salubrinal and Inflammation

The chronic inflammatory response is emerging as an important therapeutic target in progressive chronic kidney disease. A key transcription factor in the induction of chronic inflammation is NF-κB. Recent studies have demonstrated that sustained activation of the unfolded protein response (UPR) can initiate this NF-κB signaling phenomenon and thereby induce chronic kidney disease progression. A key factor influencing chronic kidney disease progression is proteinuria and this condition has now been demonstrated to induce sustained UPR activation. This review details the crosstalk between the UPR and NF-κB pathways as pertinent to chronic kidney disease. We present potential tools to study this phenomenon as well as potential therapeutics that are emerging to regulate the UPR. These therapeutics may prevent inflammation specifically induced in the kidney due to proteinuria-induced sustained UPR activation.

Topics: Butylamines; Cinnamates; Disease Progression; Endoplasmic Reticulum Stress; Humans; Inflammation; Inflammation Mediators; NF-kappa B; Proteinuria; Renal Insufficiency, Chronic; Signal Transduction; Sulfonamides; Sulfones; Thiophenes; Thiourea; Unfolded Protein Response

Steroid-resistant asthma is a troublesome clinical problem in public health. The pathogenesis of steroid-resistant asthma is complex and remains to be explored. In our work, the online Gene Expression Omnibus microarray dataset GSE7368 was used to explore differentially expressed genes (DEGs) between steroid-resistant asthma patients and steroid-sensitive asthma patients. Tissue-specific gene expression of DEGs was analyzed using BioGPS. The enrichment analyses were performed using GO, KEGG, and GSEA analysis. The protein-protein interaction network and key gene cluster were constructed using STRING, Cytoscape, MCODE, and Cytohubba. A steroid-resistant neutrophilic asthma mouse model was established using lipopolysaccharide (LPS) and ovalbumin (OVA). An LPS-stimulated J744A.1 macrophage model was prepared to validate the underlying mechanism of the interesting DEG gene using the quantitative reverse transcription-polymerase chain reaction (qRT-PCR). A total of 66 DEGs were identified, most of which were present in the hematologic/immune system. Enrichment analysis displayed that the enriched pathways were the IL-17 signaling pathway, MAPK signal pathway, Toll-like receptor signaling pathway, and so on. DUSP2, as one of the top upregulated DEGs, has not been clearly demonstrated in steroid-resistant asthma. In our study, we observed that the salubrinal administration (DUSP2 inhibitor) reversed neutrophilic airway inflammation and cytokine responses (IL-17A, TNF-α) in a steroid-resistant asthma mouse model. We also found that salubrinal treatment reduced inflammatory cytokines (CXCL10 and IL-1β) in LPS-stimulated J744A.1 macrophages. DUSP2 may be a candidate target for the therapy of steroid-resistant asthma.

Topics: Animals; Asthma; Computational Biology; Cytokines; Inflammation; Lipopolysaccharides; Mice

Psoriasiform skin inflammation is the common chronic skin inflammatory disease with no effective clinical therapy. Salubrinal is a multifunctional molecule playing a protective role in several conditions. Recently, studies have reported that Salubrinal is a potential therapeutic agent for inflammatory diseases. However, the protective role of Salubrinal in psoriasis-like skin inflammation remains unknown. In this article, imiquimod (IMQ)-induced psoriasis models were established in wild-type mice to explore the role of Salubrinal in the development of psoriasis. As a result, the IMQ-induced mouse models exhibited typical skin inflammation, which was alleviated by the administration of Salubrinal. Furthermore, RAW264.7 macrophage was stimulated with Lipopolysaccharide(LPS) in the presence or absence of Salubrinal. LPS stimulation elevated the expression of various inflammatory biomarkers, while the administration of Salubrinal abolished the function of LPS in RAW264.7 macrophages. In addition, the activation of the nuclear factor-kappa B (NF-κB) signaling pathway in both the LPS-stimulated RAW264.7 macrophage and psoriasis mouse models was antagonized by the administration of Salubrinal. Collectively, Salubrinal might be considered as a promising therapeutic agent for psoriasis-like skin inflammation.

Topics: Animals; Cinnamates; Disease Models, Animal; Imiquimod; Inflammation; Macrophages; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Protective Agents; Psoriasis; RAW 264.7 Cells; Signal Transduction; Skin; Thiourea; Tumor Necrosis Factor-alpha

Hepatic stellate cell (HSC) activation plays an indispensable role in hepatic fibrosis. Inducing apoptosis of activated HSCs can attenuate or reverse fibrogenesis. In this study, we initially found that oroxylin A (OA) protected CCl

Topics: Animals; Apoptosis; Carbon Tetrachloride; Cell Cycle Checkpoints; Cell Line; Cell Proliferation; Cinnamates; Collagen; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Flavonoids; Hepatic Stellate Cells; Inflammation; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred ICR; Signal Transduction; Thiourea

Blood reperfusion of the ischemic tissue after stroke promotes increases in the inflammatory response as well as accumulation of unfolded/misfolded proteins in the cell, leading to endoplasmic reticulum (ER) stress. Both Inflammation and ER stress are critical processes in the delayed death of the cells damaged after ischemia. The aim of this study is to check the putative synergic neuroprotective effect by combining anti-inflammatory and anti-ER stress agents after ischemia.. The study was performed on a two-vessel occlusion global cerebral ischemia model. Animals were treated with salubrinal one hour after ischemia and with robenacoxib at 8 h and 32 h after ischemia. Parameters related to the integrity of the blood-brain barrier (BBB), such as matrix metalloproteinase 9 and different cell adhesion molecules (CAMs), were analyzed by qPCR at 24 h and 48 h after ischemia. Microglia and cell components of the neurovascular unit, including neurons, endothelial cells and astrocytes, were analyzed by immunofluorescence after 48 h and seven days of reperfusion.. Pharmacologic control of ER stress by salubrinal treatment after ischemia, revealed a neuroprotective effect over neurons that reduces the transcription of molecules involved in the impairment of the BBB. Robenacoxib treatment stepped neuronal demise forward, revealing a detrimental effect of this anti-inflammatory agent. Combined treatment with robenacoxib and salubrinal after ischemia prevented neuronal loss and changes in components of the neurovascular unit and microglia observed when animals were treated only with robenacoxib.. Combined treatment with anti-ER stress and anti-inflammatory agents is able to provide enhanced neuroprotective effects reducing glial activation, which opens new avenues in therapies against stroke.

Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Cinnamates; Cyclooxygenase 2 Inhibitors; Diphenylamine; Drug Administration Schedule; Drug Therapy, Combination; Endoplasmic Reticulum Stress; Inflammation; Male; Neuroprotective Agents; Phenylacetates; Rats, Sprague-Dawley; Thiourea

Brain death (BD) can induce inflammation and injury of organs. Endoplasmic reticulum (ER) stress is associated with a variety of diseases. However, little is known about how ER stress is implicated in brain death (BD)-induced lung injury. In this study, a stable BD rat model was constructed to investigate the role of ER stress on BD-induced lung injury. H&E staining demonstrated that BD can induce lung injury in rats. The results of Western blot and immunohistochemistry showed that apoptosis was observed in the lung tissues of BD rats. And the level of GRP78, p-PERK, p-eIF2α, CHOP, and Caspase-12 was highly expressed in BD rats compared with the control group. Inhibition of ER stress with salubrinal reduced the BD-induced lung inflammation. Moreover, BD-induced increase of NF-κB activity was lowered by inhibition of ER stress. These results suggested that inhibition of ER stress alleviates BD-induced lung inflammation by regulating NF-κB signaling pathway.

Topics: Animals; Apoptosis; Brain Death; Cinnamates; Endoplasmic Reticulum Stress; Inflammation; Lung Injury; NF-kappa B; Rats; Thiourea

Dual-specificity phosphatase 2 (Dusp2; also called phosphatase of activated cells 1, PAC1) is highly expressed in activated immune cells. We examined whether a potential inhibitor of Dusp2, salubrinal, prevents inflammatory cytokine expression in immune cells and arthritic responses in a mouse model of anti-collagen antibody-induced arthritis (CAIA). Salubrinal is a synthetic chemical that inhibits de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). In this study, we examined the effects of salubrinal on expression of inflammation linked genes as well as a family of DUSP genes using genome-wide microarrays, qPCR, and RNA interference. We also evaluated the effects of salubrinal on arthritic responses in CAIA mice using clinical and histological scores. The results revealed that salubrinal decreased inflammatory gene expression in macrophages, T lymphocytes, and mast cells. Dusp2 was suppressed by salubrinal in LPS-activated macrophages as well as PMA/ionomycin-activated T lymphocytes and mast cells. Furthermore, a partial silencing of Dusp2 downregulated IL1β and Cox2, and the inflammatory signs of CAIA mice were significantly suppressed by salubrinal. Collectively, this study presents a novel therapeutic possibility of salubrinal for inflammatory arthritis such as RA through inhibition of Dusp2.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Cell Line; Cinnamates; Cytokines; Dual Specificity Phosphatase 2; Female; Gene Expression Regulation; Inflammation; Interleukin-1beta; Mice; Mice, Inbred BALB C; RNA Interference; Thiourea

Endoplasmic reticulum stress (ERS) can initiate inflammation, and the coupling of these responses is thought to be fundamental to the pathogenesis of cardiovascular disease. However, the mechanism linking ERS and inflammation in myocardial ischemia/reperfusion needs further investigation. Cultured cardiomyocytes were pretreated with SP600125 or salubrinal, followed by tunicamycin to clarify the involvement of the IRE1α and PERK pathways in ERS inflammation. The cardiomyocytes were given hypoxia/reoxygenation (H/R), and the effects of the NF-κB inhibitor, SN50, were followed. GRP78 protein levels were similar in the tunicamycin (Tm), salubrinal, and SP600125 groups, but were lower in cells treated with SN50. SN50 might effectively block the H/R-induced link between ERS and inflammation in cardiomyocytes by decreasing GRP78. This knowledge will aid in the development of therapies for myocardial ischemia/reperfusion injury.

Topics: Animals; Anthracenes; Cell Hypoxia; Cells, Cultured; Cinnamates; eIF-2 Kinase; Endoplasmic Reticulum Stress; Endoribonucleases; Heart Rate; Heat-Shock Proteins; Inflammation; Multienzyme Complexes; Myocytes, Cardiac; NF-kappa B; Peptides; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Thiourea; Tumor Necrosis Factor-alpha; Tunicamycin