Subsequent Oxidative Stress Research Articles

Recent advances in the Prevention and Treatment of Chemotherapy–induced Cardiotoxicity

The current study aimed to overview recent advances in preventing and treating chemotherapy-induced cardiotoxicity. Chemotherapy is widely used in cancer treatment, however, it can have adverse effects on the heart, leading to the development of risk factors, such as hypertension, obesity, dyslipidemia, and metabolic syndrome. Anthracycline compounds are the most commonly used chemotherapy agents and are associated with an increased risk of developing anthracycline-induced cardiotoxicity (AIC). The precise mechanisms underlying AIC remain a subject of debate, but evidence suggests that the primary causes are the generation of reactive oxygen species (ROS) and subsequent oxidative stress. Several risk factors have been linked to the development of AIC, including cumulative dose, pre-existing cardiac disease, age, gender, and cardiac risk factors. Genetic susceptibility may also play a role as a potential risk factor for AIC. In order to protect cardiac function, various strategies have been explored, such as developing less-toxic derivatives of anthracyclines, determining safer cumulative anthracycline doses, and identifying new cardioprotective agents. Prophylactic treatment with cardioprotective agents is the best approach for high-risk patients. This article reviewed the present strategies for protecting cancer patients from AIC based on effective cardioprotective drugs along with the balance between their benefits and potential adverse effects.

The role of iron in the pathogenesis of endometriosis: a systematic review.

What is the role of iron in the pathophysiology of endometriosis? Iron excess is demonstrated wherever endometriotic tissues are found and is associated with oxidative stress, an inflammatory micro-environment, and cell damage; the iron-mediated oxidative stress is independently linked to subfertility, symptom severity, and malignant transformation. Iron is found in excess in endometriotic tissues, and multiple mechanisms have been studied and posited to explain this. It is clear that iron excess plays a vital role in promoting oxidative stress and cell damage. The evidence base is large, but no comprehensive reviews exist to summarize our understanding and highlight the overarching themes to further our understanding and suggest future directions of study for the field. This systematic review with a thematic analysis retrieved studies from the PubMed, Embase, Web of Science, and Cochrane Library databases and searches were conducted from inception through to August 2022. Human and animal studies published in the English language were included and identified using a combination of exploded MeSH terms ('Iron' and 'Endometriosis') and free-text search terms ('Iron', 'Ferric', 'Ferrous', 'Endometriosis', 'Endometrioma'). This review was reported in accordance with the PRISMA guidelines. All studies reporting original data concerning the role of iron or iron complexes in the pathophysiology of endometriosis were included. Studies that did not report original data or provided a review of the field were excluded. Bias analysis was completed for each included study by using the Newcastle-Ottawa scoring system. There were 776 records identified and these were screened down to 53 studies which met the eligibility criteria, including 6 animal and 47 human studies, with 3556 individual participants. Iron excess is demonstrated in various tissues and fluids, including ovarian endometriomas, ovarian follicles, ectopic endometriotic lesions, and peritoneal fluid. Markers of oxidative stress are strongly associated with high iron levels, and aberrant expression of iron-transport proteins has been demonstrated. Abnormal resistance to ferroptosis is likely. Iron-mediated oxidative stress is responsible for a pro-inflammatory micro-environment and is linked to subfertility, symptom severity, and, possibly, malignant transformation. A minority of the included studies were of objectively low quality with a high risk of bias and may lead to misleading conclusions. Additionally, multiple studies failed to appropriately characterize the included patients by known confounding variables, such as menstrual cycle phase, which may introduce bias to the findings. Current literature depicts a central role of aberrant iron mechanics and subsequent oxidative stress in endometriosis. It is likely that iron excess is at least partly responsible for the persistence and proliferation of ectopic endometriotic lesions. As such, iron mechanics represent an attractive target for novel therapeutics, including iron chelators or effectors of the iron-oxidative stress pathway. There are significant gaps in our current understanding, and this review highlights and recommends several topics for further research. These include the role of iron chelation, resistance to ferroptosis, the relationship between iron excess and localized hypoxia, systemic iron pathophysiology in endometriosis, and the role of oxidative stress in malignant transformation. J.W. and S.G.P. are supported by clinical fellowships at Liverpool University Hospital NHS Foundation trust. No additional funding was requested or required for the completion of this work. C.J.H. is supported by a Wellbeing of Women project grant (RG2137). D.K.H. is supported by a Wellbeing of Women project grant (RG2137) and an MRC clinical research training fellowship (MR/V007238/1). The authors have no conflicts of interest to declare. A protocol was prospectively registered with the PROSPERO database in August 2021 (CRD42021272818).

3D ZnO/Activated Carbon Alginate Beads for the Removal of Antibiotic-Resistant Bacteria and Antibiotic Resistance Genes.

The worldwide prevalence of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) have become one of the most urgent issues for public health. Thus, it is critical to explore more sustainable methods with less toxicity for the long-term removal of both ARB and ARGs. In this study, we fabricated a novel material by encapsulating zinc oxide (ZnO) nanoflowers and activated carbon (AC) in an alginate biopolymer. When the dosage of ZnO was 1.0 g (≈2 g/L), the composite beads exhibited higher removal efficiency and a slight release of Zn2+ in water treatment. Fixed bed column experiments demonstrated that ZnO/AC alginate beads had excellent removal capacities. When the flow rate was 1 mL/min, and the initial concentration was 107 CFU/mL, the removal efficiency of ARB was 5.69-log, and the absolute abundance of ARGs was decreased by 2.44-2.74-log. Moreover, the mechanism demonstrated that ZnO significantly caused cell lysis, cytoplasmic leakage, and the increase of reactive oxygen species induced subsequent oxidative stress state. These findings suggested that ZnO/AC alginate beads can be a promising material for removing ARB and ARGs from wastewater with eco-friendly and sustainable properties.

SARS-CoV-2 induced liver injury: Incidence, risk factors, impact on COVID-19 severity and prognosis in different population groups.

Liver is unlikely the key organ driving mortality in coronavirus disease 2019 (COVID-19) however, liver function tests (LFTs) abnormalities are widely observed mostly in moderate and severe cases. According to this review, the overall prevalence of abnormal LFTs in COVID-19 patients ranges from 2.5% to 96.8% worldwide. The geographical variability in the prevalence of underlying diseases is the determinant for the observed discrepancies between East and West. Multifactorial mechanisms are implicated in COVID-19-induced liver injury. Among them, hypercytokinemia with "bystander hepatitis", cytokine storm syndrome with subsequent oxidative stress and endotheliopathy, hypercoagulable state and immuno-thromboinflammation are the most determinant mechanisms leading to tissue injury. Liver hypoxia may also contribute under specific conditions, while direct hepatocyte injury is an emerging mechanism. Except for initially observed severe acute respiratory distress syndrome corona virus-2 (SARS-CoV-2) tropism for cholangiocytes, more recent cumulative data show SARS-CoV-2 virions within hepatocytes and sinusoidal endothelial cells using electron microscopy (EM). The best evidence for hepatocellular invasion by the virus is the identification of replicating SARS-CoV-2 RNA, S protein RNA and viral nucleocapsid protein within hepatocytes using in-situ hybridization and immunostaining with observed intrahepatic presence of SARS-CoV-2 by EM and by in-situ hybridization. New data mostly derived from imaging findings indicate possible long-term sequelae for the liver months after recovery, suggesting a post-COVID-19 persistent live injury.

KDM4A, involved in the inflammatory and oxidative stress caused by traumatic brain injury-hemorrhagic shock, partly through the regulation of the microglia M1 polarization

BackgroundMicroglial polarization and the subsequent neuroinflammatory response and oxidative stress are contributing factors for traumatic brain injury (TBI) plus hemorrhagic shock (HS) induced brain injury. In the present work, we have explored whether Lysine (K)-specific demethylase 4 A (KDM4A) modulates microglia M1 polarization in the TBI and HS mice.ResultsMale C57BL/6J mice were used to investigate the microglia polarization in the TBI + HS model in vivo. Lipopolysaccharide (LPS)-induced BV2 cells were used to examine the mechanism of KDM4A in regulating microglia polarization in vitro. We found that TBI + HS resulted in neuronal loss and microglia M1 polarization in vivo, reflected by the increased level of Iba1, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, malondialdehyde (MDA) and the decreased level of reduced glutathione (GSH). Additionally, KDM4A was upregulated in response to TBI + HS and microglia were among the cell types showing the increased level of KDM4A. Similar to the results in vivo, KDM4A also highly expressed in LPS-induced BV2 cells. LPS-induced BV2 cells exhibited enhanced microglia M1 polarization, and enhanced level of pro-inflammatory cytokines, oxidative stress and reactive oxygen species (ROS), while this enhancement was abolished by the suppression of KDM4A.ConclusionAccordingly, our findings indicated that KDM4A was upregulated in response to TBI + HS and microglia were among the cell types showing the increased level of KDM4A. The important role of KDM4A in TBI + HS-induced inflammatory response and oxidative stress was at least partially realized through regulating microglia M1 polarization.

Impact of metal exposure on environmentally isolated Serratia marcescens’ growth, oxidative-stress resistance, biofilm formation, and proliferation in eukaryotic co-culture models

Environmental metals can be noxious to the surrounding biota, indirectly impact freshwater habitats, and also impact microbiological communities. In this study, zinc (Zn) (55.5 mg/kg), manganese (Mn) (863.4 mg/kg) and lead (Pb) (17.5 mg/kg) levels measured in Houston watershed flood plain soil samples were higher than environmental agencies’ thresholds. To investigate the effects of metal exposures, an environmentally isolated Serratia marcescens (SME), etiological agent of endocarditis and respiratory infections, and its reference strain (SMR) were exposed to Pb, Zn, and Mn, and subsequent oxidative stress responses and biofilm production were measured. Not surprisingly, SME was less sensitive to all 3 metal exposures than was SMR. Interestingly, SME produced increased biofilm and was more resistant to oxidative stress in the presence of Zn and Pb than SMR. In a 6 h lung infection model using BAES-2B cells, SME exhibited greater proliferation than SMR in all metal challenges. Similarly, in our HT29 gut infection model, SME out-proliferated SMR when challenged with Pb and Mn following the 6 h infection. Taken together, SME was better able to withstand environmental stressors than SMR, suggesting increased virulence potential of this opportunistic human pathogen.

A Review on Genotoxic and Genoprotective Effects of Biologically Active Compounds of Animal Origin.

Envenomation by animal venoms remains a serious medical and social problem, especially in tropical countries. On the other hand, animal venoms are widely used as a source of biologically active compounds for the development of novel drugs. Numerous derivatives of animal venoms are already used in clinical practice. When analysing the mechanisms of action of animal venoms, attention is usually focused on the main target of the venom's enzymes and peptides such as neurotoxic, cytotoxic or haemorrhagic effects. In the present review, we would like to draw attention to the "hidden" effects of animal venoms and their derivatives in regard to DNA damage and/or protection against DNA damage. Alkaloids and terpenoids isolated from sponges such as avarol, ingenamine G or variolin B manifest the capability to bind DNA in vitro and produce DNA breaks. Trabectidin, isolated from a sea squirt, also binds and damages DNA. A similar action is possible for peptides isolated from bee and wasp venoms such as mastoparan, melectin and melittin. However, DNA lesions produced by the crude venoms of jellyfish, scorpions, spiders and snakes arise as a consequence of cell membrane damage and the subsequent oxidative stress, whereas certain animal venoms or their components produce a genoprotective effect. Current research data point to the possibility of using animal venoms and their components in the development of various potential therapeutic agents; however, before their possible clinical use the route of injection, molecular target, mechanism of action, exact dosage, possible side effects and other fundamental parameters should be further investigated.

In silico targeting of lipoxygenase, CYP2C9, and NAD(P)H oxidase by major green tea polyphenols to subvert oxidative stress

Oxidative stress (OS) is a phenomenon caused by an imbalance between free-radical production and antioxidant activity within the body. Status of endogenous antioxidants is not always sufficient to mitigate the oxidative damage. In this case, exogenous antioxidants could help to minimize free-radical production and subsequent OS. Green tea is rich in several phenolic compounds that have strong antioxidant properties. However, their mechanism of action is still unclear. Hence, the present study aims to investigate binding affinities of six green tea polyphenols such as catechin, epicatechin, epicatechin gallate, epigallocatechin, epigallocatechin gallate, and gallocatechin for common ROS producers such as Lipoxygenase (LOX), CYP2C9, and NAD(P)H oxidase (NOX). Results indicated that polyphenols interacted with binding pockets of these enzymes through hydrogen bonds and other stable interactions such as van der waals, Pi-Pi, Pi-alkyl, and alkyl. All polyphenols showed varied binding affinities. Among them, epigallocatechin gallate and epigallocatechin showed the highest binding affinities for the ROS producers. Findings of the present study suggest that, apart from free radical scavenging activity, green tea polyphenols may directly interact with binding pockets of LOX, CYP2C9, and NOX to dampen ROS production and OS. However, studies involving animal models are required for additional validation of results.

Oxidative stress in multiple sclerosis-Emerging imaging techniques.

While conventional magnetic resonance imaging (MRI) is central to the evaluation of patients with multiple sclerosis, its role in detecting the pathophysiology underlying neurodegeneration is more limited. One of the common outcome measures for progressive multiple sclerosis trials, atrophy on brain MRI, is non-specific and reflects end-stage changes after considerable neurodegeneration has occurred. Identifying biomarkers that identify processes underlying neurodegeneration before it is irreversible and that reflect relevant neurodegenerative pathophysiology is an area of significant need. Accumulating evidence suggests that oxidative stress plays a major role in the pathogenesis of multiple neurodegenerative diseases, including multiple sclerosis. Imaging markers related to inflammation, myelination, and neuronal integrity have been areas of advancement in recent years but oxidative stress has remained an area of unrealized potential. In this article we will begin by reviewing the role of oxidative stress in the pathogenesis of multiple sclerosis. Chronic inflammation appears to be directly related to the increased production of reactive oxygen species and the effects of subsequent oxidative stress appear to be amplified by aging and accumulating disease. We will then discuss techniques in development used in the assessment of MS as well as other models of neurodegenerative disease in which oxidative stress is implicated. Multiple blood and CSF markers of oxidative stress have been evaluated in subjects with MS, but non-invasive imaging offers major upside in that it provides real-time assessment within the brain.

Membrane Integrity Assay in Ferroptosis.

Ferroptosis is a form of regulated cell death that relies on the accumulation of intracellular iron and subsequent oxidative stress. Ferroptotic cell death is characterized by uncontrolled lipid peroxidation, which leads to plasma membrane damage and rupture. The loss of plasma membrane integrity results in the release of intracellular components, including damage-associated molecular patterns, and can propagate death between cells in a synchronized manner. Understanding the mechanisms of ferroptotic membrane damage is crucial to comprehending this form of cell death. This chapter provides a summary of techniques for detecting plasma membrane integrity in ferroptosis, including transmission electron microscopy analysis, flow cytometry analysis, and assessments of oxidoreductase-mediated membrane damage.

Therapy and diagnosis of Alzheimer's disease: from discrete metal complexes to metal-organic frameworks.

Alzheimer's disease (AD) is a neurodegenerative disorder affecting 44 million people worldwide. Although many issues (pathogenesis, genetics, clinical features, and pathological aspects) are still unknown, this disease is characterized by noticeable hallmarks such as the formation of β-amyloid plaques, hyperphosphorylation of tau proteins, the overproduction of reactive oxygen species, and the reduction of acetylcholine levels. There is still no cure for AD and the current treatments are aimed at regulating the cholinesterase levels, attenuating symptoms temporarily rather than preventing the AD progression. In this context, coordination compounds are regarded as a promissing tool in AD treatment and/or diagnosis. Coordination compounds (discrete or polymeric) possess several features that make them an interesting option for developing new drugs for AD (good biocompatibility, porosity, synergetic effects of ligand-metal, fluorescence, particle size, homogeneity, monodispersity, etc.). This review discusses the recent progress in the development of novel discrete metal complexes and metal-organic frameworks (MOFs) for the treatment, diagnosis and theragnosis of AD. These advanced therapies for AD treatment are organized according to the target: Aβ peptides, hyperphosphorylated tau proteins, synaptic dysfunction, and mitochondrial failure with subsequent oxidative stress.

Type 2 diabetes mellitus and obesity impact AD‐related pathology through overlapping and independent pathways

AbstractBackgroundIt is proposed that neuronal damage in diabetes is related to hyperglycaemia and insulin resistance, whilst inflammation and subsequent oxidative stress affects cognitive function in obesity. We investigated whether obesity and diabetes present distinct neuropathological features of neurodegeneration.MethodsTo compare amyloid, tau and cerebral glucose metabolism, we processed 1973 available PET scans for 18F‐AV‐45, 18F‐flortaucipir and 18F‐fludeoxyglucose (FDG) from 971 participants with diabetes (n=194), obesity (n=377) and without diabetes or obesity (n=400) from the Alzheimer’s Disease Neuroimaging Initiative dataset. Independent t‐tests and multivariate analysis were used for regions of interest (ROIs) analysis in participant groups with diabetes vs non‐diabetic/non‐obese and obesity vs non‐diabetic/non‐obese. This was conducted across different cognitive subgroups, namely Alzheimer’s disease, mild cognitive impairment or normal cognition. Amyloid positive and negative subjects were evaluated separately. Voxel‐wise analysis using SPM was also conducted for these groups.ResultsFor diabetes, higher amyloid uptake was found in the medial temporal regions in the cognitively normal diabetic group compared to the cognitively normal (non‐diabetic/non‐obese) group. This was also found in the amyloid positive mild cognitively impaired diabetic groups compared to mild cognitively impaired (non‐diabetic/non‐obese) group. Similarly, higher amyloid deposition was seen in the hippocampus of the cognitively normal obese group compared to the cognitively normal (non‐diabetic/non‐obese) group.Additionally, higher tau uptake was found in the whole brain (global brain value), frontal, parietal and occipital lobes for cognitively normal diabetic and obese groups, compared to cognitively normal (non‐diabetic/non‐obese) groups. Higher tau was further found in the temporal lobe and anterior cingulate of AD obesity participants compared to the AD (non‐diabetic/non‐obese) participants.Discrete cerebral glucose metabolic patterns were found in diabetes and obesity. In the diabetic groups, reduced FDG uptake was found in mild cognitively impaired participants (whole brain, frontal, parietal and occipital lobes) and amyloid positive AD participants (occipital lobe) compared to non‐diabetic/non‐obese participants. In contrast, increased FDG uptake was mainly found in amyloid negative obese participants.ConclusionsGlucose hypometabolism in diabetic participants in contrast to hypermetabolism in obese participants implies that different pathological processes of neurodegeneration occur in these two conditions. This suggests that these two conditions require different therapeutic strategies to prevent neurodegeneration.

Gene Expression Profiling as a New Real-Time Assay in Human Biomonitoring of Waste-to-Energy Plant Workers.

Exposure to heavy metals represents one of the most important risk factors for the health of incinerator workers. Indeed, heavy metals can determine increased generation of reactive oxygen species (ROS). In this work, we introduced the use of transcription profiling of detoxifying genes, involved in redox balance and genome integrity, as a highly sensitive assay of heavy metal exposure and subsequent oxidative stress. For this purpose, blood mRNA levels of OGG1, ST13, NQO1 and MT1A genes, as well as urinary concentrations of nine heavy metals and the oxidized base 8-OHdG of 49 subjects (26 controls and 23 employees in the waste-to-energy plant of San Zeno, Arezzo, Italy) were determined. No significant difference between the two populations was observed, thus highlighting, as far as the biomarkers analysed are concerned, the absence of occupational exposure to heavy metals and systemic oxidative stress induction in the workers of the waste-to-energy plant of San Zeno. Correlation analyses underline a close association between heavy metals exposure and changes in expression levels of a number of genes, even at low exposure doses, thus remarking the greater capacity of detection of transcription profiling compared to other biomarkers and the importance of its introduction in future human biomonitoring programs.

Carvacrol Inhibits Expression of Transient Receptor Potential Melastatin 7 Channels and Alleviates Zinc Neurotoxicity Induced by Traumatic Brain Injury.

Carvacrol is a monoterpenoid phenol produced by aromatic plants such as oregano. Although the exact mechanism by which carvacrol acts has not yet been established, it appears to inhibit transient receptor potential melastatin 7 (TRPM7), which modulates the homeostasis of metal ions such as zinc and calcium. Several studies have demonstrated that carvacrol has protective effects against zinc neurotoxicity after ischemia and epilepsy. However, to date, no studies have investigated the effect of carvacrol on traumatic brain injury (TBI)-induced zinc neurotoxicity. In the present study, we investigated the therapeutic potential of carvacrol for the prevention of zinc-induced neuronal death after TBI. Rats were subjected to a controlled cortical impact, and carvacrol was injected at a dose of 50 mg/kg. Histological analysis was performed at 12 h, 24 h, and 7 days after TBI. We found that carvacrol reduced TBI-induced TRPM7 over-expression and free zinc accumulation. As a result, subsequent oxidative stress, dendritic damage, and neuronal degeneration were decreased. Moreover, carvacrol not only reduced microglial activation and delayed neuronal death but also improved neurological outcomes after TBI. Taken together, these findings suggest that carvacrol administration may have therapeutic potential after TBI by preventing neuronal death through the inhibition of TRPM7 expression and alleviation of zinc neurotoxicity.

HYDROCORTISONE, ASCORBIC ACID, AND THIAMINE THERAPY DECREASE RENAL OXIDATIVE STRESS AND ACUTE KIDNEY INJURY IN MURINE SEPSIS.

Background: Acute kidney injury (AKI) occurs frequently in septic patients and correlates with increased mortality. Because clinical studies investigating hydrocortisone, ascorbic acid, and thiamine (HAT) have demonstrated discordant results, studies were performed using mortality stratification for therapy to identify candidates for therapy and determine mechanisms of organ injury. Methods: Sepsis was induced using the cecal ligation and puncture (CLP) model of sepsis with fluid and antibiotic support. Heart rate (HR) measurements obtained 6 hours after CLP stratified mice into live predicted (P-Live) or die predicted (P-Die). Stratified mice were then randomized for treatment with HAT or vehicle given 7 hours after CLP. Physiologic measurements were taken again at 24 hours, and mice were killed to collect blood and organs. Results: The following five groups were created: (1) P-Live vehicle, (2) P-Live HAT, (3) P-Die vehicle, (4) P-Die HAT, and (5) naive mice. Comparisons were made to test the hypotheses that (1) P-Die vehicle mice will have significant deterioration compared with P-Live mice targeting the kidney and (2) HAT will correct these deleterious changes in P-Die mice. Compared with P-Live, P-Die mice had a significant decline in all measured physiologic parameters (HR, cardiac output, breath rate, and temperature), which were corrected with HAT therapy (P < 0.05 for all parameters). The P-Die mice had declines in the ascorbic acid within the blood, peritoneal lavage, and kidney homogenate compared with P-Live mice indicating consumption, and the decline was corrected with HAT. Elevated IL-6, KC, Macrophage Inflammatory Protein-2, and IL-1RA were found in P-Die mice and decreased with HAT. Markers of endothelial cell injury (glypican 1 and glypican 4) were elevated in the P-Die mice, and these values were decreased with HAT therapy. Low oxygen levels with subsequent oxidative stress (OS) in the kidney were visualized in histologic sections using hypoxyprobe and also with carbonyl proteins and 8-iso-prostaglandin F2α in kidney homogenates. The P-Die mice had significant elevations of renal OSs, which was ameliorated with HAT. Kidney injury was evident in the P-Die mice compared with P-Live mice with elevations in blood urea nitrogen and cystatin C, which were significantly reduced with HAT. There was no evidence of global hypoxia or organ injury because hepatic parameters remained normal. Conclusions: Our data show that in CLP-induced sepsis, P-Die mice have increased inflammation, OS, and kidney injury. Hydrocortisone, ascorbic acid, and thiamine therapy decreased renal OS and injury in the P-Die group when given after the onset of sepsis-induced physiologic changes.

New advances in medical imaging technology for the evaluation of anthracycline-induced cardiotoxicity.

New advances in medical imaging technology for the evaluation of anthracycline-induced cardiotoxicity.

Multiomics analyses uncover nanoceria triggered oxidative injury and nutrient imbalance in earthworm Eisenia fetida

The toxic stress caused by nanoceria remains vague owing to the limited efforts scrutinizing its molecular mechanisms. Herein, we investigated the impacts of nanoceria on earthworm Eisenia fetida, at the molecular level using the multiomics-based profiling approaches (transcriptomics, metabolomics, and 16 S rRNA sequencing). Nanoceria (50 and 500 mg/kg) significantly increased the contents of malondialdehyde (MDA), Fe, and K in worms, suggesting oxidative injury and nutrient imbalance. This was corroborated by the transcriptomic and metabolomic analyses. Nanoceria decreased the levels of certain genes and metabolites associated with glycerolipid and glycerophospholipid metabolisms, suggesting the production of reactive oxygen species and subsequent oxidative stress. Additionally, the ABCD3 gene belonging to ABC transporter family was upregulated, facilitating Fe uptake by worms. Moreover, the higher contents of MDA, Fe, and K after exposure were tightly associated with the imbalanced intestinal flora. Specifically, a higher relative abundance of Actinobacteriota and a lower relative abundance of Proteobacteria and Patescibacteria were induced. This study, for the first time, revealed that nanoceria at nonlethal levels caused oxidative stress and nutrient imbalance of earthworms from the perspective of genes, metabolites, and gut microbiome perturbations, and also established links between the gut microbiome and the overall physiological responses of the host.

Inflammatory Mechanisms of Diabetes and Its Vascular Complications.

The main cause of death in patients with type 2 DM is cardiovascular complications resulting from the progression of atherosclerosis. The pathophysiology of the association between diabetes and its vascular complications is complex and multifactorial and closely related to the toxic effects of hyperglycemia that causes increased generation of reactive oxygen species and promotes the secretion of pro-inflammatory cytokines. Subsequent oxidative stress and inflammation are major factors of the progression of type 2 DM and its vascular complications. Data on the pathogenesis of the development of type 2 DM and associated cardiovascular diseases, in particular atherosclerosis, open up broad prospects for the further development of new diagnostic and therapeutic approaches.

DDAH1 Promotes Lung Endothelial Barrier Repair by Decreasing Leukocyte Transendothelial Migration and Oxidative Stress in Explosion-Induced Lung Injury

Explosion-induced injury is the most commonly encountered wound in modern warfare and incidents. The vascular inflammatory response and subsequent oxidative stress are considered the key causes of morbidity and mortality among those in blast lung injury. It has been reported dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays important roles in regulating vascular endothelial injury repair and angiogenesis, but its role in explosion-induced injury remains to be explained. To explore the mechanism of vascular injury in blast lung, 40 C57BL/6 wild type mice and 40 DDAH1 knockout mice were randomly equally divided into control group and blast group, respectively. Body weight, lung weight, and dry weight of the lungs were recorded. Diffuse vascular leakage was detected by Evans blue test. The serum inflammatory factors, nitric oxide (NO) contents, and ADMA level were determined through ELISA. Hematoxylin-eosin staining and ROS detection were performed for histopathological changes. Western blot was used to detect the proteins related to oxidative stress, cell adhesion molecules and leukocyte transendothelial migration, vascular injury, endothelial barrier dysfunction, and the DDAH1/ADMA/eNOS signaling pathway. We found that DDAH1 deficiency aggravated explosion-induced body weight reduction, lung weight promotion, diffuse vascular leakage histopathological changes, and the increased levels of inflammatory-related factors. Additionally, DDAH1 deficiency also increased ROS generation, MDA, and IRE-1α expression. Regarding vascular endothelial barrier dysfunction, DDAH1 deficiency increased the expression of ICAM-1, Itgal, Rac2, VEGF, MMP9, vimentin, and N-cadherin, while lowering the expression of occludin, CD31, and dystrophin. DDAH1 deficiency also exacerbated explosion-induced increase of ADMA and decrease of eNOS activity and NO contents. Our results indicated that explosion could induce severe lung injury and pulmonary vascular insufficiency, whereas DDAH1 could promote lung endothelial barrier repair and reduce inflammation and oxidative stress by inhibiting ADMA signaling which in turn increased eNOS activity.

Prior Angiotensin Converting Enzyme Inhibition Differentially Alters Angiotensin II‐Induced Oxidative Stress in Male and Female Hypertensive Rats

Hypertension promotes fibrotic cardiac remodeling that involves oxidative stress and inflammation that contribute to heart failure. Transient angiotensin converting enzyme inhibitor (ACEi) treatment in male hypertensive rats (SHR) produces persistent changes in the left ventricle (LV) that render it resistant to future fibrosis and inflammation. Oxidative stress produced by NADPH oxidase (NOX) enzymes is linked to angiotensin II (Ang II)‐mediated fibrotic signaling. Ang II also promotes secretion of macrophage‐recruiting cytokines including monocyte chemoattractant protein 1 (MCP1) which can perpetuate oxidative stress. Thus the present study investigated the impact of transient ACEi‐induced cardio‐protection on subsequent Ang II‐induced inflammatory and oxidative stress responses. After a 2‐week ACEi treatment (enalapril, 30mg/kg/day) followed by a 2‐week washout period male and female SHRs (11 wk old) were infused with Ang II (400ng/kg/min, s.c.) or vehicle (saline, n=5‐11/group/sex) for 2 weeks. At time of euthanasia, a mid‐myocardial section was fixed and paraffin embedded and remaining LV tissue was collected for protein, RNA and DNA extraction. LV macrophage infiltration was determined histologically by staining for ED‐1. MCP1 gene expression was evaluated by RTqPCR, and pro‐oxidants (NOX2 and NOX4) and antioxidants (catalase and superoxide dismutase 2; SOD2) were measured by immunoblotting. Oxidative DNA damage was quantified using an 8‐hydroxy‐2’‐deoxyguanosine (8‐OHdG) ELISA. Cardiac MCP1 gene expression was increased by Ang II in both sexes with no impact of transient ACEi. However, Ang II induced LV macrophage infiltration (ED‐1) in males only which was attenuated by prior transient ACEi. LV NOX2 was increased by Ang II and attenuated by prior transient ACEi in both sexes. NOX4 was reduced in females previously treated with an ACEi, but not males. The antioxidant, catalase, was increased by Ang II in both sexes, but attenuated by transient ACEi in females only. Further, both catalase and SOD2 were positively correlated to NOX2 in females, but not males. This suggests that Ang II‐induced pro‐oxidant responses may be more tightly coupled with antioxidant responses in females. DNA damage as measured by 8‐OHdG was not significantly impacted by Ang II in males or females. However 8‐OHdG was reduced in males previously treated with an ACEi suggesting that an alternative antioxidant mechanism may be active in males previously treated with an ACEi. At this dose and duration of Ang II there is not significant oxidative DNA damage, but MCP1 and pro‐oxidants are increased in both sexes. Males exhibit greater macrophage infiltration, while females exhibit greater antioxidant responses; both of which are prevented by prior transient ACEi. In conclusion, there are sex‐specific inflammatory and oxidative stress responses to Ang II and transient ACEi that may impact future cardiac remodeling. Current and future studies will aim to identify mechanisms involved in transient ACEi‐mediated cardio‐protection and how these effects differ between males and females.