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Aseptic metal implant loosening due to wear particle-induced bone damage is a major complication of total joint arthroplasty often leading to revision surgery, of which the key regulators mediating the processes are not clearly defined. Here we reported that in a mouse model of calvarial osteolysis, titanium particles (TiPs) and cobalt–chromium–molybdenum particles induced severe osteolysis accompanied by marked suppression of a master redox transcriptional factor NRF2 (Nuclear factor erythroid derived 2-related factor 2). Nfe2l2 knockout mice treated with TiPs developed worse osteolytic alterations compared with wild-type mice. On the contrary, NRF2 restoration by an NRF2 agonist TBHQ (tert-butylhydroquinone) effectively alleviated the osteolysis and the abnormal expression of NRF2 downstream antioxidant enzymes, inflammatory cytokines and osteogenic factors. Further, TiPs induced adverse osteoblastogenesis and osteoclastogenesis in cultured bone cells, which were substantially blocked by TBHQ in an NRF2 inhibition-sensitive manner. Consistently, the osteoprotective effects of TBHQ observed in wild-type mice were largely limited in Nfe2l2 knockout mice. Collectively, our data suggest that NRF2 suppression is a critical causal event of metal wear particle-incurred osteolysis, and the strategies reinstating NRF2 are effective to lessen the bone damage and potentially reduce the incidence of metal implant loosening. • Metal particles induce osteolytic bone resorption with marked NRF2 suppression. • Nfe2l2 knockout mice develop worse osteolysis than wild-type mice. • NRF2 restoration by TBHQ effectively reduces the osteolytic bone damage. • NRF2 inhibition in vitro or knockout in vivo limits the osteoprotection by TBHQ. • NRF2 is an effective therapeutic target of metal particle–induced bone damage. [ABSTRACT FROM AUTHOR]

Objective. Oxidative stress has been proven to be essential in the pathogenesis of ulcerative colitis (UC). Therefore, this study was designed to investigate the effect of Gegen Qinlian decoction (GQ) on the Nrf2 pathway in the treatment of UC and explore the potential mechanism. Methods. The UC rat model was induced by 5% dextran sodium sulfate (DSS) aqueous solution, and UC rats were treated with GQ orally. The effect of GQ on UC rats was recorded. Human clonal colon adenocarcinoma cells (Caco-2) stimulated by tumor necrosis factor-α (TNF-α) were employed in this study. After being stimulated with TNF-α for 2 hours, Caco-2 cells were cultured with GQ or its major components (puerarin, baicalin, berberine, and liquiritin) for 22 hours. In addition, the Nrf2 gene of Caco-2 cells was silenced and then cultured with GQ for 22 hours. The contents of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and malondialdehyde (MDA) in colonic tissues and Caco-2 cells were detected by assay kits. Reactive oxygen species (ROS) in Caco-2 cells were analyzed by flow cytometry. Quantitative real-time PCR and western blot were employed to detect the mRNA and protein expression of Nrf2 and its related target genes in colon tissues and Caco-2 cells. Results. GQ alleviated the injured colonic mucosa and activated the expression of Nrf2 in UC rats. In TNF-α stimulated Caco-2 cells and Nrf2 silenced Caco-2 cells, GQ also reversed the inhibitory effect of Nrf2. Furthermore, the major components of GQ could activate Nrf2 signaling in TNF-α stimulated cells as well. Moreover, the contents of SOD, GSH, MDA, and ROS were restored to normal after treatment with GQ or its major components. Among these components, puerarin, berberine, and liquiritin appear to have a better effect on activating Nrf2 in vitro. Overall, GQ can alleviate UC by increasing the activity of Nrf2/ARE signaling and enhancing the effect of antioxidant stress. [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH) and hepatic fibrosis are leading causes of cirrhosis with rising morbidity and mortality worldwide. Currently, there is no appropriate treatment for NASH and hepatic fibrosis. Many studies have shown that oxidative stress is a main factor inducing NASH. Nomilin (NML) and obacunone (OBA) are limonoid compounds naturally occurring in citrus fruits with various biological properties. However, whether OBA and NML have beneficial effects on NASH remains unclear. Here, we demonstrated that OBA and NML inhibited hepatic tissue necrosis, inflammatory infiltration and liver fibrosis progression in methionine and choline‐deficient (MCD) diet, carbon tetrachloride (CCl4)‐treated and bile duct ligation (BDL) NASH and hepatic fibrosis mouse models. Mechanistic studies showed that NML and OBA enhanced anti‐oxidative effects, including reduction of malondialdehyde (MDA) level, increase of catalase (CAT) activity and the gene expression of glutathione S‐transferases (GSTs) and Nrf2‐keap1 signaling. Additional, NML and OBA inhibited the expression of inflammatory gene interleukin 6 (Il‐6), and regulated the bile acid metabolism genes Cyp3a11, Cyp7a1, multidrug resistance‐associated protein 3 (Mrp3). Overall, these findings indicate that NML and OBA may alleviate NASH and liver fibrosis in mice via enhancing antioxidant and anti‐inflammation capacity. Our study proposed that NML and OBA may be potential strategies for NASH treatment. [ABSTRACT FROM AUTHOR]

Stem cell-derived exosomes (SC-Exos) have been shown to protect cells from chemical-induced deoxyribonucleic acid (DNA) damage. However, there has been no systematic comparison of the efficacy of exosomes against different types of DNA damage. Therefore, in this study, we assessed the protective effect of exosomes derived from human embryonic stem cell-induced mesenchymal stem cells (hESC-MSC-Exos) on two types of DNA damage, namely, intra-/inter-strand crosslinks and DNA double-strand breaks induced by cisplatin (Pt) and bleomycin (BLM), respectively, in HeLa cells. The alkaline comet assay demonstrated that hESC-MSC-Exos effectively inhibited Pt- and BLM-induced DNA damage in a dose-dependent manner. When the concentration of hESC-MSC-Exos reaches 2.0 × 106 and 4.0 × 106 particles/mL in Pt- and BLM-treated groups, respectively, there was a significant decrease in tail DNA percentage (Pt: 20.80 ± 1.61 vs 9.40 ± 1.14, p < 0.01; BLM: 21.80 ± 1.31 vs 6.70 ± 0.60, p < 0.01), tail moment (Pt: 10.00 ± 1.21 vs 2.08 ± 0.51, p < 0.01; BLM: 12.00 ± 0.81 vs 2.00 ± 0.21, p < 0.01), and olive tail moment (Pt: 6.01 ± 0.55 vs 2.09 ± 0.25, p < 0.01; BLM: 6.03 ± 0.37 vs 1.53 ± 0.13, p < 0.01). Phospho-histone H2AX (γH2AX) immunofluorescence and western blotting showed an over 50 % decrease in γH2AX expression when the cells were pretreated with hESC-MSC-Exos. As reactive oxygen species (ROS) are important mediators of Pt- and BLM-induced DNA damage, dichloro-dihydro-fluorescein diacetate staining indicated that hESC-MSC-Exos inhibited the increase in intracellular ROS in drug-treated cells. In conclusion, our findings suggest that hESC-MSC-Exos can protect cells from the two types of DNA-damaging drugs and that reduced intracellular ROS is involved in this effect. • hESC-MSC-Exos suppress cisplatin (Pt)- and bleomycin (BLM)- induced DNA damage. • hESC-MSC-Exos inhibit Pt- and BLM- induced decrease of HeLa cell viability. • hESC-MSC-Exos inhibit the generation of intracellular ROS induced by Pt and BLM. [ABSTRACT FROM AUTHOR]

Caveolae are intracellular vesicles with diameters ranging from 50 to 100 nm. The role of caveolins in mediating oxidative stress, autophagy, apoptosis, fibrosis, and vascular remodeling has attracted increasing attention in cardiovascular therapy. Several studies have suggested that caveolin could be a therapeutic target for the treatment of cardiac and/or vascular injury via several pathophysiological mechanisms. Despite substantial advances in our understanding of the basic biology of vesicles over the past decade, the relevance and specific role of these mechanisms in cardiovascular homeostasis remains ambiguous. Here, we review the macroscopic role of caveolins in protecting cardiac function and, at the microscopic level, examine possible cardioprotective caveolar mechanisms, including their antioxidative stress, antiapoptosis, autophagy‐regulatory, antifibrosis, and angiogenesis‐promoting properties. We believe that the role of caveolins in cardiac functioning has not been fully elucidated and is an important line of future research with several cardioprotective implications. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 21 (FGF21) is a metabolism‐regulating hepatokine, and its expression is finely controlled by the nutrients and cellular stressors. α‐Lipoic acid (ALA) regulates fuel metabolism as a nutrient, but it also arouses mitochondrial and endoplasmic reticulum (ER) stress as well as oxidative stress in hepatocytes. However, the role of cellular stress in ALA‐regulated FGF21 expression has not been demonstrated as yet. The present study found that ALA up‐regulated FGF21 gene expression while it reduced FGF21 protein levels in HepG2 cells, which was accompanied by mitochondrial damage that was shown by ATP reduction and ROS elevation. ALA led to mitochondrial stress and ER stress as shown by the increased expression of HSP60, ATF6 and ATF4. Inhibition of ER stress by 4‐PBA significantly attenuated ALA‐stimulated FGF21 gene expression while it did not influence the reduction of FGF21 protein levels. H2O2‐induced oxidative stress reduced FGF21 protein levels in HepG2 cells, and anti‐oxidation by Tempol blocked ALA‐induced reduction of FGF21 proteins. In conclusion, ALA up‐regulates FGF21 gene expression through the stimulation of mitochondrial and ER stress while it reduces FGF21 protein levels through the induction of oxidative stress in HepG2 cells. Further studies are needed to demonstrate the in vivo effect of ALA on hepatic FGF21 expression. [ABSTRACT FROM AUTHOR]

The slow proliferation rate and poor osteodifferentiation ability of inflammatory periodontal membrane stem cells extracted from periodontitis tissues (i-PDLSCs) account for poor efficiency in treating inflammatory bone loss. Exosomes reportedly have inducible and relatively stable components, allowing them to promote inflammatory bone repair, but obtaining i-PDLSCs exosomes with the ability to promote osteodifferentiation is challenging. In the present study, i-PDLSCs were extracted from periodontal membrane tissues of patients with severe periodontitis, and in vitro induction with gallic acid (GA) significantly promoted the proliferative activity of i-PDLSCs at a concentration of 10 mM, with TC0 of 11.057 mM and TC50 of 67.56 mM for i-PDLSCs. After mRNA sequencing, we found that GA could alleviate oxidative stress in i-PDLSCs and increase its mitochondrial membrane potential and glucose aerobic metabolism level, thus promoting the osteodifferentiation of i-PDLSCs. After exosomes of i-PDLSCs after GA induction (i-EXO-GA) were isolated by differential centrifugation, we found that 200 ug/mL of i-EXO-GA could remarkably promote the osteodifferentiation of i-PDLSCs. Overall, our results suggest that GA induction can enhance the proliferation and osteodifferentiation in primary cultures of i-PDLSCs in vitro, mediated by alleviating oxidative stress and glycometabolism levels in cells, which further influences the osteodifferentiation-promoting ability of i-EXO-GA. Overall, we provide a viable cell and exosome induction culture method for treating inflammatory alveolar defects associated with periodontitis. [ABSTRACT FROM AUTHOR]

Aims: The pathogenesis of osteoarthritis (OA) is characterized by oxidative stress (OS) and sustained inflammation that are substantially associated with epigenetic DNA methylation alterations of osteogenic gene expression. Diacerein as an anthraquinone anti-OA drug exhibits multiple chondroprotective properties, but less clarified pharmacological actions. Since anthraquinone contain an epigenetic modulating property, in this study we investigate whether the anti-OA functions of diacerein involve DNA methylation modulation and antioxidant signaling. Results: The OA mice incurred by destabilization of medial meniscus exhibited marked suppression of peroxisome proliferator-activated receptor-gamma (PPARγ), a chondroprotective transcription factor with anti-inflammation and OS-balancing properties, aberrant upregulations of DNA methyltransferase (DNMT)1/3a, and PPARγ promoter hypermethylation in knee joint cartilage. Diacerein treatment mitigated the cartilage damage and significantly inhibited the DNMT1/3a upregulation, the PPARγ promoter hypermethylation, and the PPARγ loss, and it effectively corrected the adverse expression of antioxidant enzymes and inflammatory cytokines. In cultured chondrocytes, diacerein reduced the interleukin-1β-induced PPARγ suppression and the abnormal expression of its downstream antioxidant enzymes in a gain of DNMT and PPARγ inhibition-sensitive manner, and in PPARγ knockout mice, the anti-OA effects of diacerein were significantly reduced. Innovation: Our work reveals a novel anti-OA pharmacological property of diacerein and identifies the aberrant DNMT elevation and the resultant PPARγ suppression as an important epigenetic pathway that mediates diacerein's anti-OA activities. Conclusion: DNA methylation aberration and the resultant PPARγ suppression contribute significantly to epigenetic OA pathogenesis, and targeting PPARγ suppression via DNA demethylation is an important component of diacerein's anti-OA functions. Antioxid. Redox Signal. 37, 40–53. [ABSTRACT FROM AUTHOR]

Background/Aims: Daphnetin (7,8-dihydroxycoumarin, DAP) exhibits various bioactivities, such as anti-inflammatory and antioxidant activities. However, the role of DAP in myocardial ischaemia/reperfusion (I/R) injury and I/R-related arrhythmia is still uncertain. This study aimed to investigate the mechanisms underlying the effects of DAP on myocardial I/R injury and electrophysiological properties in vivo and in vitro. Methods: Myocardial infarct size was measured by triphenyltetrazolium chloride staining. Cardiac function was assessed by echocardiographic and haemodynamic analyses. The levels of creatine kinase-MB, lactate dehydrogenase, malondialdehyde, superoxide dismutase, interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α) were detected using commercial kits. Apoptosis was measured by terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labelling staining and flow cytometry. The viability of H9c2 cells was determined by the Cell Counting Kit-8 assay. In vitro, the levels of IL-6 and TNF-α were measured by quantitative PCR. The expression levels of proteins associated with apoptosis, inflammation, and the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor kappa B (TLR4/MyD88/NF-κB) signalling pathway were detected by Western blot analysis. The RR, PR, QRS, and QTc intervals were assessed by surface ECG. The 90% action potential duration (APD90), threshold of APD alternans, and ventricular tachycardia inducibility were measured by the Langendorff perfusion technique. Results: DAP preconditioning decreased myocardial I/R injury and hypoxia/reoxygenation (H/R) injury in cells. DAP preconditioning improved cardiac function after myocardial I/R injury. DAP preconditioning also suppressed apoptosis, attenuated oxidative stress, and inhibited inflammatory responses in vivo and in vitro. Furthermore, DAP preconditioning decreased the susceptibility to ventricular arrhythmia after myocardial I/R. Finally, DAP preconditioning inhibited the expression of TLR4, MyD88, and phosphorylated NF-κB (p-NF-κB)/P65 in mice subjected to I/R and cells subjected to H/R. Conclusions: DAP preconditioning protected against myocardial I/R injury and decreased susceptibility to ventricular arrhythmia by inhibiting the TLR4/MyD88/NF-κB signalling pathway. [ABSTRACT FROM AUTHOR]