced inflammatory response, and energy wasting. Mechanistically, endoplasmic reticulum (ER) stress triggers excessive hormone sensitive lipases (HSL) mediated lipolysis which contributes to adipose inflammation via activation of JAK-STAT, stress kinases (ERK1/2, P38, JNK), and release of multiple proinflammatory mediators. Treatment with a JAK-STAT inhibitor (tofacitinib) partially rescued the inflammatory lipodystrophic phenotype and improved survival of Clec16aΔUBC mice by silencing cytokine release and modulating ER stress, lipolysis, mitophagy and autophagy. These results establish a mechanistic link between CLEC16A, lipid metabolism and the immune system perturbations. In summary, our Clec16aΔUBC mouse model highlights multifaceted roles of Clec16a in normal physiology, including a novel target for weight regulation and mutation-induced pathophysiology.

Pharmacological mechanism of immunomodulatory agents for the treatment of severe cases of COVID-19 infection.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a world-wide pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, treatment of severe COVID-19 is far from clear. Therefore, it is urgent to develop an effective option for the treatment of patients with COVID-19. Most patients with severe COVID-19 exhibit markedly increased serum levels of pro-inflammatory cytokines, including interferon (IFN)-α, IFN-γ, and interleukin (IL)-1ß. Immunotherapeutic strategies have an important role in the suppression of cytokine storm and respiratory failure in patients with COVID-19. METHODS: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar preprint database using all available MeSH terms for Coronavirus, SARS-CoV-2, anti-rheumatoid agents, COVID-19, cytokine storm, immunotherapeutic drugs, IFN, interleukin, JAK/STAT inhibitors, MCP, MIP, TNF. RESULTS: Here, we first review common complications of COVID-19 patients, particularly neurological symptoms. We next explain host immune responses against COVID-19 particles. Finally, we summarize the existing experimental and clinical immunotherapeutic strategies, particularly anti-rheumatoid agents and also plasma (with a high level of gamma globulin) therapy for severe COVID-19 patients. We discuss both their therapeutic effects and side effects that should be taken into consideration for their clinical application. CONCLUSION: It is suggested that immunosuppressants, such as anti-rheumatoid drugs, could be considered as a potential approach for the treatment of cytokine storm in severe cases of COVID-19. One possible limitation of immunosuppressant therapy is their inhibitory effects on host anti-viral immune response. So, the appropriate timing of administration should be carefully considered.

Screening interferon antagonists from accessory proteins encoded by P gene for immune escape of Caprine parainfluenza virus 3.

The Caprine parainfluenza virus 3 (CPIV3) is a novel Paramyxovirus that is isolated from goats suffering from respiratory diseases. Presently, the pathogenesis of CPIV3 infection has not yet been fully characterized. The Type I interferon (IFN) is a key mediator of innate antiviral responses, as many viruses have developed strategies to circumvent IFN response, whether or how CPIV3 antagonizes type I IFN antiviral effects have not yet been characterized. This study observed that CPIV3 was resistant to IFN-α treatment and antagonized IFN-α antiviral responses on MDBK and goat tracheal epithelial (GTE) cell models. Western blot analysis showed that CPIV3 infection reduced STAT1 expression and phosphorylation, which inhibited IFN-α signal transduction on GTE cells. By screening and utilizing specific monoclonal antibodies (mAbs), three CPIV3 accessory proteins C, V and D were identified during the virus infection process on the GTE cell models. Accessory proteins C and V, but not protein D, was identified to antagonize IFN-α antiviral signaling. Furthermore, accessory protein C, but not protein V, reduced the level of IFN-α driven phosphorylated STAT1 (pSTAT1), and then inhibit STAT1 signaling. Genetic variation analysis to the PIV3 accessory protein C has found two highly variable regions (VR), with VR2 (31-70th aa) being involved in for the CPIV3 accessory protein C to hijack the STAT1 signaling activation. The above data indicated that CPIV3 is capable of inhibiting IFN-α signal transduction by reducing STAT1 expression and activation, and that the accessory protein C, plays vital roles in the immune escape process.

Inhibition of JAK-STAT Signaling by Baricitinib Reduces Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells.

Sjögren's syndrome (SS) is a chronic autoimmune disease targeting salivary and lacrimal glands. C-X-C motif chemokine ligand 10 (CXCL10) expression is upregulated in lip salivary glands (LSGs) of primary SS (pSS) patients, and CXCL10 involved in SS pathogenesis via immune-cell accumulation. Moreover, interferon (IFN)-γ enhances CXCL10 production via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. We investigated the effects of baricitinib, a selective JAK1/2 inhibitor, on both IFN-γ-induced CXCL10 production and immune-cell chemotaxis. We used immunohistochemical staining to determine the expression levels and localization of JAK1 and JAK2 in LSGs of SS patients (n = 12) and healthy controls (n = 3). We then evaluated the effect of baricitinib in an immortalized normal human salivary gland ductal (NS-SV-DC) cell line. Immunohistochemical analysis of LSGs from pSS patients revealed strong JAK1 and JAK2 expression in ductal and acinar cells, respectively. Baricitinib significantly inhibited IFN-γ-induced CXCL10 expression as well as the protein levels in an immortalized human salivary gland ductal-cell clone in a dose-dependent manner. Additionally, western blot analysis showed that baricitinib suppressed the IFN-γ-induced phosphorylation of STAT1 and STAT3, with a stronger effect observed in the case of STAT1. It also inhibited IFN-γ-mediated chemotaxis of Jurkat T cells. These results suggested that baricitinib suppressed IFN-γ-induced CXCL10 expression and attenuated immune-cell chemotaxis by inhibiting JAK/STAT signaling, suggesting its potential as a therapeutic strategy for pSS.

Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma.

Objectives Malignant pleural mesothelioma (MPM) is an occupational disease mainly due to asbestos exposure. Effective therapies for MPM are lacking, making this tumour type a fatal disease. Materials and Methods In order to meet this need and in view of a future "drug repositioning" approach, here we screened five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model, with a library of 1170 FDA-approved drugs. Results Among several potential compounds, we found that fludarabine (F-araA) and, to a lesser extent, risedronic acid (RIS) were cytotoxic in MPM cells, in comparison to the non-malignant Met-5A cells. In particular, F-araA reduced the proliferation and the colony formation ability of the MPM malignant cells, in comparison to the non-malignant control cells, as demonstrated by proliferation and colony formation assays, in addition to measurement of the phospho-ERK/total-ERK ratio. We have shown that the response to F-araA was not dependent upon the expression of DCK and NT5E enzymes, nor upon their functional polymorphisms (rs11544786 and rs2295890, respectively). Conclusion This drug repositioning screening approach has identified that F-araA could be therapeutically active against MPM cells, in addition to other tumour types, by inhibiting STAT1 expression and nucleic acids synthesis. Further experiments are required to fully investigate this.

Luteolin inhibits respiratory syncytial virus replication by regulating the MiR-155/SOCS1/STAT1 signaling pathway.

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-ß 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 regulate STAT1 were determined by Western blotting. Then cells were transfected with suppressor of cytokine signaling 1 (SOCS1) plasmid and virus replication and ISGs expression were determined. Luciferase reporter assay and Western blotting were 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.

Protective Effect of Epigallocatechin-3-Gallate (EGCG) in Diseases with Uncontrolled Immune Activation: Could Such a Scenario Be Helpful to Counteract COVID-19?

Some coronavirus disease 2019 (COVID-19) patients develop acute pneumonia which can result in a cytokine storm syndrome in response to Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection. The most effective anti-inflammatory drugs employed so far in severe COVID-19 belong to the cytokine-directed biological agents, widely used in the management of many autoimmune diseases. In this paper we analyze the efficacy of epigallocatechin 3-gallate (EGCG), the most abundant ingredient in green tea leaves and a well-known antioxidant, in counteracting autoimmune diseases, which are dominated by a massive cytokines production. Indeed, many studies registered that EGCG inhibits signal transducer and activator of transcription (STAT)1/3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factors, whose activities are crucial in a multiplicity of downstream pro-inflammatory signaling pathways. Importantly, the safety of EGCG/green tea extract supplementation is well documented in many clinical trials, as discussed in this review. Since EGCG can restore the natural immunological homeostasis in many different autoimmune diseases, we propose here a supplementation therapy with EGCG in COVID-19 patients. Besides some antiviral and anti-sepsis actions, the major EGCG benefits lie in its anti-fibrotic effect and in the ability to simultaneously downregulate expression and signaling of many inflammatory mediators. In conclusion, EGCG can be considered a potential safe natural supplement to counteract hyper-inflammation growing in COVID-19.

Thienochromene derivatives inhibit pSTAT1 and pSTAT5 signaling induced by cytokines.

Furanocoumarins, particularly furo[3,2-c]coumarins, are found in many natural products. However, coumarins annulated to a thiophene ring have received scarce attention to date in the literature. Therefore, we synthesized 4-oxo-4H-thieno[3,2-c]chromene derivatives and tested in vitro their anti-inflammatory activity. Anti-inflammatory potential of the synthesized compounds (1, 2, 6-8, 9a-e and 10a-c) has been evaluated by measuring various pSTAT (signal transducer and activator of transcription) inhibition within the JAK (Janus-activated family kinase)/STAT signaling pathway. Ethyl 7-hydroxy-4-oxo-4H-thieno[3,2-c]chromene-2-carboxylate (7) showed best inhibition properties on pSTAT5 in GM-CSF (Granulocyte-macrophage colony-stimulating factor)-triggered PBMC assay, with IC50 value of 5.0 µM.

Attenuated Interferon and Proinflammatory Response in SARS-CoV-2-Infected Human Dendritic Cells Is Associated With Viral Antagonism of STAT1 Phosphorylation.

Clinical manifestations of coronavirus disease 2019 (COVID-19) vary from asymptomatic virus shedding, nonspecific pharyngitis, to pneumonia with silent hypoxia and respiratory failure. Dendritic cells and macrophages are sentinel cells for innate and adaptive immunity that affect the pathogenesis of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). The interplay between SARS-CoV-2 and these cell types remains unknown. We investigated infection and host responses of monocyte-derived dendritic cells (moDCs) and macrophages (MDMs) infected by SARS-CoV-2. MoDCs and MDMs were permissive to SARS-CoV-2 infection and protein expression but did not support productive virus replication. Importantly, SARS-CoV-2 launched an attenuated interferon response in both cell types and triggered significant proinflammatory cytokine/chemokine expression in MDMs but not moDCs. Investigations suggested that this attenuated immune response to SARS-CoV-2 in moDCs was associated with viral antagonism of STAT1 phosphorylation. These findings may explain the mild and insidious course of COVID-19 until late deterioration.

Sevoflurane reduces inflammatory factor expression, increases viability and inhibits apoptosis of lung cells in acute lung injury by microRNA-34a-3p upregulation and STAT1 downregulation.

OBJECTIVE: Evidence has shown that sevoflurane plays a protective role in acute lung injury (ALI) due to its anti-inflammatory and apoptotic-regulating activity. Nevertheless, the mechanism of sevoflurane is still not completely understood. This study intends to discuss the mechanism of sevoflurane on ALI and the possible mechanisms involved. METHODS: ALI model of rats was established through intravenous injection of endotoxin lipopolysaccharide. microRNA-34a-3p (miR-34a-3p) and signal transducers and activators of transcription 1 (STAT1) expression in lung tissues of ALI rats were detected. The optimal inhaled concentration of sevoflurane was screened, and then the modeled rats were injected with miR-34a-3p inhibitors, overexpressed STAT1 and inhaled 1.0 Minimum Alveolar Concentration (MAC) sevoflurane to determine mean arterial pressure (MAP) of rats, wet weight/dry weight ratio and myeloperoxidase (MPO) activity, oxidative stress- and inflammation-related factors in lung tissues of rats, along with lung cell viability and apoptosis. RESULTS: MiR-34a-3p was downregulated while STAT1 was upregulated in ALI rats. Sevoflurane of 1.0 MAC was selected as the optimal inhalation concentration. Sevoflurane (1.0 MAC) increased MAP at T3 and reduced MPO activity, alleviated pathological damage, suppressed apoptosis, oxidative stress and inflammation, and induced cell viability in lung tissues of ALI rats. Down-regulated miR-34a-3p or up-regulated STAT reversed the functions of sevoflurane (1.0 MAC) on ALI rats. CONCLUSION: Collectively, we demonstrate that sevoflurane reduces inflammatory factor expression, increases lung cell viability and inhibits lung cell apoptosis in ALI through upregulation of miR-34a-3p and downregulation of STAT1, which provides new clues for ALI treatment.

Cordycepin Attenuates IFN-γ-Induced Macrophage IP-10 and Mig Expressions by Inhibiting STAT1 Activity in CFA-Induced Inflammation Mice Model.

Cordycepin, a natural derivative of adenosine, has been shown to exert pharmacological properties including anti-oxidation, antitumor, and immune regulation. It is reported that cordycepin is involved in the regulation of macrophage function. However, the effect of cordycepin on inflammatory cell infiltration in inflammation remains ambiguous. In this study, we investigated the potential role of cordycepin playing in macrophage function in CFA-induced inflammation mice model. In this model, we found that cordycepin prevented against macrophage infiltration in paw tissue and reduced interferon-γ (IFN-γ) production in both serum and paw tissue. Using luciferase reporter assay, we found that cordycepin suppressed IFN-γ-induced activators of transcription-1 (STAT1) transcriptional activity in a dose-dependent manner. Moreover, western blotting data demonstrated that cordycepin inhibited IFN-γ-induced STAT1 activation through attenuating STAT1 phosphorylation. Further investigations revealed that cordycepin inhibited the expressions of IFN-γ-inducible protein 10 (IP-10) and monokine induced by IFN-γ (Mig), which were the effector genes in IFN-γ-induced STAT1 signaling. Meanwhile, the excessive inflammatory cell infiltration in paw tissue was reduced by cordycepin. These findings demonstrate that cordycepin alleviates excessive inflammatory cell infiltration through down-regulation of macrophage IP-10 and Mig expressions via suppressing STAT1 phosphorylation. Thus, cordycepin may be a potential therapeutic approach to prevent and treat inflammation-associated diseases.

Antagonism of STAT1 by Nipah virus P gene products modulates disease course but not lethal outcome in the ferret model.

Nipah virus (NiV) is a pathogenic paramyxovirus and zoononis with very high human fatality rates. Previous protein over-expression studies have shown that various mutations to the common N-terminal STAT1-binding motif of the NiV P, V, and W proteins affected the STAT1-binding ability of these proteins thus interfering with he JAK/STAT pathway and reducing their ability to inhibit type-I IFN signaling, but due to differing techniques it was unclear which amino acids were most important in this interaction or what impact this had on pathogenesis in vivo. We compared all previously described mutations in parallel and found the amino acid mutation Y116E demonstrated the greatest reduction in binding to STAT1 and the greatest reduction in interferon antagonism. A similar reduction in binding and activity was seen for a deletion of twenty amino acids constituting the described STAT1-binding domain. To investigate the contribution of this STAT1-binding motif in NiV-mediated disease, we produced rNiVs with complete deletion of the STAT1-binding motif or the Y116E mutation for ferret challenge studies (rNiVM-STAT1blind). Despite the reduced IFN inhibitory function, ferrets challenged with these rNiVM-STAT1blind mutants had a lethal, albeit altered, NiV-mediated disease course. These data, together with our previously published data, suggest that the major role of NiV P, V, and W in NiV-mediated disease in the ferret model are likely to be in the inhibition of viral recognition/innate immune signaling induction with a minor role for inhibition of IFN signaling.