bims-noxint 2022-08-14 papers

Issue of 2022–08–14
four papers selected by
Laia Caja Puigsubira, Uppsala University

Int Immunopharmacol. 2022 Aug 05. pii: S1567-5769(22)00605-1. [Epub ahead of print]111 109121

α-Iso-cubebene attenuates neointima formation by inhibiting HMGB1-induced monocyte to macrophage differentiation via suppressing ROS production.

Seung Eun Baek, Eun Jeong Jang, Jong Min Choi, Young Whan Choi, Chi Dae Kim.

α-Iso-cubebene (ICB) is a dibenzocyclooctadiene lignin contained in Schisandra chinensis, a medicinal herb used to improve cardiovascular symptoms. To investigate the mechanisms involved, the effects of ICB on cellular production of reactive oxygen species (ROS) was determined using cultured human THP-1 cells. When THP-1 cells were stimulated with HMGB1, cellular concentration of ROS was increased in dose- and time-dependent manners. These increases were significantly attenuated in cells pretreated with NADPH oxidase inhibitors, diphenyleneiodonium chloride and apocynin, but not by other inhibitors related to ROS generation in monocytes. The expression of constitutively expressed NADPH oxidase (NOX) subunits including NOX1, NOX2, NOX4 and NOX5 was not affected by HMGB1, but HMGB1-induced ROS production was exclusively attenuated in NOX2-deficient cells using siRNA, suggesting an enhanced NOX2 complex assembly. When cells were stimulated with HMGB1, p47phox phosphorylation at ser345, ser359 and ser370 was increased in dose- and time-dependent manners, which were significantly attenuated in ICB (3-10 μg/mL)-pretreated cells. In addition, HMGB1-induced monocyte-macrophage differentiation (MMD) in bone marrow-derived cells isolated from mice were significantly attenuated in cells treated with apocynin and ICB. Also, macrophage infiltration and intimal hyperplasia in the wire-injured femoral artery were significantly attenuated in ICB-treated mice compared to wild-type control mice. The results of this study show that ICB inhibits HMGB1-induced MMD by suppressing ROS production in monocytes, thus suggest that ICB has therapeutic potential for vascular inflammation with subsequent intimal hyperplasia related to vascular injury.

Keywords: High mobility group box 1; Monocyte to Macrophage differentiation; Reactive oxygen species; Vascular inflammation; α-Iso-cubebene

DOI: https://doi.org/10.1016/j.intimp.2022.109121

Redox Biol. 2022 Jul 31. pii: S2213-2317(22)00191-4. [Epub ahead of print]55 102419

The loss of pancreatic islet NADPH oxidase (NOX)2 improves islet transplantation.

Selina Wrublewsky, Julia Glas, Christopher Carlein, Lisa Nalbach, Markus Daniel Alexander Hoffmann, Mandy Pack, Eloisa Aparecida Vilas-Boas, Nathan Ribot, Reinhard Kappl, Michael D Menger, Matthias W Laschke, Emmanuel Ampofo, Leticia Prates Roma.

Islet transplantation is a promising treatment strategy for type 1 diabetes mellitus (T1DM) patients. However, oxidative stress-induced graft failure due to an insufficient revascularization is a major problem of this therapeutic approach. NADPH oxidase (NOX)2 is an important producer of reactive oxygen species (ROS) and several studies have already reported that this enzyme plays a crucial role in the endocrine function and viability of β-cells. Therefore, we hypothesized that targeting islet NOX2 improves the outcome of islet transplantation. To test this, we analyzed the cellular composition and viability of isolated wild-type (WT) and Nox2-/- islets by immunohistochemistry as well as different viability assays. Ex vivo, the effect of Nox2 deficiency on superoxide production, endocrine function and anti-oxidant protein expression was studied under hypoxic conditions. In vivo, we transplanted WT and Nox2-/- islets into mouse dorsal skinfold chambers and under the kidney capsule of diabetic mice to assess their revascularization and endocrine function, respectively. We found that the loss of NOX2 does not affect the cellular composition and viability of isolated islets. However, decreased superoxide production, higher glucose-stimulated insulin secretion as well as expression of nuclear factor erythroid 2-related factor (Nrf)2, heme oxygenase (HO)-1 and superoxide dismutase 1 (SOD1) was detected in hypoxic Nox2-/- islets when compared to WT islets. Moreover, we detected an early revascularization, a higher take rate and restoration of normoglycemia in diabetic mice transplanted with Nox2-/- islets. These findings indicate that the suppression of NOX2 activity represents a promising therapeutic strategy to improve engraftment and function of isolated islets.

Keywords: Diabetes; HO-1; Insulin secretion; Islet transplantation; NADPH oxidase; NOX2; Nrf2; ROS; Revascularization; β-cells

DOI: https://doi.org/10.1016/j.redox.2022.102419

Medicine (Baltimore). 2022 Aug 12. 101(32): e30028

Increased NOX1 and DUOX2 expression in the colonic mucosa of patients with chronic functional constipation.

Xiuqin Wei, Mei Xue, Chunbo Kang, Lei Gao, Mengqiao Zhang, Chao Ma, Wei Jia, Yufeng Zheng, Lei Cao, Pan Chen, Shujing Jiang, Fong-Fong Chu, Qiang Gao.

To determine whether oxidative stress and inflammation are associated with constipation by examining the expression of the main producers of reactive oxygen species, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, and pro-inflammatory cytokines in the colon of patients with chronic functional constipation. The colonic biopsies were collected from 32 patients with chronic functional constipation and 30 healthy subjects who underwent colonoscopy. Colonic mucosal histology was observed. Interleukin (IL)-1β, IL-6, IL-8 messenger RNA (mRNA), and 4 members of NADPH oxidase (NOX1, NOX2, DUOX2, and NOX4) protein and mRNA were assessed by immunohistochemistry, western blotting, and reverse transcription polymerase chain reaction. The tissues from both patients and healthy subjects showed normal histological structure without increase of inflammatory cells. NOX1 protein and mRNA levels were significantly increased compared to controls (P < .05). DUOX2 protein, but not mRNA, was increased by 2-fold compared to controls (P < .05). The levels of NOX2 and NOX4 protein and mRNA demonstrated no significant difference between patients and control subjects. The levels of IL-1β and IL-6 mRNA were significantly higher in constipation patients (P < .05), while IL-8 mRNA level was no different between the 2 groups. NADPH oxidase and pro-inflammatory cytokine might be involved in the pathogeneses of chronic functional constipation.

DOI: https://doi.org/10.1097/MD.0000000000030028

Chem Biol Interact. 2022 Aug 09. pii: S0009-2797(22)00279-4. [Epub ahead of print] 110074

Aucubin ameliorates liver fibrosis and hepatic stellate cells activation in diabetic mice via inhibiting ER stress-mediated IRE1α/TXNIP/NLRP3 inflammasome through NOX4/ROS pathway.

Xiaowen Bao, Jiaqi Li, Chaoxing Ren, Jingxun Wei, Xuanzhao Lu, Xiaoxuan Wang, Wei Du, Xin Jin, Beiting Ma, Qi Zhang, Bo Ma.

Type 2 diabetes (T2DM) is closely associated with hepatic injury, which could promote/exacerbate hepatic inflammation, steatosis, and accelerate liver fibrosis progression. Aucubin (AU), as an active ingredient isolated from Eucommia ulmoides, exists a nutritional value in hepatoprotective effect and diabetic complications. However, whether it possesses more outstanding features on improving liver injury in diabetic conditions and the underlying mechanism is unclear. Our research investigated the treatment of AU on liver fibrosis and potential mechanisms on high-fat diet/streptozotocin-induced diabetic mice and high glucose (HG)&TGF-β1-induced LX-2 cells. Results showed that AU restored hepatic function without affecting blood sugar levels in diabetic mice. Meanwhile, the enhanced levels of total cholesterol, triglycerides, and LDL-c were reversed in hepatic tissue after AU treatment. Histomorphology assays including H&E, Masson, PAS, Oil red and Sirius red staining showed that AU treatment reduced liver swelling, steatosis and fibrosis. Mechanistic studies showed that AU alleviated NLRP3 inflammasome activation and inflammatory responses via inhibiting ER stress-mediated IRE1α/TXNIP signaling pathway, which could postpone the development of T2DM induced hepatic fibrosis. In addition, the ROS generation and the up-regulated expression of NADHP oxidase 4 (NOX4) in the liver tissue were suppressed by AU treatment. Moreover, in vitro model, NOX4 activation was prominently enhanced and AU treatment blocked HG&TGF-β1-induced NOX4 derived superoxide generation and thereby ameliorating hepatic stellate cell activation, which can be abrogated in the overexpression of NOX4 LX-2 cells. In addition, inhibition effects on ER stress-mediated IRE1α/TXNIP/NLRP3 inflammasome by AU treatment also were abolished in the overexpression of NOX4 LX-2 cells. Meanwhile, molecular docking results indicated that AU and NOX4 protein have a higher affinity. Taken together, AU might be a potential nutraceutical or therapeutic drug to ameliorate hepatic impairment and fibrosis in T2DM.

Keywords: Aucubin; Diabetes; ER stress; Liver fibrosis; NADPH Oxidase 4 (NOX4); NLRP3

DOI: https://doi.org/10.1016/j.cbi.2022.110074