IL-13 downregulates PPAR-γ/heme oxygenase-1 via ER stress-stimulated calpain activation: aggravation of activated microglia death

Although there is a therapeutic treatment to combat diabetes, the identification of agents that may deal with its more serious aspects is an important medical field for research. Diabetes, which contributes to the risk of cardiovascular disease, is associated with a low-grade chronic inflammation (inflammatory stress), oxidative stress, and endoplasmic reticulum (ER) stress. Because the integration of these stresses is critical to the pathogenesis of diabetes, agents and cellular molecules that can modulate these stress responses are emerging as potential targets for intervention and treatment of diabetic diseases. It has been recognized that heme oxygenase-1 (HO-1) plays an important role in cellular protection. Because HO-1 can reduce oxidative stress, inflammatory stress, and ER stress, in part by exerting antioxidant, anti-inflammatory, and antiapoptotic effects, HO-1 has been suggested to play important roles in pathogenesis of diabetes. In the present review, we will explore our current understanding of the protective mechanisms of HO-1 in diabetes and present some emerging therapeutic options for HO-1 expression in treating diabetic diseases, together with the therapeutic potential of curcumin analogues that have their ability to induce HO-1 expression.

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Anti-neuroinflammatory effect of 6,8,1′-tri- O -methylaverantin, a metabolite from a marine-derived fungal strain Aspergillus sp., via upregulation of heme oxygenase-1 in lipopolysaccharide-activated microglia

Neurochemistry International ◽

10.1016/j.neuint.2017.11.010 ◽

2018 ◽

Vol 113 ◽

pp. 8-22 ◽

Cited By ~ 3

Author(s):

Kwan-Woo Kim ◽

Hye Jin Kim ◽

Jae Hak Sohn ◽

Joung Han Yim ◽

Youn-Chul Kim ◽

...

Keyword(s):

Heme Oxygenase ◽

Fungal Strain ◽

Heme Oxygenase 1 ◽

Activated Microglia ◽

Aspergillus Sp

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Activation of PPAR-γ ameliorates pulmonary arterial hypertension via inducing heme oxygenase-1 and p21WAF1: An in vivo study in rats

Life Sciences ◽

10.1016/j.lfs.2013.12.208 ◽

2014 ◽

Vol 98 (1) ◽

pp. 39-43 ◽

Cited By ~ 28

Author(s):

Dexin Zhang ◽

Guizuo Wang ◽

Dong Han ◽

Yonghong Zhang ◽

Jing Xu ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Heme Oxygenase ◽

In Vivo Study ◽

Heme Oxygenase 1 ◽

Ppar Γ ◽

Pulmonary Arterial

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P09235-AMINOLEVULINIC ACID PREVENTS LIPID-INDUCED ER STRESS AND APOPTOSIS BY INDUCING HEME OXYGENASE-1

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0923 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Yukari Mae ◽

Yui Kobayashi ◽

Tomoaki Takata ◽

Kohshiro Hosokawa ◽

Takaaki Sugihara ◽

...

Keyword(s):

Palmitic Acid ◽

Er Stress ◽

Therapeutic Effect ◽

Heme Oxygenase ◽

Renal Tubule ◽

Aminolevulinic Acid ◽

Protoporphyrin Ix ◽

Kidney Injury ◽

Heme Oxygenase 1 ◽

Related Factor

Abstract Background and Aims A growing number of evidence indicates the association with dyslipidemia and the progression of chronic kidney disease. Endoplasmic reticulum (ER) stress and apoptosis in renal tubule are suggested to be linked to the pathophysiology of toxic lipid-induced kidney injury. 5-aminolevulinic acid (ALA) is a precursor of heme oxygenase (HO)-1, which plays an important role in protecting cells from various stresses. In the present study, we aimed to investigate the therapeutic effect of ALA, on toxic lipid-induced ER stress and apoptosis in the renal tubule. Method Renal proximal tubular epithelial cells (RPTECs) were treated with palmitic acid to induce ER stress and apoptosis. ALA was also added with palmitic acid (PA). The gene and protein expressions of NF E2-related factor 2, HO-1, glucose-regulated protein (GRP)78, and C/EBP-homologous protein (CHOP) were quantified. Apoptotic cells were evaluated by caspase-3/7 assay. An HO-1 inhibitor, Zn-protoporphyrin IX, was added to investigate the involvement of HO-1 in ALA-mediated therapeutic effect on the ER stress and apoptosis. Results The expressions of GRP78 and CHOP increased in cells treated with PA. Apoptotic signals also increased with PA treatment. ALA induced a significant increase in the HO-1 expression and that led to the suppression of ER stress response. Apoptotic signals in PA-treated cells also decreased with ALA and the effect of ALA disappeared when combined with Zn-protoporphyrin IX. Conclusion PA-induced ER stress and apoptosis in RPTECs. ALA has a therapeutic effect by suppressing ER stress, possibly through HO-1 induction.

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Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis

AJP Renal Physiology ◽

10.1152/ajprenal.00495.2014 ◽

2015 ◽

Vol 308 (3) ◽

pp. F226-F236 ◽

Cited By ~ 64

Author(s):

Hyosang Kim ◽

Soo Young Moon ◽

Joon-Seok Kim ◽

Chung Hee Baek ◽

Miyeon Kim ◽

...

Keyword(s):

Protein Kinase ◽

Mouse Model ◽

Er Stress ◽

Heme Oxygenase ◽

Renal Fibrosis ◽

Transforming Growth Factor ◽

Initiation Factor ◽

Heme Oxygenase 1 ◽

Compound C ◽

Amp Activated Protein Kinase

It has been suggested that endoplasmic reticulum (ER) stress facilitates fibrotic remodeling. Therefore, modulation of ER stress may serve as one of the possible therapeutic approaches to renal fibrosis. We examined whether and how activation of AMP-activated protein kinase (AMPK) suppressed ER stress induced by chemical ER stress inducers [tunicamycin (TM) and thapsigargin (TG)] and also nonchemical inducers in tubular HK-2 cells. We further investigated the in vivo effects of AMPK on ER stress and renal fibrosis. Western blot analysis, immunofluorescence, small interfering (si)RNA experiments, and immunohistochemical staining were performed. Metformin (the best known clinical activator of AMPK) suppressed TM- or TG-induced ER stress, as shown by the inhibition of TM- or TG-induced upregulation of glucose-related protein (GRP)78 and phosphorylated eukaryotic initiation factor-2α through induction of heme oxygenase-1. Metformin inhibited TM- or TG-induced epithelial-mesenchymal transitions as well. Compound C (AMPK inhibitor) blocked the effect of metformin, and 5-aminoimidazole-4-carboxamide-1β riboside (another AMPK activator) exerted the same effects as metformin. Transfection with siRNA targeting AMPK blocked the effect of metformin. Consistent with the results of cell culture experiments, metformin reduced renal cortical GRP78 expression and increased heme oxygenase-1 expression in a mouse model of ER stress-induced acute kidney injury by TM. Activation of AMPK also suppressed ER stress by transforming growth factor-β, ANG II, aldosterone, and high glucose. Furthermore, metformin reduced GRP78 expression and renal fibrosis in a mouse model of unilateral ureteral obstruction. In conclusion, AMPK may serve as a promising therapeutic target through reducing ER stress and renal fibrosis.

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Betulin Protects HT-22 Hippocampal Cells against ER Stress through Induction of Heme Oxygenase-1 and Inhibition of ROS Production

Natural Product Communications ◽

10.1177/1934578x19896684 ◽

2019 ◽

Vol 14 (12) ◽

pp. 1934578X1989668 ◽

Cited By ~ 1

Author(s):

Phil Jun Lee ◽

Hye-Jin Park ◽

Hee Min Yoo ◽

Namki Cho

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Er Stress ◽

Heme Oxygenase ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ros Generation ◽

Heme Oxygenase 1 ◽

Ros Scavenging ◽

Neuroprotective Effects

A key pathologic event in neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, is endoplasmic reticulum (ER) stress-induced neuronal cell death. ER stress-induced generation of reactive oxygen species (ROS) has been implicated in neurological disease processes. Betulin is one of the major triterpenoids found in Betula platyphylla that possesses several biological properties, including cytoprotective and antioxidative effects. Therefore, we investigated whether betulin could prevent ER stress-induced neurotoxicity in HT-22 hippocampal neuronal cells. We observed that betulin reduced the thapsigargin (TG, an ER stress inducer)-induced apoptosis of HT-22 cells. Moreover, the cytoprotective effects of betulin were comparable to those of tauroursodeoxycholic acid, a potent ER stress-reducing agent. In our study, we confirmed that the ER stress-induced accumulation of ROS plays an important role in HT-22 cell death. Betulin also displayed cytoprotective effects in TG-injured HT-22 cells by reducing ROS generation; these results were comparable to those for N-acetyl-L-cysteine, a known ROS inhibitor. In addition, SnPP, a heme oxygenase-1 (HO-1) inhibitor significantly blocked the cytoprotective effects and ROS scavenging activity of betulin. Based on these results, we believe that betulin-mediated induction of HO-1 may contribute to the neuroprotective effects against ER stress in HT-22 hippocampal cells. We also found that betulin significantly inhibited the TG-induced expression of CHOP and caspase-12. These results demonstrated that betulin could serve as a potential therapeutic agent against ER stress-induced neurodegenerative diseases.

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Heme, Heme Oxygenase, and Endoplasmic Reticulum Stress—A New Insight into the Pathophysiology of Vascular Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms20153675 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3675 ◽

Cited By ~ 14

Author(s):

Gáll ◽

Balla ◽

Balla

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Er Stress ◽

Heme Oxygenase ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Vascular Diseases ◽

Heme Oxygenase 1 ◽

Vascular Disorders ◽

Ferroxidase Activity

The prevalence of vascular disorders continues to rise worldwide. Parallel with that, new pathophysiological pathways have been discovered, providing possible remedies for prevention and therapy in vascular diseases. Growing evidence suggests that endoplasmic reticulum (ER) stress is involved in a number of vasculopathies, including atherosclerosis, vascular brain events, and diabetes. Heme, which is released from hemoglobin or other heme proteins, triggers various pathophysiological consequence, including heme stress as well as ER stress. The potentially toxic free heme is converted by heme oxygenases (HOs) into carbon monoxide (CO), iron, and biliverdin (BV), the latter of which is reduced to bilirubin (BR). Redox-active iron is oxidized and stored by ferritin, an iron sequestering protein which exhibits ferroxidase activity. In recent years, CO, BV, and BR have been shown to control cellular processes such as inflammation, apoptosis, and antioxidant defense. This review covers our current knowledge about how heme induced endoplasmic reticulum stress (HIERS) participates in the pathogenesis of vascular disorders and highlights recent discoveries in the molecular mechanisms of HO-mediated cytoprotection in heme stress and ER stress, as well as crosstalk between ER stress and HO-1. Furthermore, we focus on the translational potential of HIERS and heme oxygenase-1 (HO-1) in atherosclerosis, diabetes mellitus, and brain hemorrhage.

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Ketamine-induced hepatoprotection: the role of heme oxygenase-1

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00038.2009 ◽

2009 ◽

Vol 296 (6) ◽

pp. G1360-G1369 ◽

Cited By ~ 9

Author(s):

James W. Suliburk ◽

Jeremy L. Ward ◽

Kenneth S. Helmer ◽

Sasha D. Adams ◽

Brian S. Zuckerbraun ◽

...

Keyword(s):

Heme Oxygenase ◽

Hepatic Injury ◽

Protoporphyrin Ix ◽

Heme Oxygenase 1 ◽

Hepatocellular Injury ◽

Ppar Γ ◽

Hepatoprotective Effects ◽

Cox 2 ◽

Oxide Synthase

Lipopolysaccharide (LPS) causes hepatic injury that is mediated, in part, by upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Ketamine has been shown to prevent these effects. Because upregulation of heme oxygenase-1 (HO-1) has hepatoprotective effects, as does carbon monoxide (CO), an end product of the HO-1 catalytic reaction, we examined the effects of HO-1 inhibition on ketamine-induced hepatoprotection and assessed whether CO could attenuate LPS-induced hepatic injury. One group of rats received ketamine (70 mg/kg ip) or saline concurrently with either the HO-1 inhibitor tin protoporphyrin IX (50 μmol/kg ip) or saline. Another group of rats received inhalational CO (250 ppm over 1 h) or room air. All rats were given LPS (20 mg/kg ip) or saline 1 h later and euthanized 5 h after LPS or saline. Liver was collected for iNOS, COX-2, and HO-1 (Western blot), NF-κB and PPAR-γ analysis (EMSA), and iNOS and COX-2 mRNA analysis (RT-PCR). Serum was collected to measure alanine aminotransferase as an index of hepatocellular injury. HO-1 inhibition attenuated ketamine-induced hepatoprotection and downregulation of iNOS and COX-2 protein. CO prevented LPS-induced hepatic injury and upregulation of iNOS and COX-2 proteins. Although CO abolished the ability of LPS to diminish PPAR-γ activity, it enhanced NF-κB activity. These data suggest that the hepatoprotective effects of ketamine are mediated primarily by HO-1 and its end product CO.

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