- Impaired SIRT3 activity mediates cardiac dysfunction in endotoxemia by calpain-dependent disruption of ATP synthesis. [Journal Article]
- JMJ Mol Cell Cardiol 2019 Jun 12
- CONCLUSIONS: Impaired SIRT3 activity may mediate cardiac dysfunction in endotoxemia by facilitating calpain-mediated disruption of ATP synthesis, suggesting SIRT3 activation as a potential therapeutic strategy to treat septic cardiomyopathy.
- Prognostic value of vasoactive-inotropic score following continuous flow left ventricular assist device implantation. [Journal Article]
- JHJ Heart Lung Transplant 2019 May 24
- CONCLUSIONS: A high post-operative VIS is associated with adverse in-hospital outcomes and is a better predictor of in-hospital mortality compared with existing LVAD risk models. Whether early hemodynamic stabilization using RVAD may benefit patients with a high VIS remains to be investigated.
- Inducible nitric oxide synthase: Regulation, structure, and inhibition. [Review]
- MRMed Res Rev 2019 Jun 13
- A considerable number of human diseases have an inflammatory component, and a key mediator of immune activation and inflammation is inducible nitric oxide synthase (iNOS), which produces nitric oxide…
A considerable number of human diseases have an inflammatory component, and a key mediator of immune activation and inflammation is inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO) from l-arginine. Overexpressed or dysregulated iNOS has been implicated in numerous pathologies including sepsis, cancer, neurodegeneration, and various types of pain. Extensive knowledge has been accumulated about the roles iNOS plays in different tissues and organs. Additionally, X-ray crystal and cryogenic electron microscopy structures have shed new insights on the structure and regulation of this enzyme. Many potent iNOS inhibitors with high selectivity over related NOS isoforms, neuronal NOS, and endothelial NOS, have been discovered, and these drugs have shown promise in animal models of endotoxemia, inflammatory and neuropathic pain, arthritis, and other disorders. A major issue in iNOS inhibitor development is that promising results in animal studies have not translated to humans; there are no iNOS inhibitors approved for human use. In addition to assay limitations, both the dual modalities of iNOS and NO in disease states (ie, protective vs harmful effects) and the different roles and localizations of NOS isoforms create challenges for therapeutic intervention. This review summarizes the structure, function, and regulation of iNOS, with focus on the development of iNOS inhibitors (historical and recent). A better understanding of iNOS' complex functions is necessary before specific drug candidates can be identified for classical indications such as sepsis, heart failure, and pain; however, newer promising indications for iNOS inhibition, such as depression, neurodegenerative disorders, and epilepsy, have been discovered.
- Resveratrol attenuates high-fat diet-induced non-alcoholic steatohepatitis by maintaining gut barrier integrity and inhibiting gut inflammation through regulation of the endocannabinoid system. [Journal Article]
- CNClin Nutr 2019 May 30
- CONCLUSIONS: These data indicate that the ECS, particularly the expressions of CB1 and CB2, appears to play a crucial role in the RSV induced anti-NASH effect by maintaining the gut barrier integrity and inhibiting gut inflammation.
- HIF1α-Induced Glycolysis in Macrophage Is Essential for the Protective Effect of Ouabain during Endotoxemia. [Journal Article]
- OMOxid Med Cell Longev 2019; 2019:7136585
- Ouabain, a steroid binding to the Na+/K+-ATPase, has several pharmacological effects. In addition to the recognized effects of blood pressure, there is more convincing evidence suggesting that ouabai…
Ouabain, a steroid binding to the Na+/K+-ATPase, has several pharmacological effects. In addition to the recognized effects of blood pressure, there is more convincing evidence suggesting that ouabain is involved in immunologic functions and inflammation. Hypoxia-inducible factor 1α (HIF-1α) is a metabolic regulator which plays a considerable role in immune responses. Previous studies had shown that HIF-1α-induced glycolysis results in functional reshaping in macrophages. In this study, we investigated the role of glycolytic pathway activation in the anti-inflammatory effect of ouabain. We found that ouabain is involved in anti-inflammatory effects both in vivo and in vitro. Additionally, ouabain can inhibit LPS-induced upregulation of GLUT1 and HK2 at the transcriptional level. GM-CSF pretreatment almost completely reversed the inhibitory effect of ouabain on LPS-induced release of proinflammatory cytokines. Alterations in glycolytic pathway activation were required for the anti-inflammatory effect of ouabain. Ouabain can significantly inhibit the upregulation of HIF-1α at the protein level. Our results also revealed that the overexpression of HIF-1α can reverse the anti-inflammatory effect of ouabain. Thus, we conclude that the HIF-1α-dependent glycolytic pathway is essential for the anti-inflammatory effect of ouabain.
- The combined effect of a farnesoid X receptor agonist and dipeptidyl peptidase-4 inhibitor on hepatic fibrosis. [Journal Article]
- HRHepatol Res 2019 Jun 08
- CONCLUSIONS: OCA+sitagliptin synergistically affect hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing Ac-HSC proliferation, respectively. Thus, OCA+sitagliptin may be a promising therapeutic strategy for NASH.
- The role of serpin protein on the natural immune defense against pathogen infection in Lampetra japonica. [Journal Article]
- FSFish Shellfish Immunol 2019 Jun 05; 92:196-208
- Serine protease inhibitors (serpins) are a large protein family that is involved in various physiological processes and is known to regulate innate immunity pathways. However, research for the functi…
Serine protease inhibitors (serpins) are a large protein family that is involved in various physiological processes and is known to regulate innate immunity pathways. However, research for the functional study of serpins in lamprey is limited. In the present study, a serpin gene was cloned and characterized from Lampetra japonica at molecular, protein and cellular levels, named L-serpin which belongs to family F serine protease inhibitors (serpin family). The L-serpin includes a serpin domain in the N-terminus. The mRNA transcript of L-serpin was extensively expressed in kidney, supraneural body, intestine, liver, heart, gill and the highest expression in leukocytes. The mRNA expression level of L-serpin increased significantly after Vibrio anguillarum, Staphylocccus aureus and Poly I:C stimulation and dramatically peak at 8 h. It is demonstrated that the L-serpin protected cells from lethal Gram-negative endotoxemia through associating with inhibition of lipopolysaccharide (LPS)-triggered cell death and inflammatory factors expression. Surface plasmon resonance (SPR) and the microbe binding assay were used to determine that L-serpin interacts directly with LPS (KD = 6.14 × 10-7 M). Furthermore, we confirmed L-serpin is a major inhibitor of complement activation by inactivating lamprey-C1q protein (KD = 2.06 × 10-6 M). Taken together, these findings suggest that L-serpin is a endogenous anti-inflammatory factor to defend against Gram-negative bacterial challenge and involved in lamprey innate immunity.
- The effect of cycling in the heat on gastrointestinal-induced damage and neuromuscular fatigue. [Journal Article]
- EJEur J Appl Physiol 2019 Jun 07
- CONCLUSIONS: This research provides evidence that short-duration cycling in the heat results in sub-optimal neuromuscular activation and increased expression of gastrointestinal damage markers, without a simultaneous elevation in circulating endotoxins or pro-inflammatory cytokines.
- Drug repositioning of TANK-binding kinase 1 inhibitor CYT387 as an alternative for the treatment of Gram-negative bacterial sepsis. [Journal Article]
- IIInt Immunopharmacol 2019 Jun 04; 73:482-490
- There is currently no specific drug for the treatment of sepsis and antibiotic administration is considered the best option, despite numerous issues. Therefore, the development of drugs to control th…
There is currently no specific drug for the treatment of sepsis and antibiotic administration is considered the best option, despite numerous issues. Therefore, the development of drugs to control the pathogen-induced inflammatory responses associated with sepsis is essential. To address this, our study examined the transcriptomes of lipopolysaccharide (LPS)-induced dendritic cells (DCs), identifying TANK-binding kinase1 (Tbk1) as a key factor involved in the inflammatory response. These data suggested drug repositioning of the Tbk1 inhibitor CYT387, currently used for the treatment of myelofibrosis and some cancers, as a candidate for regulating the LPS-induced inflammatory response. CYT387 also inhibited pro-inflammatory cytokine and surface molecule expression by mature DCs after LPS exposure. These effects correlated with both Akt phosphorylation and IκBα degradation. Finally, CYT387 demonstrated therapeutic effects in LPS-induced endotoxemia and Escherichia coli K1-induced mouse models of sepsis and decreased the expression of pro-inflammatory cytokines. In conclusion, our study suggests that drug repositioning of CYT387 may serve as a potential therapeutic for sepsis.
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- MicroRNA-141 ameliorates alcoholic hepatitis‑induced intestinal injury and intestinal endotoxemia partially via a TLR4-dependent mechanism. [Journal Article]
- IJInt J Mol Med 2019 May 30
- Alcoholic hepatitis (AH) is a fatal inflammatory syndrome with no effective treatments. Intestinal injury and intestinal endotoxemia (IETM) contribute greatly in the development of AH. MicroRNAs (miR…
Alcoholic hepatitis (AH) is a fatal inflammatory syndrome with no effective treatments. Intestinal injury and intestinal endotoxemia (IETM) contribute greatly in the development of AH. MicroRNAs (miRNAs/miRs) have been reported to affect intestinal injury. The present study aims to investigate the role of miR‑141 in intestinal injury and IETM of AH. An AH model was successfully established in mice and they were the injected with a series of miR‑141 mimic, miR‑141 inhibitor or toll like receptor 4 monoclonal antibody (TLR4mAb; an inhibitor of the Toll‑like receptor TLR pathway). After that, the intestinal tissues and intestinal epithelial cells were isolated from differently treated AH mice. The expression of miR‑141 and TLR pathway‑associated genes and the levels of inflammatory factors were determined. Furthermore, a target prediction program and a luciferase reporter assay were employed to examine whether miR‑141 targets TLR4. Finally, MTT and transwell assays were carried out to detect cell viability and cell permeability. Intestinal tissues from AH mice treated with miR‑141 mimic or TLR4mAb exhibited lower levels of inflammatory factors and reduced expression of the TLR pathway‑associated genes, suggesting a decreased inflammatory response as well as inactivation of the TLR pathway by miR‑141. The luciferase reporter assay suggested that miR‑141 negatively regulated TLR4. Intestinal epithelial cells treated with miR‑141 mimic or TLR4mAb demonstrated enhanced viability and reduced permeability. Opposite results were observed in AH mice treated with a miR‑141 inhibitor. Collectively, the results of the present study demonstrated that miR‑141 could ameliorate intestinal injury and repress the progression of IETM through targeting TLR4 and inhibiting the TLR pathway.