Oxidative Medicine and Cellular Longevity

Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin chloride (MnTE-2-PyPCl₅, BMX-010, and AEOL10113) is among the most studied superoxide dismutase (SOD) mimics and redox-active therapeutics, being currently tested as a drug candidate in a phase II clinical trial on atopic dermatitis and itch. The thermal stability of active pharmaceutical ingredients (API) is useful for estimating the expiration date and shelf life of pharmaceutical products under various storage and handling conditions. The thermal decomposition and kinetic parameters of MnTE-2-PyPCl₅ were determined by thermogravimetry (TG) under nonisothermal and isothermal conditions. The first thermal degradation pathway affecting Mn-porphyrin structural integrity and, thus, activity and bioavailability was associated with loss of ethyl chloride via N-dealkylation reaction. The thermal stability kinetics of the N-dealkylation process leading to MnTE-2-PyPCl₅ decomposition was investigated by using isoconversional models and artificial neural network. The new multilayer perceptron (MLP) artificial neural network approach allowed the simultaneous study of ten solid-state kinetic models and showed that MnTE-2-PyPCl₅ degradation is better explained by a combination of various mechanisms, with major contributions from the contraction models R1 and R2. The calculated activation energy values from isothermal and nonisothermal data were about 90 kJ mol^–1 on average and agreed with one another. According to the R1 modelling of the isothermal decomposition data, the estimated shelf life value for 10% decomposition () of MnTE-2-PyPCl₅ at 25°C was approximately 17 years, which is consistent with the high solid-state stability of the compound. These results represent the first study on the solid-state decomposition kinetics of Mn(III) 2-N-alkylpyridylporphyrins, contributing to the development of this class of redox-active therapeutics and SOD mimics and providing supporting data to protocols on purification, handling, storage, formulation, expiration date, and general use of these compounds.

Background. Obesity is related to dyslipidemia and increased circulating oxidated LDL (ox-LDL) concentrations that may predispose to atherosclerosis. Bariatric surgery may lower the risk of cardiovascular mortality. Elevated plasma ox-LDL has been associated with atherogenesis and atherosclerotic cardiovascular disease (ASCVD) events. The aim of this meta-analysis was to investigate the impact of bariatric surgery on proatherogenic circulating ox-LDL levels in patients with severe obesity. Methods. Four databases were systematically searched from inception to May 1, 2021. Also, to clarify the heterogeneity of studies with regard to treatment duration, research design, and the demographic features, a random-effects model and the generic inverse variance weighting approach were utilized. To determine the association with the estimated effect size, a random-effect meta-regression approach was performed. Finally, a meta-regression analysis was conducted to explore the influence of, respectively, baseline and changes in body mass index (BMI), baseline ox-LDL, and postsurgery follow-up period with the estimated effect size of surgery on ox-LDL levels. Results. Meta-analysis of 11 studies including 470 subjects showed a significant decline in circulating ox-LDL following bariatric surgery (SMD: -0.971, 95% CI: -1.317, -0.626, , : 89.43%). The results of meta-regression did not show any significant association between the changes in ox-LDL after bariatric surgery and baseline BMI, duration of follow-up or baseline ox-LDL values. However, there was a significant association between ox-LDL alteration and percentage of BMI change. Conclusion. Bariatric surgery in patients who had severe obesity causes a decrease of circulating ox-LDL that was apparently dependent in BMI changes.

Oxidative stress is a key pathological feature implicated in both acute and chronic liver diseases, including drug-induced liver injury (DILI). The latter describes hepatic injury arising as a direct toxic effect of administered drugs or their metabolites. Although still underreported, DILI remains a significant cause of liver failure, especially in developed nations. Currently, it is understood that mitochondrial-generated oxidative stress and abnormalities in phase I/II metabolism, leading to glutathione (GSH) suppression, drive the onset of DILI. N-Acetyl cysteine (NAC) has attracted a lot of interest as a therapeutic agent against DILI because of its strong antioxidant properties, especially in relation to enhancing endogenous GSH content to counteract oxidative stress. Thus, in addition to updating information on the pathophysiological mechanisms implicated in oxidative-induced hepatic injury, the current review critically discusses clinical evidence on the protective effects of NAC against DILI, including the reduction of patient mortality. Besides injury caused by paracetamol, NAC can also improve liver function in relation to other forms of liver injury such as those induced by excessive alcohol intake. The implicated therapeutic mechanisms of NAC extend from enhancing hepatic GSH levels to reducing biomarkers of paracetamol toxicity such as keratin-18 and circulating caspase-cleaved cytokeratin-18. However, there is still lack of evidence confirming the benefits of using NAC in combination with other therapies in patients with DILI.

Lactobacillus plantarum ZS62 is a newly isolated strain from naturally fermented yogurt that might offer some beneficial effects in the setting of alcohol-induced subacute liver injury. The liver-protective effect of L. plantarum ZS62 was investigated by gavage feeding of mice with this Lactobacillus strain ( CFU/kg _BW) before alcohol administration daily for 7 days. We then compared hepatic morphology, liver function indexes, liver lipid levels, inflammation, oxidative stress levels, and mRNA expression of oxidative metabolism- and inflammation-related genes in mice that had been pretreated with Lactobacillus plantarum versus control mice that had not been pretreated. Our results showed that L. plantarum ZS62 attenuated alcohol-induced weight loss; prevented morphological changes in hepatocytes; reduced markers of liver damage including aspartate aminotransaminase (AST), alanine aminotransaminase (ALT), hyaluronidase (HAase), precollagen III (PC III), and inflammatory cytokines; and enhanced the antioxidative status. L. plantarum ZS62 also significantly downregulated inflammation-related genes and upregulated lipid- and oxidative-metabolism genes. Thus, Lactobacillus plantarum pretreatment appears to confer hepatic protection by reducing inflammation and enhancing antioxidative capacity. The protective effect of L. plantarum ZS62 was even better than that of a commonly used commercial lactic acid bacteria (Lactobacillus delbrueckii subsp. Bulgaricus). The L. plantarum ZS62 might be a potentially beneficial prophylactic treatment for people who frequently drink alcoholic beverages.

Colorectal cancer (CRC) is a highly malignant tumor associated with poor prognosis, yet the molecular mechanisms are not fully understood. In this study, we showed that LYAR, a nucleolar protein, is expressed at a higher level in CRC tissue than in adjacent normal tissue and that LYAR expression is closely associated with distant CRC metastasis. LYAR not only significantly promotes the migration and invasion of CRC cells in vitro, but knockdown (KD) of LYAR in CRC cells also inhibits xenograft tumor metastasis in vivo. Microarray analysis of LYAR KD cells combined with a chromatin immunoprecipitation (ChIP) assay, gene reporter assay, and rescue experiment indicated that FSCN1 (encoding fascin actin-bundling protein 1 (Fascin-1)) serves as a novel key regulator of LYAR-promoted migration and invasion of CRC cells. Knockdown of FSCN1 significantly inhibits subcutaneous tumorigenesis of CRC cells and leads to the downregulation of FASN and SCD, genes encoding key enzymes in fatty acid synthesis. In summary, this study reveals a novel mechanism by which LYAR promotes tumor cell migration and invasion by upregulating FSCN1 expression and affecting fatty acid metabolism in CRC.

Background. Peripheral arterial disease (PAD) is a typical disease of atherosclerosis, most commonly influencing the lower extremities. In patients with PAD, revascularization remains a preferred treatment strategy. Buyang Huanwu decoction (BHD) is a popular Chinese herbal prescription which has showed effects of cardiovascular protection through conducting antioxidant, antiapoptotic, and anti-inflammatory effects. Here, we intend to study the effect of BHD on promoting revascularization via the Akt/GSK3β/NRF2 pathway in diabetic hindlimb ischemia (HLI) model of mice. Materials and Methods. All db/db mice () were randomly divided into 6 groups by table of random number. (1) Sham group (): 7-0 suture thread passed through the underneath of the femoral artery and vein without occlusion. The remaining 5 groups were treated differently on the basis of the HLI (the femoral artery and vein from the inguinal ligament to the knee joint were transected and the vascular stump was ligated with 7-0 silk sutures) model: (2) HLI+NS group (): 0.2 ml NS was gavaged daily for 3 days before modeling and 14 days after occlusion; (3) HLI+BHD group (): 0.2 ml BHD (20 g/kg/day) was gavaged daily for 3 days before modeling and 14 days after occlusion; (4) HLI+BHD+sh-NC group (): local injection of adenovirus vector carrying the nonsense shRNA (Ad-GFP) in the hindlimbs of mice before treatment; (5) HLI+BHD+sh-NRF2 group (): knockdown of NRF2 in the hindlimbs of mice by local intramuscular injection of adenovirus vector carrying NRF2 shRNA (Ad-NRF2-shRNA) before treatment; and (6) HLI+BHD+LY294002 group (): intravenous injection of LY294002 (1.5 mg/kg) once a day for 14 days on the basis of the HLI+BHD group. Laser Doppler examination, vascular cast, and immunofluorescence staining were applied to detect the revascularization of lower limbs in mice. Western blot analysis was used to detect the expression of vascular endothelial growth factor (VEGF), interleukin-1beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor- (TNF-) α, heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase quinone-1 (NQO-1), catalase (CAT), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphorylated protein kinase B (p-AKT), and phosphorylated glycogen synthase kinase-3 beta (p-GSK3β). HE staining was used to assess the level of muscle tissue damage and inflammation in the lower extremities. Local multipoint injection of Ad-NRF2-shRNA was used to knock down NRF2, and qPCR was applied to detect the mRNA level of NRF2. The blood glucose, triglyceride, cholesterol, MDA, and SOD levels of mice were tested using corresponding kits. The SPSS 20.0 software and GraphPad Prism 6.05 were used to do all statistics. Values of were considered as statistically significant. Results and Conclusions. BHD could enhance the revascularization of lower limbs in HLI mice, while BHD has no effect on blood glucose and lipid level in db/db mice (). BHD could elevate the protein expression of VEGF, HO-1, NQO-1, and CAT () and decrease the expression of IL-1β, IL-6, and TNF-α () in HLI mice. Meanwhile, BHD could activate NRF2 and promote the phosphorylation of AKT/GSK3β during revascularization (). In contrast, knockdown of NRF2 impaired the protective effects of BHD on HLI (). LY294002 inhibited the upregulation of NRF2 activated by BHD through inhibiting the phosphorylation of the AKT/GSK3β pathway (). The present study demonstrated that BHD could promote revascularization on db/db mice with HLI through targeting antioxidation, anti-inflammation, and angiogenesis via the AKT/GSK3β/NRF2 pathway.