Systemic Oxidative Stress Research Articles

Dynamics of oxidative stress and immune responses in neonatal calves during diarrhea

Oxidative stress is the imbalanced redox status between oxidant production and their scavengers leading to intestinal physiological dysfunction. However, the role of systemic and local oxidative status during neonatal calf diarrhea is not known. This study assessed systemic (serum) and local (fecal) oxidative status when calves either naturally developed diarrhea or naturally recovered. Healthy calves were enrolled in the study at d 18 of age, and their health status was monitored from the enrollment. Based on their enteric health status on d 21 and 28, calves were grouped as continuous diarrhea from d 21 to 28 (n = 14), diarrhea at d 21 but recovered at d 28 (DH group, n = 19), healthy at d 21 but developed diarrhea at d 28 (HD group, n = 15), and healthy throughout the study (HH group, n = 16). Serum and fecal samples were collected at d 21 and 28 from all calves in the morning 2 h after feeding. Dynamics of oxidative stress indicators including reactive oxygen species (ROS), malondialdehyde (MDA), H2O2, 8-hydroxy-2'-deoxyguanosine (8-OHDG), glutathione peroxidase, superoxide dismutase, catalase (CAT), and total antioxidant capacity and inflammatory indicators TNF-α, IL-1β, IL-4, IL-6, IL-10, and IFN-γ were evaluated using serum samples. In addition, fecal oxidative stress indicators ROS and MDA were measured. Serum ROS, MDA, 8-OHDG, as well as fecal ROS and MDA, were higher, whereas serum CAT and H2O2 were lower in diarrheic calves than those of healthy calves. Serum ROS, MDA, and 8OHDG and fecal ROS and MDA increased in the HD group from d 21 to 28 as they developed diarrhea. In contrast, all these oxidative stress markers decreased in the DH group from d 21 to 28 as they recovered. However, serum H2O2 had an opposite changing trend, which became lower in the HD group and higher in the DH group at d 28. In conclusion, both systemic and local oxidative stress markers and cytokine profiles altered as calves moved from being healthy to having diarrhea or vice versa. Serum ROS, MDA, and 8-OHDG can be used to develop biomarkers to screen calves prone to enteric infections during the preweaning period.

Arsenic exposure and lung function decline in chronic obstructive pulmonary disease patients: The mediating influence of systematic inflammation and oxidative stress

Lung tissue is one of the target sites of arsenic (As). The goal of this investigation was to assess the associations of blood As concentration with pulmonary function indicators in patients with chronic obstructive pulmonary disease (COPD), as well as the roles of systemic inflammation and oxidative stress in this relationship. All 791 COPD patients were selected. Blood As concentration, and tumour necrosis factor-α (TNF-α) and 8-iso-prostaglandin-F2α (8-iso-PGF2α) were detected in the serum of COPD cases. Blood As was robustly related to pulmonary function parameters in an inverse dose-dependent manner. Multivariate linear regression analyses verified that a 1-unit increase of blood As was linked to declines of 0.263 L in FVC, 0.288 L in FEV1, 3.454 in FEV1/FVC%, and 0.538 in predicted FEV1%, respectively. The potential for pulmonary function decline gradually increased across the elevated tertiles of blood As. Nonsmokers were susceptible to As-induced pulmonary function reduction. Blood As was positively linked to the levels of TNF-α and 8-iso-PGF2α. Increased TNF-α and 8-iso-PGF2α partially mediated As-induced the reductions in FEV1 and FVC among COPD patients. As exposure is intensely linked to pulmonary function reduction. Systematic inflammation and oxidative stress partially mediate such associations in COPD patients.

Impact on oxidative stress of oral, high-dose, iron supplementation for management of iron deficiency after bariatric surgery, a preliminary study

ObjectivesHigh-dose oral iron supplementation for patients who develop iron deficiency after bariatric surgery may induce oxidative stress in the gastrointestine. The study’s objective was to test this hypothesis by determining the impact of high-dose oral iron on systemic oxidative stress. MethodsWe used archived plasma samples from a randomized controlled clinical trial (NCT 02404012) comparing FeSO4 (195 mg/day, NatureMade®, West Hills, CA) with a heme iron polypeptide (HIP, 60.4 mg/day, Proferrin®, Colorado Biolabs, Lafayette, CO) for 8 weeks. Systemic oxidative stress was measured using malondialdehyde and total antioxidant capacity (MDA, Abcam, ab238537 and TAC, Abcam, ab65329 Cambridge, UK) assays. Data was log-transformed and presented as means and standard deviations; a mixed model was used to determine the effects of time (0, 2, 4, and 8 weeks) and treatment (FeSO4 versus HIP) on oxidative stress. ResultsThe FeSO4 (N = 8) and HIP (N = 5) participants were balanced in body mass index (35.0 ± 5.5 kg/m2), race (93 % White), time post-surgery (7.3 ± 3.3 years), as well as serum concentrations of iron (P > 0.05). The FeSO4 group tended to be older (44.3 ± 4.5 years) and they had lower concentrations of serum ferritin (6.5 ± 2.7 µg/mL) than the HIP (38.2 ± 9.3 years, and 12.9 ± 16.8 µg/mL) group (P = 0.080, and P = 0.017 respectively). We observed a larger increase in serum iron in the FeSO4 group during the 8 weeks of Fe supplementation, compared to that in the HIP group (p = 0.004). We observed a decreasing trend in MDA over the 8 weeks (p = 0.080) in the FeSO4 treatment group. There were no significant differences in TAC between and within FeSO4 and HIP groups over the 8 week supplementation period. ConclusionsThis preliminary study suggests that high-dose oral iron supplementation for iron deficiency does not adversely impact systemic oxidative stress in patients undergoing bariatric surgery.

Antioxidative effects of vitamin D in muscle dysfunction

Graphical abstract Abstract Pathological conditions characterized by systemic inflammation and oxidative stress can often impair the muscle cells efficiency. The gradual decline of muscle mass and tone drastically reduces the motor skills of the patient affecting the simplest daily activities. Muscle dysfunction, resulting in the deterioration of muscle tissue, can lead to a serious situation of muscle wasting that can evolve into sarcopenia. In addition, muscle dysfunction causing metabolic disorders impairs the quality of life. The function of skeletal muscle is deeply conditioned by environmental, nutritional, physical, and genetic factors. Proper nutrition with balanced protein and vitamins intake and an active lifestyle helps to strengthen tissues and counteract pathological conditions and generalized weakness. Vitamin D performs antioxidant actions, indispensable in skeletal muscle. Epidemiological data indicate that vitamin D deficiency is a widespread status in the world. Vitamin D deficiency induces mitochondrial failure, reduced production of adenosine triphosphate, oxidative injury, and compromised muscle function. Among the different types of antioxidants, vitamin D has been identified as the main compound that can improve the effectiveness of the treatment for muscle weakness and improve conditions related to sarcopenia. The purpose of this review is to analyze molecular processes used by vitamin D against oxidative stress and how it can affect muscle function in order to assess whether its use as a supplement in inflammatory pathologies and oxidative stress can be useful to prevent deterioration and improve/maintain muscle function.

Sirtuin 3 mitigates oxidative-stress-induced apoptosis in bovine mammary epithelial cells

Ketosis is often accompanied by a reduction in milk production in dairy cows, but the molecular mechanism has not been fully elucidated. Ketotic cows possess systemic oxidative stress (OS), which may implicate apoptosis in mammary glands. Sirtuin 3 (SIRT3) is a vital regulator of cellular redox homeostasis and is under the control of AMP-activated protein kinase (AMPK) signaling in nonruminants. Thus, we aimed to investigate (1) the AMPK-SIRT3 and apoptosis status of mammary glands from ketotic cows, (2) the effect of SIRT3 on OS-induced apoptosis in bovine mammary epithelial cells (BMEC), and (3) the role of AMPK signaling on SIRT3-mediated effects on apoptosis. Mammary gland samples were reused from a previous study, which contained healthy and ketotic cows (both n = 15). BMEC were incubated with 0, 0.3, 0.6, or 0.9 mM H2O2 for 6 h with/without a 30 min incubation of an antioxidant MitoQ (1 μM). Then BMEC were incubated with SIRT3 overexpression adenovirus (Ad-SIRT3) for 6 h followed by a 6 h incubation with 0.6 mM H2O2. Finally, BMEC were treated with the AMPK inhibitor Compound C (Cd C,10 μM) for 30 min before the H2O2 challenge, or cells were initially treated with the AMPK agonist MK8722 (10 μM) for 30 min followed by a 30-h culture with/without si-SIRT3 and eventually the H2O2 exposure. Ketotic cows displayed higher levels of Bax, Caspase-3 and Bax/Bcl-2 but lower levels of Bcl-2 in mammary glands. H2O2 incubation displayed similar results, exhibiting a dose-dependent manner between the H2O2 concentration and the apoptosis degree. Mito Q pretreatment reduced cellular reactive oxygen species and rescued cells from apoptosis. Ketotic cows had a lower mammary protein abundance of SIRT3. Similarly, H2O2 incubation downregulated both mRNA and protein levels of SIRT3 in a dose- and time-dependent manner. Ad-SIRT3 infection lowered levels of cellular reactive oxygen species, Bax, Caspase-3 and Bax/Bcl-2 but increased levels of Bcl-2. TUNEL assays confirmed that Ad-SIRT3 infection mitigated H2O2-induced apoptosis. Both ketotic cows and H2O2-induced BMEC had lower levels of p-AMPK and p-AMPK/AMPK. Additionally, Cd C pretreatment decreased SIRT3 and Bcl-2 expression but increased levels of Bax and Caspase-3. Contrary to the inhibitor, MK8722 had opposite effects and reduced the percentage of apoptotic cells. However, these effects of MK8722 were reversed upon SIRT3 silencing. In conclusion, in vivo data confirmed that ketosis is associated with greater apoptosis and restricted AMPK-SIRT3 signaling in mammary glands; in vitro data indicated that SIRT3 mitigates OS-induced apoptosis via AMPK signaling. As such, there may be potential benefits for targeting the AMPK-SIRT3 axis to help counteract the negative effects of mammary glands during ketosis.

Multiple ammonia-induced episodes of hepatic encephalopathy provoke neuronal cell loss in bile-duct ligated rats

Hepatic encephalopathy (HE) is defined as a reversible syndrome and therefore should resolve following liver transplantation (LT). However, neurological complications have been reported in up to 47% of LT recipients, which have been documented to be associated with a history of overt HE pre-LT. We hypothesise that multiple episodes of HE lead to permanent cell injury and exacerbate neurological dysfunction. Our goal was to evaluate the impact of cumulative HE episodes on neurological status and brain integrity in rats with chronic liver disease. Episodes of overt HE (loss of righting reflex) were induced following injection of ammonium acetate in bile duct ligation (BDL) rats (BDL-Ammonia) every 4 days starting at week 3 post-BDL. Neurobehaviour was evaluated after the last episode. Upon sacrifice, plasma ammonia, systemic oxidative stress, and inflammation markers were assessed. Neuronal markers including neuron-specific nuclear antigen and SMI311 (anti-neurofilament marker) and apoptotic markers (cleaved caspase-3, Bax, and Bcl2) were measured. Total antioxidant capacity, oxidative stress marker (4-hydroxynonenal), and proinflammatory cytokines (tumour necrosis factor-alpha and interleukin-1β) were measured in brain (hippocampus, frontal cortex, and cerebellum). Proteomic analysis was conducted in the hippocampus. In hippocampus of BDL-Ammonia rats, cleaved caspase-3 and Bax/Bcl2 ratio were significantly increased, whereas NeuN and SMI311 were significantly decreased compared with BDL-Vehicle rats. Higher levels of oxidative stress-induced post-translational modified proteins were found in hippocampus of BDL-Ammonia group which were associated with a lower total antioxidant capacity. Ammonia-induced episodes of overt HE caused neuronal cell injury/death in BDL rats. These results suggest that multiple bouts of HE can be detrimental on the integrity of the brain, translating to irreversibility and hence neurological complications post-LT. Hepatic encephalopathy (HE) is defined as a reversible neuropsychiatric syndrome resolving following liver transplantation (LT); however, ∼47% of patients demonstrate neurological impairments after LT, which are associated with a previous history of overt HE pre-LT. Our study indicates that multiple episodes of overt HE can cause permanent neuronal damage which may lead to neurological complications after LT. Nevertheless, preventing the occurrence of overt HE episodes is critical for reducing the risk of irreversible neuronal injury in patients with cirrhosis.

ФЕНОТИП ВИБРАЦИОННОЙ БОЛЕЗНИ В СОЧЕТАНИИ С АРТЕРИАЛЬНОЙ ГИПЕРТЕНЗИЕЙ: НОВЫЕ МИШЕНИ НУТРИТИВНО-МЕТАБОЛИЧЕСКИХ НАРУШЕНИЙ

Introduction. Comorbidity in the modern world is a predictor of a more severe course of most diseases and has a significant impact on the characteristics, course and outcomes of the disease in the structure of occupational pathology. This is characterized by an increase in clinical syndromes, a deterioration in the quality of life and disability. Purpose of the study. Optimization of diagnostics in the form of studying clinical, functional and nutritional and metabolic parameters in professional patients on a model of comorbid pathology of vibration disease in combination with arterial hypertension. Materials and methods. In the course of a single-stage open, descriptive, comparative clinical study, 431 patients were examined in the conditions of the regional center of professional pathology in the city of Novosibirsk. Patients were divided into groups: patients with isolated vibration disease (n = 104), a group of comorbid WB+AH model (n = 101), a comparison group were patients with arterial hypertension (107 patients), a control group of conditionally healthy individuals (119 people) . The study duration was 4.9 ± 0.25 years. The indicators of the main analyzers, nutritional and metabolic status, nutritional adequacy, indicators of protein, lipid, carbohydrate metabolism, adipokine status, blood 25OH vitamin D, indicators of endothelial dysfunction, RAAS components, oxidative stress and systemic inflammation were evaluated. Results and its discussion. With VP+AH, the most unfavorable metabolic status was revealed. In this group, higher levels of insulin, glycated hemoglobin, HOMA-IR index, total cholesterol, LDL, triglycerides, atherogenic coefficient were determined in comparison with the isolated WB group and the control group, respectively. The phenotype of WB and AH shows the highest concentration of resistin, significantly higher than in the comparison and control groups, against the background of low levels of adiponectin, as well as an increase in the level of free leptin against the background of a decrease in the leptin-binding receptor. In the course of bioimpedancemetry, significant deviations were found in the group of the comorbid model of HF in combination with AH in the following indicators: an increase in fat mass normalized for growth and extracellular fluid with a decrease in the parameters of lean and active cell mass and phase angle. In the group of the comorbid model of WB and AH, changes were also detected in the following indicators of the molecular endotype: an increase in markers of oxidative stress (total antioxidant status of serum, Cu/ZnSOD, concentration of free radicals, lipid peroxides, protein oxidation products), the RAAS system, markers of endothelial dysfunction (endothelin 1, nitric oxide, tissue factor) and systemic inflammation (IL1 β, MCP-1, FGF 2, cardiotrophin, MMP 1, MMP 9, pentraxin 3, neutrophil elastase). Conclusions. A variant of the comorbid model is characterized by clinical-molecular and nutritional-metabolic features in professional patients, which are caused by a multifactorial pathomorphosis of a combination of vibration disease and arterial hypertension. In this variant, indicators of worse metabolic and adipokine status relative to the compared groups, pronounced processes of systemic inflammation, oxidative stress, and endothelial dysfunction were revealed.

A standardized nutraceutical supplement contributes to pain relief, improves quality of life and regulates inflammation in knee osteoarthritis patients; A randomized clinical trial

Osteoarthritis (OA) is a degenerative disease of the joints that affects greatly the elderly population and the health care systems and is on the increase due to aging and obesity. Interventions aim at palliative care and pharmaceutical therapies entail serious adverse events. Whereas polyphenols constitute a promising holistic approach in the arsenal of physicians, trials investigating biomarkers and questionnaires are scarce. As such, a randomized controlled trial (RCT) was conducted to evaluate the potency of a standardized polyphenolic supplement in the management of systemic inflammation, oxidative stress, pain and general quality of life (QoL) in patients with osteoarthritis. Sixty subjects were randomized to receive either a polyphenol supplement (curcuma phospholipid, rosemary extract, resveratrol, ascorbic acid), or an active comparator (ascorbic acid) twice, daily for 12 weeks. The group that received the polyphenols exhibited significantly lower symptoms of pain and improved physical function and QoL as it was depicted by validated questionnaires, compared to the control group. Furthermore, post intervention, inflammation was restrained in the polyphenol group. Since systemic inflammation promotes local inflammation, the decrease of pain herein might be attributed to the attenuation of systemic inflammation by the polyphenols.

Preliminary Comparison of Molecular Antioxidant and Inflammatory Mechanisms Determined in the Peripheral Blood Granulocytes of COVID-19 Patients.

The aim of this study was to evaluate selected parameters of redox signaling and inflammation in the granulocytes of COVID-19 patients who recovered and those who died. Upon admission, the patients did not differ in terms of any relevant clinical parameter apart from the percentage of granulocytes, which was 6% higher on average in those patients who died. Granulocytes were isolated from the blood of 15 healthy people and survivors and 15 patients who died within a week, and who were selected post hoc for analysis according to their matching gender and age. They differed only in the lethal outcome, which could not be predicted upon arrival at the hospital. The proteins level (respective ELISA), antioxidant activity (spectrophotometry), and lipid mediators (UPUPLC-MS) were measured in the peripheral blood granulocytes obtained via gradient centrifugation. The levels of Nrf2, HO-1, NFκB, and IL-6 were higher in the granulocytes of COVID-19 patients who died within a week, while the activity of cytoplasmic Cu,Zn-SOD and mitochondrial Mn-SOD and IL-2/IL-10 were lower in comparison to the levels observed in survivors. Furthermore, in the granulocytes of those patients who died, an increase in pro-inflammatory eicosanoids (PGE2 and TXB2), together with elevated cannabinoid receptors 1 and 2 (associated with a decrease in the anti-inflammatory 15d-PGJ2), were found. Hence, this study suggests that by triggering transcription factors, granulocytes activate inflammatory and redox signaling, leading to the production of pro-inflammatory eicosanoids while reducing cellular antioxidant capacity through SOD, thus expressing an altered response to COVID-19, which may result in the onset of systemic oxidative stress, ARDS, and the death of the patient.

Preventive effects of Capparis Spinose extract on experimental periodontitis in rats: a histopathological and biochemical study.

This study aimed to assess the effectiveness of Capparis Spinose (CS) in preventing the initiation and progression of experimental periodontitis and to evaluate the effect of its on systemic oxidative stress in rats by experimental periodontitis model. Twenty-four male rats were equally divided into; Ligatured (L), non-ligatured (NL), and Ligatured with CS (11 days/day per 20 mg/kg) (LC) groups. Experimental periodontitis was induced with the silk suture technic. Alveolar bone loss was examined, and total antioxidant capacity(TAOC), total oxidant status(TOS), and oxidative stress index(OSI) were analyzed in rat serum. Although; alveolar bone loss showed statistically significant lower values in the LC group compared to L (p < 0.05), not NL. In the LC group, osteoclast and osteoblast numbers were statistically significant compared to L, but there were no statistical differences between LC and NL. Serum TAOC levels were significantly lower in group L compared to others and also LC group showed significant differences from NL. TOS and OSI levels were significantly higher in group L than in other groups. Within the limitation of the present study, it can be said that the destruction via local inflammation that may occur after the experimental periodontitis can be prevented by using CS.

Omega-3 Fatty Acids and COVID-19: Prevention or Adjuvant Therapy?

The mechanisms of COVID-19 complications are multifactorial, including long-term tissue dam-ages from direct viral attack, dysregulation of both immunity and renin-angiotensin-aldosterone system and coagulation system, unresolved systemic inflammation and oxidative stress. Omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) might have favorable effects on immunity, inflammation, oxidative stress at different stages of SARS-CoV-2 infection. Omega-3 and their metabolites including specialized proresolvin mediators, have shown effects in reducing pro-inflammatory cytokines, accelerating the resolution of chronic inflammation and restoring tissue homeostasis, and therefore offer a promising strategy against COVID-19. This article will discuss the inflammatory condition during COVID-19 pandemic, focus on the mechanisms that may contribute to the likely benefits of omega-3 and provide potential recommendations to pro-mote strategies for wellness.

Fish oil omega-3 Fatty Acids Alleviate Postoperative delirium-like Behavior in aged mice by Attenuating Neuroinflammation and Oxidative Stress.

Postoperative delirium (POD) is a common and serious neuropsychiatric syndrome among older patients, and lacks effective therapies. Omega-3 fatty acids, possessing anti-inflammatory and antioxidant properties, have shown potent neuroprotective effects in several diseases. The present study investigated whether omega-3 fatty acids could exert a neuroprotective role against POD in aged mice. A mouse model of POD was established to explore the role of omega-3 fatty acids in laparotomy-induced delirium-like behavior by evaluating systemic inflammatory changes, neuroinflammation, oxidative stress, and behavior at different time points in aged mice. Oral gavage with omega-3 fatty acids (300mg/kg) for 3 weeks before surgery significantly attenuated anesthesia/surgery-induced POD-like behavior and the accumulation of proinflammatory cytokines from the peripheral blood in aged mice. Moreover, it also remarkably mitigated neuroinflammation and the oxidative stress response (malondialdehyde [MDA] and superoxide dismutase [SOD]) in the prefrontal cortex and hippocampus of surgical mice. Our findings provided evidence that pretreatment with omega-3 fatty acids may play a vital role in the treatment of POD through mechanisms involving its anti-inflammatory and antioxidant effects, which may be a promising prevention strategy for POD in aged patients.

Pan-Nox inhibitor treatment improves renal function in aging murine diabetic kidneys.

Aging is a risk factor for development of chronic kidney disease and diabetes mellitus with commonly shared features of chronic inflammation and increased oxidative stress. Here, we investigated the effect of pan-Nox-inhibitor, APX-115, on renal function in aging diabetic mice. Diabetes was induced by intraperitoneal injection of streptozotocin at 50 mg/kg/day for 5 days in 52-week-old C57BL/6J mice. APX-115 was administered by oral gavage at a dose of 60 mg/kg/day for 12 weeks in nondiabetic and diabetic aging mice. APX-115 significantly improved insulin resistance in diabetic aging mice. Urinary level of 8-isoprostane was significantly increased in diabetic aging mice than nondiabetic aging mice, and APX-115 treatment reduced 8-isoprostane level. Urinary albumin and nephrin excretion were significantly higher in diabetic aging mice than nondiabetic aging mice. Although APX-115 did not significantly decrease albuminuria, APX-115 markedly improved mesangial expansion, macrophage infiltration, and expression of fibrosis molecules such as transforming growth factor beta 1 and plasminogen activator inhibitor 1. Interestingly, the expression of all Nox isoforms including Nox1, Nox2, and Nox4 was significantly increased in diabetic aging kidneys, and APX-115 treatment decreased Nox1, Nox2, and Nox4 protein expression in the kidney. Furthermore, Klotho expression was significantly decreased in diabetic aging kidneys, and APX-115 restored Klotho level. Our results provide evidence that pan-Nox inhibition may improve systemic insulin resistance and decrease oxidative stress, inflammation, and fibrosis in aging diabetic status and may have potential protective effects on aging diabetic kidney.

Higher oxidative balance scores are associated with lower nonalcoholic fatty liver disease and not with fibrosis in US adults

Background and aimsLittle research have focused on the relationship between systemic oxidative stress status and NAFLD and fibrosis. The Oxidative Balance Score (OBS) is employed to evaluate whole-body lifestyle and diet exposures related to oxidative stress, with higher OBS scores implying exposure to more antioxidants. This study aimed to explore whether OBS is correlated with NAFLD and NAFLD-related fibrosis. Methods and results12,223 participants from NHANES 2003–2018 were enrolled in this study. NAFLD was defined as USFLI ≥30 and liver fibrosis was determined as FIB-4 ≥ 2.67. OBS was scored by 20 lifestyle and dietary factors. Weighted logistic regression and restricted cubic splines were used to assess the association between OBS and NAFLD and fibrosis. The prevalence of NAFLD was 29.67%. There was a significant negative correlation between OBS, dietary OBS, lifestyle OBS and NAFLD and no correlation with NAFLD-related fibrosis. Compared to the lowest quartile, the adjusted ORs for the highest quartile of OBS, lifestyle OBS, dietary OBS and NAFLD were 0.55(95%CI:0.35,0.85), 0.12(95%CI:0.08,0.16), 0.70(95%CI:0.52,0.94) respectively. In stratified analyses, lifestyle OBS was negatively associated with NAFLD across gender, dietary OBS was only negatively correlated with NAFLD in men, and any OBS was not observed to be relevant to NAFLD-related fibrosis. ConclusionsOBS was negatively associated with NAFLD, but not with NAFLD-related fibrosis. The findings underline the significance of adhering to an antioxidant lifestyle and diet, which can help prevent NAFLD but seems to be ineffective in preventing fibrosis in individuals with NAFLD.

Serum Oxidative and Nitrosative Stress Markers in Clear Cell Renal Cell Carcinoma.

Oxidative stress is believed to be a factor in the development and progression of renal cell carcinoma (RCC). The identification of the oxidative and nitrosative modification of proteins and the definition of their roles in clear cell RCC (ccRCC) may be helpful in the elaboration of targeted therapeutic approaches to mitigate protein damage. This study aimed to investigate the status of oxidative/nitrosative stress and to explore its role in the development and progression. The studied group consisted of 48 newly diagnosed ccRCC and 30 healthy controls. Serum levels of oxidative stress markers-advanced oxidation protein products (AOPP), thiol groups, Amadori reaction products, 3-nitrotyrosine, nitrate/nitrite, malondialdehyde (MDA), 4-hydroxy-2-nonenal and total antioxidant capacity (TAC)-were determined. Additionally, associations between tumour stage assessed according to TNM classification, histological grade, and the effect of the presence of angioinvasion on the level of stress markers were evaluated. The levels of Amadori products, 3-nitrotyrosine, and nitrate/nitrite were elevated, while the levels of thiol groups and TAC decreased in the ccRCC group. The levels of AOPP, Amadori, and 3-nitrotyrosine increased, and thiol groups and TAC levels decreased with the increasing pathological stage of the tumour. In the case of advanced histological assessment of the tumour, we found decreasing levels of thiol groups and increasing levels of MDA. In patients with angioinvasion, nitrate/nitrite and MDA levels were significantly elevated compared to those in patients without angioinvasion. Oxidative stress increased with the progression of the disease assessed according to the TNM and histological grade. These results demonstrate systemic oxidative stress in ccRCC, suggesting the therapeutic application of antioxidants.

Metal-phenolic capsules with ROS scavenging reshape the oxidative microenvironment of atherosclerosis

Arterial injury makes the tissue in a state of high oxidative stress. At the same time, abnormal lipid metabolism can further lead to bleeding and thrombosis. Therefore, the anti-inflammatory and anti-oxidant polyphenol, EGCG was organically complexed with Fe3+ to form a metal-phenolic framework carrier. And the antihyperlipidemic drug, atorvastatin (ATV) was loaded into the carrier to enhance the bioavailability, and simultaneously alleviate the oxidative stress of the inflammatory site and abnormal lipid metabolism. The results confirmed that the obtained material EGCG-Fe-ATV had good biocompatibility and biosafety effect. In addition, EGCG-Fe-ATV showed outstanding anti-inflammatory, anti-oxidant and lipid-lowering properties. These therapeutic outcomes of EGCG-Fe-ATV were achieved by reducing systemic and local oxidative stress and inflammation, alleviating inflammatory cell infiltration in plaques, and modulating lipid synthesis and transferase to alter cholesterol transport. In conclusion, the combination of metal-phenolic capsules with ATV provides a new strategy for reshaping the oxidative microenvironment of atherosclerosis.

PAK2/beta-catenin/c-Myc/PKM2 signal transduction suppresses ovarian granulosa cell apoptosis in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) exhibits the highest morbidity among endocrine diseases in women ranging from age 18 to 44. However, its pathogenesis remains unclear. The imbalance between systemic and ovarian oxidative stress (OS) is a key characteristic of PCOS, and accumulating evidence indicates that the antioxidative protein nuclear factor erythroid-2-related factor 2 (Nrf2) is implicated in cell apoptosis and inflammation caused by OS. The activated kinase 2 (PAK2)/-catenin/c-Myc/pyruvate kinase M2 (PKM2) axis is a newly identified signaling pathway that may regulate Nrf2 expression and thereby influence OS. In this study, we sought to identify PAK2 expression and function in PCOS cells. PAK2 and downstream PKM2 expression in KGN cells and tissues were detected by microarray and qPCR. Cell viability was determined using CCK-8 and colony formation assays (CFAs). Apoptosis was examined by flow cytometry. qPCR and ELISA were used to examine cell inflammation. Oxidant and OS-related enzymes were examined by ELISA. We found that PAK2 and PKM2 expression levels were reduced in KGN cells and PCOS ovarian cortex tissues. PAK2 overexpression activated β-catenin/c-Myc/PKM2 while PAK2 silencing deactivated it. PAK2 overexpression was reduced, whereas PAK2 silencing promoted, KGN cell proliferation and colony formation. Cell apoptosis and inflammation were also induced by PAK2 overexpression but were alleviated by its silencing. Furthermore, increased peroxidation product levels decreased antioxidative protein activities, and deactivated antioxidative Nrf2/HO-1 pathway were detected in PAK2-overexpressing KGN cells, whereas these effects were counteracted in PAK2 silenced cells. Our data suggest that PAK2 and its associated β-catenin/c-Myc/PKM2 inhibited cell viability and induced apoptosis and inflammation by triggering OS by deactivating the Nrf2/HO-1 pathway, suggesting the potential of PAK2 as a therapeutic PCOS treatment target.

Alterations of hepatic energy metabolism in murine models of obesity, diabetes and fatty liver diseases.

Disturbed hepatic energy metabolism contributes to non-alcoholic fatty liver (NAFLD), but the development of changes over time and obesity- or diabetes-related mechanisms remained unclear. Two-day old male C57BL/6j mice received streptozotocin (STZ) or placebo (PLC) and then high-fat (HFD) or regular chow diet (RCD) from week 4 (W4) to either W8 or W16, yielding control [CTRL=PLC+RCD], diabetes [DIAB=STZ+RCD], obesity [OBES=PLC+HFD] and diabetes-related non-alcoholic steatohepatitis [NASH=STZ+HFD] models. Mitochondrial respiration was measured by high-resolution respirometry and insulin-sensitive glucose metabolism by hyperinsulinemic-euglycemic clamps with stable isotope dilution. NASH showed higher steatosis and NAFLD activity already at W8 and liver fibrosis at W16 (all p<0.01 vs CTRL). Ballooning was increased in DIAB and NASH at W16 (p<0.01 vs CTRL). At W16, insulin sensitivity was 47%, 58% and 75% lower in DIAB, NASH and OBES (p<0.001 vs CTRL). Hepatic uncoupled fatty acid oxidation (FAO)-associated respiration was reduced in OBES at W8, but doubled in DIAB and NASH at W16 (p<0.01 vs CTRL) and correlated with biomarkers of unfolded protein response (UPR), oxidative stress and hepatic expression of certain enzymes (acetyl-CoA carboxylase 2, Acc2; carnitine palmitoyltransferase I, Cpt1a). Tricarboxylic acid cycle (TCA)-driven respiration was lower in OBES at W8 and doubled in DIAB at W16 (p<0.0001 vs CTRL), which positively correlated with expression of genes related to lipolysis. Hepatic mitochondria adapt to various metabolic challenges with increasing FAO-driven respiration, which is linked to dysfunctional UPR, systemic oxidative stress, insulin resistance and altered lipid metabolism. In a diabetes model, higher TCA-linked respiration reflected mitochondrial adaptation to greater hepatic lipid turnover. Funding bodies that contributed to this study were listed in the acknowledgements section.

Selenium and coenzyme Q10 improve the systemic redox status while reducing cardiovascular mortality in elderly population-based individuals.

Serum sulfhydryl groups (R-SH, free thiols) reflect the systemic redox status in health and disease, and may be amenable to therapeutic modulation. Since R-SH are readily oxidized by reactive species, oxidative stress is characterized by reduced serum R-SH levels. Selenium and coenzyme Q10 supplementation may improve the systemic redox status. This study aimed to evaluate the effect of supplementation with selenium and coenzyme Q10 on serum free thiols and to study associations with the risk of cardiovascular mortality in elderly community-dwelling individuals. In this randomized, double-blind, placebo-controlled trial, serum R-SH were measured colorimetrically and adjusted for albumin in 434 individuals at baseline and after 48 months of intervention. Selenium yeast (200 μg/day) and coenzyme Q10 (200 mg/day) or placebo were provided as dietary supplements. After 48 months of intervention, participants receiving combined selenium and coenzyme Q10 supplementation demonstrated increased levels of serum R-SH compared to placebo (P = 0.002). In prospective association analysis, the highest rate of cardiovascular mortality after a median follow-up of 10 years (IQR: 6.8-10.5) was observed in the lowest quartile (Q1) of R-SH levels. Baseline albumin-adjusted serum R-SH were significantly associated with the risk of cardiovascular mortality, even after adjustment for potential confounding factors (hazard ratio [HR] 1.98 per SD, 95% CI: 1.34-2.91, P < 0.001). Supplementation with selenium and coenzyme Q10 to an elderly community-dwelling population low on the two substances, significantly improved serum R-SH levels, supporting a reduction in systemic oxidative stress. Low serum R-SH levels were significantly associated with an increased risk of cardiovascular mortality in elderly individuals.

Systemic oxidative stress and circulating long non-coding RNAs as potential novel cardiovascular risk factors in the general population

Systemic oxidative stress and circulating long non-coding RNAs as potential novel cardiovascular risk factors in the general population