Uncontrolled Oxidative Stress Research Articles

The diterpene Manool extracted from Salvia tingitana lowers free radical production in retinal rod outer segments by inhibiting the extramitochondrial F1 Fo ATP synthase.

Uncontrolled oxidative stress production, especially in the outer retina is one of the causes of retinal degenerations. Mitochondria are considered the principal source of oxidative stress. However, a Reactive Oxygen Intermediates (ROI) production in the retinal photoreceptor layer seems to depend also on the expression of an extramitochondrial oxidative phosphorylation (OxPhos) machinery in the rod outer segments (OS). In fact, OS conduct aerobic metabolism, producing ATP through oxygen consumption, although it is devoid of mitochondria. As diterpenes display an antioxidant effect, we have evaluated the effect Manool, extracted from Salvia tingitana, on the extramitochondrial OxPhos and the ROI production in the retinal rod OS. Results confirm that the OxPhos machinery is ectopically expressed in the OS and that F1 Fo -ATP synthase is a target of Manool, which inhibited the OS ATP synthesis, binding the F1 moiety with high affinity, as analysed by molecular docking. Moreover, the overall slowdown of OxPhos metabolism reduced the ROI production elicited in the OS by light exposure, in vitro. In conclusion, data are consistent with the antioxidant properties of Salvia spp., suggesting its ability to lower oxidative stress production, a primary risk factor for degenerative retinal diseases. SIGNIFICANCE OF THE STUDY: Here we show that Manool, a diterpene extracted from Salvia tingitana has the potential to lower the free radical production by light-exposed rod outer segments in vitro, by specifically targeting the rod OS F1 Fo -ATP synthase belonging to the extramitochondrial OxPhos expressed on the disk membrane. The chosen experimental model allowed to show that the rod OS is a primary producer of oxidative stress linked to the pathogenesis of degenerative retinal diseases. Data are also consistent with the antioxidant and anti-inflammatory action of Salvia spp., suggesting a beneficial effect also in vivo.

Difference between kwashiorkor and marasmus: Comparative meta-analysis of pathogenic characteristics and implications for treatment

Kwashiorkor and marasmus are two clinical syndromes observed in severe acute malnutrition. In this review, we highlighted the differences between these two syndromes by reviewing the data comparing kwashiorkor and marasmus in literature, combined with recent microbiological findings and meta-analysis. Depletion of antioxidants, vitamins and minerals were more severe in kwashiorkor than marasmus. This was consistent with the severe and uncontrolled oxidative stress associated with the depletion of gut anaerobes and the relative proliferation of aerotolerant gut pathogens. This relative proliferation and invasion of gut microbes belonging to the aerotolerant Proteobacteria phylum and pathogens suggested a specific microbial process critical in the pathogenesis of kwashiorkor. Liver mitochondrial and peroxisomal dysfunction could be secondary to toxic microbial compounds produced in the gut such as ethanol, lipopolysaccharides and endotoxins produced by Proteobacteria, particularly Klebsiella pneumoniae, and aflatoxin produced by Aspergillus species. The gut-liver axis alteration is characterized by oedema and a fatty and enlarged liver and was associated with a dramatic depletion of methionine and glutathione, an excessive level of free circulating iron and frequent lethal bacteraemia by enteric pathogens. This was consistent with the fact that antibiotics improved survival only in children with kwashiorkor but not marasmus. The specific pathogenic characteristics of kwashiorkor identified in this review open new avenues to develop more targeted and effective treatments for both marasmus and/or kwashiorkor. Urgent correction of plasma glutathione depletion, alongside supply of specific essential amino acids, particularly methionine and cysteine, early detection of pathogens and an antibiotic more efficient than amoxicillin in supressing gut Proteobacteria including K. pneumoniae, and probiotics to restore the human gut anaerobic mature microbiota could save many more children with kwashiorkor.

Neuronal Calcium Imaging, Excitability, and Plasticity Changes in the Aldh2-/- Mouse Model of Sporadic Alzheimer's Disease.

Background:Dysregulated signaling in neurons and astrocytes participates in pathophysiological alterations seen in the Alzheimer’s disease brain, including increases in amyloid-β, hyperphosphorylated tau, inflammation, calcium dysregulation, and oxidative stress. These are often noted prior to the development of behavioral, cognitive, and non-cognitive deficits. However, the extent to which these pathological changes function together or independently is unclear.Objective:Little is known about the temporal relationship between calcium dysregulation and oxidative stress, as some reports suggest that dysregulated calcium promotes increased formation of reactive oxygen species, while others support the opposite. Prior work has quantified several key outcome measures associated with oxidative stress in aldehyde dehydrogenase 2 knockout (Aldh2–/–) mice, a non-transgenic model of sporadic Alzheimer’s disease.Methods:Here, we tested the hypothesis that early oxidative stress can promote calcium dysregulation across aging by measuring calcium-dependent processes using electrophysiological and imaging methods and focusing on the afterhyperpolarization (AHP), synaptic activation, somatic calcium, and long-term potentiation in the Aldh2–/– mouse.Results:Our results show a significant age-related decrease in the AHP along with an increase in the slow AHP amplitude in Aldh2–/– animals. Measures of synaptic excitability were unaltered, although significant reductions in long-term potentiation maintenance were noted in the Aldh2–/– animals compared to wild-type.Conclusion:With so few changes in calcium and calcium-dependent processes in an animal model that shows significant increases in HNE adducts, Aβ, p-tau, and activated caspases across age, the current findings do not support a direct link between neuronal calcium dysregulation and uncontrolled oxidative stress.

MiRNAs Regulating Oxidative Stress: A Correlation with Doppler Sonography of Uteroplacental Complex and Clinical State Assessments of Newborns in Fetal Growth Restriction.

Overproduction of reactive oxygen species (ROS) and, as a result, uncontrolled oxidative stress (OS) can play a central role in disorders of fetal hemodynamics and subsequent development of adverse perinatal outcomes in newborns with fetal growth restriction (FGR). Given the epigenetic nature of such disorders, the aim of our study was to evaluate the expression of miRNAs associated with OS and endothelial dysfunction (miR-27a-3p, miR-30b-5p, miR-125b-5p, miR-221-3p, miR-451a and miR-574-3p) in umbilical cord blood using real-time quantitative RT-PCR. ΜiRNA expression was evaluated in patients with FGR delivery before (n = 9 pregnant) and after 34 weeks of gestation (n = 13 pregnant), and the control groups corresponding to the main groups by gestational age (13 pregnant women in each group, respectively). A significant increase in miR-451a expression was detected in late-onset FGR and correlations with fetoplacental and cerebral circulation were established (increase of resistance in the umbilical artery (pulsatility index, PI UA (umbilical artery): r = −0.59, p = 0.001) and a decrease in cerebral blood flow (CPR: r = 0.48, p = 0.009)). The change in miR-125b-5p expression in the placenta is associated with reduced Doppler of cerebral hemodynamics (CPR: r = 0.73, p = 0.003; PI MCA (middle cerebral artery): r = 0.79, p = 0.0007), and newborn weight (r = 0.56, p = 0.04) in early-onset FGR. In addition, significant changes in miR-125b-5p and miR-451a expression in umbilical cord blood plasma were found in newborns with neonatal respiratory distress syndrome (NRDS) (in early-onset FGR) and very low birth weight (VLBW) (in late-onset FGR). A number of key signaling pathways have been identified in which the regulation of the studied miRNAs is involved, including angiogenesis, neurotrophin signaling pathway and oxidative stress response. In general, our study showed that changes of the redox homeostasis in the mother-placenta-fetus system in FGR and subsequent perinatal outcomes may be due to differential expression of oxidative stress-associated miRNAs.

Implications of Oxidative Stress and Potential Role of Mitochondrial Dysfunction in COVID-19: Therapeutic Effects of Vitamin D.

Due to its high degree of contagiousness and like almost no other virus, SARS-CoV-2 has put the health of the world population on alert. COVID-19 can provoke an acute inflammatory process and uncontrolled oxidative stress, which predisposes one to respiratory syndrome, and in the worst case, death. Recent evidence suggests the mechanistic role of mitochondria and vitamin D in the development of COVID-19. Indeed, mitochondrial dynamics contribute to the maintenance of cellular homeostasis, and its uncoupling involves pathological situations. SARS-CoV-2 infection is associated with altered mitochondrial dynamics with consequent oxidative stress, pro-inflammatory state, cytokine production, and cell death. Furthermore, vitamin D deficiency seems to be associated with increased COVID-19 risk. In contrast, vitamin D can normalize mitochondrial dynamics, which would improve oxidative stress, pro-inflammatory state, and cytokine production. Furthermore, vitamin D reduces renin–angiotensin–aldosterone system activation and, consequently, decreases ROS generation and improves the prognosis of SARS-CoV-2 infection. Thus, the purpose of this review is to deepen the knowledge about the role of mitochondria and vitamin D directly involved in the regulation of oxidative stress and the inflammatory state in SARS-CoV-2 infection. As future prospects, evidence suggests enhancing the vitamin D levels of the world population, especially of those individuals with additional risk factors that predispose to the lethal consequences of SARS-CoV-2 infection.

The Antioxidants Glutathione, Ascorbic Acid and Uric Acid Maintain Butyrate Production by Human Gut Clostridia in The Presence of Oxygen In Vitro

Uncontrolled oxidative stress, reported in Salmonella and HIV infections, colorectal cancer or severe acute malnutrition, has been associated with anaerobic gut microbiome alteration, impaired butyrate production, mucosal immunity dysregulation and disruption of host-bacterial mutualism. However, the role of major antioxidant molecules in the human body, such as glutathione, ascorbic acid and uric acid, has been neglected in this context. Here, we performed an in vitro metabolomics study of the 3 most odorous anaerobic microbes isolated from the human gut in our laboratory (Clostridium sporogenes, Clostridium subterminale and Romboutsia lituseburensis) when grown in anaerobiosis or in aerobiosis with these 3 antioxidant molecules via gas and liquid chromatography-mass spectrometry (GC/MS and LC/MS). There was no growth or volatile organic compound production in aerobic cultures without the 3 antioxidant molecules. In anaerobiosis, the major metabolic products of the bacteria were thiols, alcohols and short-chain fatty acid esters. The production of alkanes, cycloheptatriene and, paradoxically, increased butyrate production, was observed in the cultures grown in aerobiosis with the 3 antioxidant molecules. The qualitative shift suggests specific molecular mechanisms that remain to be elucidated. The increased production of butyrate, but also isobutyrate and isovalerate in vitro suggests that these 3 antioxidant molecules contributed to the maintenance and active resilience of host-bacterial mutualism against mucosal oxygen and uncontrolled oxidative stress in vivo.

Prenatal stress and its role in children's pathology: historical aspects and the current status of the question (review of literature)

The article presents an analysis of fundamental data on the problem of stress and its role in the development of stressful diseases. Scientific evidence on the role of stress in childhood pathology indicates the extreme pathogenetic significance of stress. It is proved that stress has three interconnected faces: stress as a link in the adaptation mechanism, stress as a link in the pathogenesis of diseases and adaptation to stressful situations as a natural prevention of stressful diseases. The scientific substantiation of the main evolutionarily determined role of stress as an adaptation link indicates the possibility of acquiring some degree of resistance to stressful situations. Prevention of reducing the excess of stress reactions and reducing the possibility of its transformation into a link in the pathogenesis of diseases limits the complex of mechanisms designated as a stress-limiting system. Important information is the development and coordination of the stress response, which is provided by a complex set of mechanisms of neuroendocrine regulation, united by the concept of “stress-implementing system”. The most common forms of stress are fetal hypoxia, metabolic disturbances, and toxic effects leading to uncontrolled oxidative stress at the cellular and tissue levels with the development of pregnancy complications, intrauterine growth retardation syndrome (IUGR), persistent changes and pathological conditions. As the fetus grows, the flow of oxygen and nutrients from the mother through the placenta increases, which is accompanied by an increased risk of the formation of pathologies of the brain, heart, liver and kidneys with the development of a multi-organ pathology in the subsequent life. It has been proven that oxidative stress combined with stress of malnutrition in the prenatal period increases the risk of endocrinopathies, kidney diseases, and a number of other chronic diseases in the adult state. In practical terms, the negative effects of stress are of particular interest. Early detection of psychosocial and sympathomimetic factors causing stress is the basis for the prevention of childhood pathology.

Structural characterization, thermal, DFT, cytotoxicity, and antimetastatic properties of cocaine complexes with La(III), Er(III), and Yb(III)

Reaction of cocaine (Cn) with Ln(III) chloride salts [where Ln = La(III), Er(III), and Yb(III)] afforded complexes of the [Ln(Cn)Cl(OH2)3].2Cl type which were structurally characterized by elemental analysis, conductance measurements, spectroscopic methods, and mass spectrometry. Their thermal properties and kinetic thermodynamic parameters were studied. Theoretical calculations including geometry optimization, thermal energies, and some quantum chemical parameters were carried out at DFT/B3LYP/LANL2DZ level of theory. TD-DFT calculations were also performed to assign their electronic spectra. The in vitro antitumor activity of the newly synthesized complexes was investigated by MTT assay on MCF-7 and HepG-2 cell lines. Er(III) complex exhibited promising cytotoxic activity comparable to that of cisplatin on MCF-7 cell line with high safety on normal human cells. Further molecular mechanistic investigations revealed that Er(III) complex was an apoptotic inducer as it elevated the cellular levels of caspase-3 and caspase-9 in MCF-7 cells. In addition, it displayed an elevating effect on the concentrations of the P21 and P27 tumor suppressor nuclear proteins in MCF-7 cells. Moreover, Er(III) complex hindered the cellular scavenger system of the reactive oxygen species by reducing the cellular level of glutathione peroxidase (GPx) imperiling MCF-7 cells by uncontrolled oxidative stress. Furthermore, Er(III) complex showed antimetastatic properties as it decreased the cellular levels of matrix metalloproteinases MMP-3 and MMP-9. These results concluded that the Er(III) complex is a promising anticancer metal-based agent that exerts its cytotoxic action through various molecular mechanisms with high safety on normal human cells and with additional antimetastatic properties. Er(III)complex of Cn, as a representative example, was synthesized as a promising cytotoxic metal-based agent against human HepG-2 and MCF-7 cancer cells and structurally characterized by different spectral and analytical techniques such as elemental analysis, spectroscopic methods, molar conductivity, thermal analysis, and DFT studies. It exerts its action through various molecular mechanisms such as displaying significant antimetastatic effects by decreasing the secretion of MMP-3 and MMP-9, exhibiting remarkable induction of apoptosis by elevating the levels of caspase-3 and caspase-9proteins, inducing the expression of p21 and p27 tumor suppressor genes, and raising the glutathione peroxidase (GPx) activity.

Role of Tilianin against Acute Lung Injury in In Vitro LPS-Induced Alveolar Macrophage Cells and an In Vivo C57BL/6 Mice Model.

Acute lung injury (ALI) is a disorder of pulmonary tissue caused by prolonged inflammation and uncontrolled oxidative stress. Tilianin is a natural polyphenol, acknowledged for its anti-inflammatory and antioxidant activities. The goal of this work was to explore the effect of tilianin in an LPS-challenged ALI model. The mechanistic investigation was carried out using both in vitro and in vivo experiments. The RAW264.7 macrophage cell and C57BL/6 mice were treated with Tilianin (10 and 20 μM) and then induced with LPS (1 μg/mL) overnight. The C57BL/6 mouse was administered LPS intratracheally (2 mg/kg) to induce ALI prior to tilianin intraperitoneal treatment (10 mg/kg). In vitro, the results showed that Tilianin reduced secretion of LPS-induced proinflammatory cytokine. In vivo, prophylactic treatment with tilianin attenuated infiltration of macrophages and histopathological changes and improved inflammation as shown by a marked reduction in inflammatory mediators found in bronchoalveolar lavage fluid (BALF). Furthermore, tilianin effectively suppressed MDA levels and GSH and SOD in ALI were increased. Collectively, these findings suggest that tilianin is a potential agent for ameliorating LPS-induced ALI.

Human papillomavirus type 18 E5 oncoprotein cooperates with E6 and E7 in promoting cell viability and invasion and in modulating the cellular redox state.

BACKGROUND High-risk human papillomaviruses (HR-HPVs) are the etiological agents of cervical cancer. Among them, types 16 and 18 are the most prevalent worldwide. The HPV genome encodes three oncoproteins (E5, E6, and E7) that possess a high transformation potential in culture cells when transduced simultaneously. In the present study, we analysed how these oncoproteins cooperate to boost key cancer cell features such as uncontrolled cell proliferation, invasion potential, and cellular redox state imbalance. Oxidative stress is known to contribute to the carcinogenic process, as reactive oxygen species (ROS) constitute a potentially harmful by-product of many cellular reactions, and an efficient clearance mechanism is therefore required. Cells infected with HR-HPVs can adapt to oxidative stress conditions by upregulating the formation of endogenous antioxidants such as catalase, glutathione (GSH), and peroxiredoxin (PRX).OBJECTIVES The primary aim of this work was to study how these oncoproteins cooperate to promote the development of certain cancer cell features such as uncontrolled cell proliferation, invasion potential, and oxidative stress that are known to aid in the carcinogenic process.METHODS To perform this study, we generated three different HaCaT cell lines using retroviral transduction that stably expressed combinations of HPV-18 oncogenes that included HaCaT E5-18, HaCaT E6/E7-18, and HaCaT E5/E6/E7-18.FINDINGS Our results revealed a statistically significant increment in cell viability as measured by MTT assay, cell proliferation, and invasion assays in the cell line containing the three viral oncogenes. Additionally, we observed that cells expressing HPV-18 E5/E6/E7 exhibited a decrease in catalase activity and a significant augmentation of GSH and PRX1 levels relative to those of E5, E6/E7, and HaCaT cells.MAIN CONCLUSIONS This study demonstrates for the first time that HPV-18 E5, E6, and E7 oncoproteins can cooperate to enhance malignant transformation.

Synergistic effect of halofuginone and dexamethasone on LPS‑induced acute lung injury in type II alveolar epithelial cells and a rat model.

Acute lung injury (ALI) is characterized by neutrophilic infiltration, uncontrolled oxidative stress and inflammatory processes. Despite various therapeutic regimes having been performed, there remains no effective pharmacotherapy available to treat ALI. Halofuginone (HF), a ketone isolated from Dichroafebrifuga, exhibits significant anti‑inflammatory and antifibrotic effects. Dexamethasone (DEX), a synthetic glucocorticoid, has been routinely used as an adjuvant therapy in treating inflammatory diseases, including ALI. The present study aimed to investigate the effects of the combination of HF and DEX in the treatment of ALI. The present results suggested that the simultaneous administration of HF and DEX markedly decreased the level of pro‑inflammatory cytokines and increased the level of anti‑inflammatory cytokines, as assessed by western blot analysis. In addition, HF and DEX effectively decreased nuclear factor‑κB activity via suppressing the phosphorylation of P65 in lipopolysaccharide (LPS)‑induced human pulmonary alveolar epithelial cells (HPAEpiC) and lung tissues extracted from ALI rats, as determined by immunofluorescence. Furthermore, invivo experiments demonstrated that the combination of HF and DEX in LPS‑induced ALI rats defended against lung fibrosis, perivascular inflammation, congestion and edema of pulmonary alveoli, as assessed by histopathological analysis, TUNEL staining and immunohistochemistry assay. Taken together, the present study indicated the synergistic effect of HF and DEX on LPS‑induced ALI in HPAEpiC cells and a rat model. These results offer a novel therapeutic approach for the treatment of ALI.

Roles of Growth Differentiation Factor 15 in Atherosclerosis and Coronary Artery Disease.

The majority of acute cardiovascular events (CVE) in patients are caused by occlusive thrombosis because of rupture or erosion of atherosclerotic plaques.1 Growth differentiation factor 15 (GDF‐15), a stress‐responsive member of the transforming growth factor‐β (TGF‐β) cytokine superfamily, has been shown to be a strong and independent predictor of mortality and disease progression in patients with atherosclerosis and coronary artery disease (CAD), such as acute coronary syndromes (ACS) and stable angina pectoris.2 The development of atherosclerosis is dependent upon a high‐inflammatory content, which has been shown to modulate lesion initiation, progression, and potentially devastating thrombotic complications.3 Angiogenesis plays an important role in the progression of atherosclerotic plaque and complications.4, 5, 6 Atherosclerosis and cancer arise from multiple factors and are consolidated from the very early stages of development up to the advanced forms in inflammatory processes. Uncontrolled cell proliferation and oxidative stress and angiogenesis appear to be unifying causal factors in both diseases.7 A local inflammatory state occurring in atherosclerotic lesions has been implicated in angiogenesis through activation of endothelial cells, release of chemokines, cytokines, growth factors, lipid mediators, proteases, and increase of endothelial metabolic rate. The angiogenesis allows extravasation of the plasma component, leading to future thromboembolic events.8, 9, 10, 11 GDF‐15 might be an acute phase modifier of TGF‐βRII‐dependent proinflammatory responses to atherosclerotic plaque rupture and thrombus formation12 (Figure). Although the exact biological functions of GDF‐15 are still poorly understood, it has been shown to regulate inflammatory and angiogenesis pathways (Figure). GDF‐15 exhibits differing and even opposing functions under various circumstances. For instance, GDF‐15 has proapoptosis, antiapoptosis, proangiogenesis, antiangiogenesis, proinflammatory, and anti‐inflammatory properties.12, 13 Therefore, GDF‐15 exhibits a complex pattern with beneficial and harmful functions. GDF‐15 promoter contains p53‐transcription factor binding sites that are required and sufficient for the induction of GDF‐15 expression.14 Activation of p53 is a fundamental cellular response to inflammation, oxidative stress, hypoxia, telomere erosion, and oncogene activation. The circulating levels of GDF‐15 reflect these acute and chronic inflammatory conditions linked with atherosclerosis and CAD. Open in a separate window Figure 1 Schematic overview of a vulnerable plaque in advanced atherosclerosis. Plaque formation is initiated by endothelial cell dysfunction and subsequent angiogenesis and release of proinflammatory factors mediated by GDF‐15, contributing to the progression of atherosclerotic lesions and the development of plaque rupture and thrombus formation in atherosclerotic status. CRP indicates C‐reactive protein; GDF‐15, growth differentiation factor 15; MAPK, mitogen‐activated protein kinase; M‐CSF, macrophage colony‐stimulating factor; TGF‐βRII, transforming growth factor‐βRII; TNF‐α, tumor necrosis factor‐α.

Factors affecting the pathophysiology of sepsis, an inflammatory disorder: Key roles of oxidative and nitrosative stress

Sepsis, one of the primary causes of mortality in the intensive care units, occurs due to the host’s dysregulated immune responses to an infection. Consequently, persistent systemic inflammation along with suppressed adaptive immunity ensues, resulting in deranged metabolism, recurrent infections, tissue damage and multi-organ failure. The uncontrolled oxidative stress mediated by the imbalance between the generation of reactive oxygen species and their neutralization by the host’s antioxidant system is involved in inflammation-induced damage. The profound deleterious effects in the host range from mitochondrial dysfunction and endothelial damage to reduced cardiac output. Therefore, antioxidant therapy was actively considered to have therapeutic benefits in sepsis patients. Although some success has been obtained with the use of antioxidants in sepsis patients, considerable ambiguity persists that prevents their routine use. Another key molecule that may dictate the outcome and prognosis during sepsis is nitric oxide (NO). This pleiotropic molecule plays a central role in inflammation and in leukocyte recruitment at the site of inflammation. NO is synthesized by three different isoforms of nitric oxide synthases (NOS) and significantly high and sustained levels of NOS2 have been reported in sepsis. Abundant literature supports the protective roles of NO during sepsis; however, there is uncertainty in various reports. The administration of NO donors in clinical trials for sepsis treatment has encountered limited success. NO, during sepsis, acts like a double-edged sword: increased NO levels can result in hypotension, whereas reduced levels contribute to poor organ perfusion and an elevated susceptibility to infection. Therefore, several parameters need to be evaluated, while considering the potential of antioxidant and NO-based therapy during sepsis.

Protective Effect of Methane-Rich Saline on Acetic Acid-Induced Ulcerative Colitis via Blocking the TLR4/NF-κB/MAPK Pathway and Promoting IL-10/JAK1/STAT3-Mediated Anti-inflammatory Response.

Ulcerative colitis (UC) is an inflammation-related disease involved in uncontrolled inflammation and oxidative stress and is characterized by high recurrence and relapse risk. As a rising star in gas medicine, methane owns the properties of anti-inflammation, antioxidation, and antiapoptosis. Based on the possible mechanism, we aimed to investigate the effect of methane on UC. Methane-rich saline (MRS) was introduced here, and UC was induced by acetic acid. All the C57BL/6 mice were allocated into groups as follows: control group, colitis model group, colitis treated with salazosulfapyridine (SASP) group, and colitis treated with MRS (1 or 10 ml/kg) groups. Tissue damage, the degree of inflammation, oxidative stress, and apoptosis were evaluated in the study, as well as the TLR4/NF-κB/MAPK and IL-10/JAK1/STAT3 signaling pathways for further exploration of the potential mechanism. The results showed that MRS (1) alleviated tissue damage caused by acetic acid, (2) controlled acetic acid-induced inflammation, (3) inhibited acetic acid-caused oxidative stress, (4) reduced colonic cell apoptosis due to acetic acid, (5) suppressed the TLR-4/NF-κB/MAPK signaling pathway, and (6) activated IL-10/JAK1/STAT3 anti-inflammatory response to improve the injury induced by acetic acid. We conclude that MRS has a protective effect on acetic acid-induced ulcerative colitis in mice via blocking the TLR4/NF-κB/MAPK signaling pathway and promoting the IL-10/JAK1/STAT3-mediated anti-inflammatory response.

Corilagin alleviates acetaminophen-induced hepatotoxicity via enhancing the AMPK/GSK3\u03b2-Nrf2 signaling pathway

BackgroundAcetaminophen (APAP) overdose-induced acute liver failure (ALF) is mainly resulted from uncontrolled oxidative stress. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a key antioxidant transcription factor, is essential for alleviating APAP-induced hepatotoxicity. Corilagin (Cori) is a natural polyphenol compound that possesses effective antioxidant activity; however, the protective effect of Cori on APAP-induced hepatotoxicity is still unknown. The current study aimed to explore whether Cori could mitigate hepatotoxicity caused by APAP and the underlying molecular mechanisms of action.MethodsCell counting kit-8 (CCK-8) assays, Western blotting analysis, dual-luciferase reporter assays, a mouse model, CRISPR/Cas9 knockout technology, and hematoxylin-eosin (H & E) staining were employed to explore the mechanisms by which Cori exerts a protective effect on hepatotoxicity in HepG2 cells and in a mouse model.ResultsOur findings suggested that Cori efficiently decreased APAP-triggered the generation of reactive oxygen species (ROS) and cell death in HepG2 cells. Additionally, Cori significantly induced the expression of several antioxidant enzymes, and this induced expression was closely linked to the upregulation of Nrf2, inhibition of Keap1 protein expression, and promotion of antioxidant response element (ARE) activity in HepG2 cells. Moreover, Cori clearly induced the phosphorylation of AMP-activated protein kinase (AMPK), glycogen synthase kinase-3β (GSK3β), liver kinase B1 (LKB1) and acetyl-CoA carboxylase (ACC). Furthermore, Cori-mediated GSK3β inactivation, Nrf2 upregulation and cytoprotection were abolished by an AMPK inhibitor (Compound C) in HepG2 cells. Lastly, we found that Cori inhibited APAP-induced hepatotoxicity and mediated the expression of many antioxidant enzymes; these results were reversed in Nrf2 −/− HepG2 cells. In vivo, Cori significantly protected against APAP-induced ALF by reducing mortality and alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, attenuating histopathological liver changes, inhibiting myeloperoxidase (MPO) and malondialdehyde (MDA) levels, and increasing the superoxide dismutase (SOD) content and GSH-to-GSSG ratio as well as suppressing c-jun N-terminal kinase (JNK) phosphorylation. However, Cori-induced reductions in mortality, AST and ALT levels, and histopathological liver changes induced by APAP were clearly abrogated in Nrf2-deficienct mice.ConclusionsThese findings principally indicated that Cori effectively protects against APAP-induced ALF via the upregulation of the AMPK/GSK3β-Nrf2 signaling pathway.

Anti-hyperglycemic potential of Hyptis verticillata jacq in streptozotocin-induced diabetic rats

Uncontrolled hyperglycaemia and oxidative stress have been implicated in the pathophysiology of diabetes mellitus. Hyptis verticillata is reportedly explored traditionally for its therapeutic benefits. Resulting from the paucity of information on the anti-hyperglycaemic potential of this plant, the present study assessed the anti-hyperglycaemic activity of H. verticillata leaf extract. Fifty-four albino Wistar rats were divided into two main groups consisting of diabetic and non-diabetic rats. The diabetic and non-diabetic rats were either treated with oral doses of metformin (500 mg/kg b.w.), quercetin (10 mg/kg b.w.), ethanol extract of H. verticillata leaf (low dose: 250 mg/kg b.w.) or H. verticillata (high dose: 500 mg/kg b.w.) for 28 days. Results showed significantly decreased body weight, increased fasting blood glucose (FBG) and glycated haemoglobin (HbA1c) levels, decreased pancreatic islet area and β-cell number in the diabetic untreated group, relative to normal control. H. verticillata – treated diabetic rats showed decreased FBG and HbA1c, increased body weight, pancreatic islet area and β-cell number, comparable to the effects of metformin. GCMS analysis of H. verticillata showed the presence of ten bioactive volatile compounds, with squalene which possess strong antioxidant, hypoglycaemic and hypotriglyceridemic effects, as the most abundant. We therefore conclude that H. verticillata has anti-hyperglycaemic properties.

Linking gut redox to human microbiome

Uncontrolled oxidative stress has been associated with many diseases and aging. We previously report an increased gut redox and depletion of the anaerobic microbiome in severe acute malnutrition. Here, we extended the analysis to test if this link could be generalized by including individuals with various age and dietary status. Seventy individuals (children and adults, French and African, healthy individuals and teenagers with anorexia nervosa, marasmus and kwashiorkor) were included. Fecal redox potential was measured using a simple redox probe. v3v4 16S gene targeted metagenomics was used to characterize the microbiota. The Metagenomic Aerotolerant Predominance Index (MAPI) was defined as the natural logarithm of the ratio of the relative abundance of aerotolerant on strict anaerobic species. This index is easily understandable (MAPI > 0: aerotolerant predominance, MAPI < 0: anaerobic predominance), can be calculated for any metagenome and follows a normal distribution among our 70 included individuals. Fecal redox potential (mV) and the Metagenomic Aerotolerant Predominance Index were dose-dependently related (linear regression, p < .001). This link, if confirmed, will allow humans to take care of their microbiome and prevent, treat and/or alleviate gut redox associated chronic diseases by (i) controlling the concentration of reactive species in the gut by avoiding behavior associated with uncontrolled oxidative stress (alcoholism,…) in the gut and using reduced water, and (ii) by improving gut anti-oxidant capacities by an adequate diet rich in nutrients allowing the human gut to maintain a very low redox potential in the gut as a key for homeostasis.

Beneficial Effects Exerted by Paeonol in the Management of Atherosclerosis.

Atherosclerosis, a chronic luminal stenosis disorder occurred in large and medium arteries, is the principle pathological basis of cardiovascular diseases with the highest morbidity and mortality worldwide. In oriental countries, traditional Chinese medicine Cortex Moutan has been widely used for the treatment of atherosclerosis-related illnesses for thousands of years. Paeonol, a bioactive monomer extracted from Cortex Moutan, is an important pharmacological component responsible for the antiatherosclerotic effects. Numerous lines of findings have established that paeonol offers beneficial roles against the initiation and progression of atherosclerotic lesions through inhibiting proatherogenic processes, such as endothelium damage, chronic inflammation, disturbance of lipid metabolism, uncontrolled oxidative stress, excessive growth, and mobilization of vascular smooth muscle cells as well as abnormality of platelet activation. Investigations identifying the atheroprotective effects of paeonol present substantial evidence for potential clinical application of paeonol as a therapeutic agent in atherosclerosis management. In this review, we summarize the antiatherosclerotic actions by which paeonol suppresses atherogenesis and provide newly insights into its atheroprotective mechanisms and the future clinical practice.

A new direction for Alzheimer's research.

Despite decades of research, at present there is no curative therapy for Alzheimer's disease. Changes in the way new drugs are tested appear to be necessary. Three changes are presented here and will be discussed. The first change is that Alzheimer's disease must be considered a disease of four major pathological processes, not one. The four processes are: 1) vascular hypoperfusion of the brain with associated mitochondrial dysfunction, 2) destructive protein inclusions, 3) uncontrolled oxidative stress, and 4) proinflammatory immune processes secondary to microglial and astrocytic dysfunction in the brain. The second change recommended is to alter the standard cognitive measurement tools used to quantify mental decline in test patients. Specifically the Dementia Severity Rating Scale (DSRS) should supersede Mini-Mental State Examination (MMSE) and other popular tests, and a measurement scale developed in research should be used to produce a linear and non-irregular baseline. Finally, accepting the concept that four etiologies cause Alzheimer's disease leads to the last necessary change, that new therapies must be employed directed against all four causes, likely as a combination. There are drugs ready to be employed in such a combinations which are available and used clinically for other purposes so can be used “off label” and one such combination is suggested.

Influence of the phenotype of the disease on the parameters of the antioxidant defense system and the level of some interleukins in the blood of patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a common disease involving the pathological process, of bronchopulmonary and cardiovascular systems. This is a complex disease in which inflammation plays a leading role in the formation of the whole complex of pathological changes. COPD accompanies local deficit of antiproteases, excessive formation of active forms of oxygen, inducing uncontrolled lipid peroxidation and oxidative stress. An increase in the level of proinflammatory cytokines, such as IL-6, IL-8, TNF-α, is particularly significant in the combination of chronic obstructive disease with metabolic syndrome. Determination of a specific phenotype of COPD, and the degree of disruption of protective and adaptive systems in these forms of the disease course allows optimizing the treatment regimens for patients. The purpose of this work was to identify additional biochemical and biophysical markers of phenotyping and monitoring of therapy in patients with COPD of different phenotype and severity level in the acute stage on the basis of studying the main indicators of the system of antioxidant protection of blood and some cytokines. Significant differences in antioxidant system (AOS) indices in patients with COPD of different phenotype and severity were determined. The established differences in the activity of erythrocyte enzymes and the overall antioxidant activity of blood plasma can serve as an important additional link for the phenotyping of COPD. Complex treatment with the use of anticoagulants, normalizing the rheological properties of blood and mucolytics with pronounced antioxidant properties, reduces the level of prooxidant load on the body due to correction of metabolic processes and has the most pronounced effect on AOS blood parameters and cytokine profile.