Lipid Peroxidation Modification Research Articles

Hesperetin alleviates aflatoxin B1 induced liver toxicity in mice: Modulating lipid peroxidation and ferritin autophagy

One of the ways Aflatoxin B1 damages the liver is through ferroptosis. Ferroptosis is characterized by the build-up of lipid peroxides and reactive oxygen species (ROS) due to an excess of iron. Dietary supplements have emerged as a promising strategy for treating ferroptosis in the liver. The flavonoid component hesperetin, which is mostly present in citrus fruits, has a number of pharmacological actions, such as those against liver fibrosis, cancer, and hyperglycemia. However, hesperetin's effects and mechanisms against hepatic ferroptosis are still unknown. In this study, 24 male C57BL/6 J mice were randomly assigned to CON, AFB1 (0.45 mg/kg/day), and AFB1+ hesperetin treatment groups (40 mg/kg/day). The results showed that hesperetin improved the structural damage of the mouse liver, down-regulated inflammatory factors (Cxcl1, Cxcl2, CD80, and F4/80), and alleviated liver fibrosis induced by aflatoxin B1. Hesperetin reduced hepatic lipid peroxidation induced by iron accumulation by up-regulating the levels of antioxidant enzymes (GPX4, GSH-Px, CAT, and T-AOC). It is worth noting that hesperetin not only improved lipid peroxidation but also maintained the dynamic balance of iron ions by reducing ferritin autophagy. Mechanistically, hesperetin's ability to regulate ferritin autophagy mostly depends on the PI3K/AKT/mTOR/ULK1 pathway. In AFB1-induced HepG2 cells, the addition of PI3K inhibitor (LY294002) and AKT inhibitor (Miransertib) confirmed that hesperetin regulated the PI3K/AKT/mTOR/ULK1 pathway to inhibit ferritin autophagy and reduced the degradation of ferritin in lysosomes. In summary, our results suggest that hesperetin not only regulates the antioxidant system but also inhibits AFB1-induced ferritin hyperautophagy, thereby reducing the accumulation of iron ions to mitigate lipid peroxidation. This work provides a fresh perspective on the mechanism behind hesperetin and AFB1-induced liver damage in mice.

Elucidating PAR1 as a therapeutic target for delayed traumatic brain injury: Unveiling the PPAR-γ/Nrf2/HO-1/GPX4 axis to suppress ferroptosis and alleviate NLRP3 inflammasome activation in rats

Repetitive traumatic brain injury (RTBI) is acknowledged as a silent overlooked public health crisis, with an incomplete understanding of its pathomechanistic signaling pathways. Mounting evidence suggests the involvement of thrombin and its receptor, the protease-activated receptor (PAR)1, in the development of secondary injury in TBI; however, the consequences of PAR1 modulation and its impact on ferroptosis-redox signaling, and NLRP3 inflammasome activation in RTBI, remain unclear. Further, the utilitarian function of PAR1 as a therapeutic target in RTBI has not been elucidated. To study this crosstalk, RTBI was induced in Wistar rats by daily weight drops on the right frontal region for five days. Three groups were included: normal control, untreated RTBI, and RTBI+SCH79797 (a PAR1 inhibitor administered post-trauma at 25 μg/kg/day). The concomitant treatment of PAR1 antagonism improved altered behavior function, cortical histoarchitecture, and neuronal cell survival. Moreover, the receptor blockade downregulated mRNA expression of PAR1 but upregulatedthat of the neuroprotective receptor PPAR-γ. The anti-inflammatory impact of SCH79797 was signified by the low immune expression/levels of NF-κB p65,TNF-α, IL-1β, and IL-18. Consequently, the PAR1 blocker hindered the formation of inflammasome components NLRP3, ASC, and activated caspase-1. Ultimately, SCH79797 treatment abated ferroptosis-dependent iron redox signaling through the activation of the antioxidant Nrf2/HO-1 axis and its subsequent antioxidant machinery (GPX4, SOD) to limit lipid peroxidation, iron accumulation, and transferrin serum increment. Collectively, SCH79797 offered putative preventive mechanisms against secondary RTBI consequences in rats by impeding ferroptosis and NLRP3 inflammasome through activating the PPAR-γ/Nrf2 antioxidant cue.

Abstract 360: Dissecting the role of oncogenic KRAS and ferroptosis within colorectal cancer

Abstract Introduction: Ferroptosis is a novel iron-dependent regulated cell death mechanism triggered by a toxic accumulation of membrane lipid peroxidation. This mechanism is counteracted by ferroptosis defense systems, such as the GPX4/GSH system, which function as antioxidants that limit lipid peroxidation. Oncogenic KRAS (KRASmut) is a key driver for many aggressive cancers, including colorectal cancer (CRC). Previous studies have suggested that oncogenic KRAS plays a pleiotropic role in the ferroptosis pathway. Yet, the interplay between oncogenic KRAS and ferroptosis has not been fully elucidated in CRC. Here, we aimed to dissect the role of oncogenic KRAS in ferroptosis using CRC as a cancer model. Methods: Cells from a KRAS-inducible model (iKAP) were seeded and treated with ferroptosis-inducing drugs (e.g., Erastin and RSL3) and/or a KRAS inhibitor (MRTX1133). Lipid peroxidation was then measured by BODIPY assay followed by flow cytometry to detect the quantity of BODIPY-stained cells. Protein expression of known ferroptosis defense mechanisms was also profiled (e.g., SLC7A11 [xCT] and GPX4). Results: Results from this study demonstrate that KRASmut activation leads to a reduction in mean fluorescence intensity when compared to KRASWT of BODIPY-stained cells. This decreased mean fluorescence intensity is indicative of lower levels of lipid peroxidation and, consequently, ferroptosis. KRASmut cells were also found to be resistant to ferroptosis following treatment with ferroptosis inducers. To replicate a pharmacologically induced KRASWT phenotype, iKAP cells were treated with MRTX1133, which led to a significant decrease in viability when combined with RSL3. We observed a decreased protein expression of the membrane antiporter xCT following treatment with MRTX1133, which we believe works synergistically with the GPX4 inhibition of RSL3. Conclusion: We observed that KRASmut may induce resistance to ferroptosis in vitro in CRC cells. Genetic and pharmacological inhibition of KRAS resulted in sensitization to ferroptosis inducers. Future work will uncover mechanisms through which oncogenic KRAS leads to ferroptosis resistance in CRC. More importantly, understanding the interaction between ferroptosis, oncogenic KRAS, and its antagonist systems has significant therapeutic potential in oncology. Citation Format: Alexandra Rosa-Vázquez, Vincent Bernard-Pagan, Jasper Chen, Cullen Taniguchi. Dissecting the role of oncogenic KRAS and ferroptosis within colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 360.

Glycitein prevents reserpine-induced depression and associated comorbidities in mice: modulation of lipid peroxidation and TNF-α levels.

Depression is a debilitating mood disorder affecting millions worldwide and continues to pose a significant global health burden. Due to the multifaceted nature of depression, the current treatment regimens are not up to mark in terms of their multitargeting potential and least side effect profile. Molecules within the isoflavone class demonstrate promising potential in alleviating depression and associated conditions, offering a multifaceted approach to manage mental health concerns. Therefore, the current study was designed to explore the potential of glycitein, an isoflavone in managing reserpine-induced depression and associated comorbidities in mice. Reserpine (0.5mg/kg; i.p.) administration for the first 3days induced depression and associated comorbidities as evidenced by increased immobility time in forced swim test (FST) and tail suspension test (TST), along with reduced locomotor activity in the open field test (OFT) and increased latency to reach the platform in the Morris water maze (MWM) test. Reserpine treatment also upregulated and downregulated the brain thiobarbituric acid reactive substance (TBARS) and glutathione (GSH) levels, respectively. Furthermore, reserpine administration also uplifted the level of TNF-α in the serum samples. Glycitein (3mg/kg and 6mg/kg; p.o.) treatment for 5days prevented the depressive effect of reserpine. It also improved the spatial memory at both dose levels. Moreover, in biochemical analysis, glycitein also reduced the brain TBARS and serum tumor necrosis factor-alpha (TNF-α) levels. Whereas, no significant effect was seen on the brain GSH level. Glycitein (6mg/kg) was found to be more effective than the 3mg/kg dose of glycitein. Overall results delineate that glycitein has the potential to manage depression and impaired memory by inhibiting lipid peroxidation and inflammatory stress.

6-Gingerol ameliorates ulcerative colitis by inhibiting ferroptosis based on the integrative analysis of plasma metabolomics and network pharmacology.

6-Gingerol (6-G), an active ingredient of ginger with anti-inflammation and anti-oxidation properties, can treat ulcerative colitis (UC). However, its underlying mechanism is still unclear. In this study, the pharmacodynamic evaluation of 6-G for treating UC was performed, and the mechanism of 6-G in ameliorating UC was excavated by plasma metabolomics and network pharmacology analysis, which was further validated by experimental and molecular docking. The results showed that 6-G could notably reduce diarrhea, weight loss, colonic pathological damage, and inflammation in UC mice. Plasma metabolomic results indicated that 6-G could regulate 19 differential metabolites, and its metabolic pathways mainly involved linoleic acid metabolism and arachidonic acid metabolism, which were closely associated with ferroptosis. Moreover, 60 potential targets for 6-G intervention on ferroptosis in UC were identified by network pharmacology, and enrichment analysis revealed that 6-G suppressed ferroptosis by modulating lipid peroxidation. Besides, the integration of metabolomics and network pharmacology showed that the regulation of 6-G on ferroptosis focused on 3 key targets, including ALOX5, ALOX15, and PTGS2. Further investigation indicated that 6-G significantly inhibited ferroptosis by decreasing iron load and malondialdehyde (MDA), and enhanced antioxidant capacity by reducing the content of glutathione disulfide (GSSG) and increasing the levels of superoxide dismutase (SOD) and glutathione (GSH) in UC mice and RSL3-induced Caco-2 cells. Furthermore, molecular docking showed the high affinity of 6-G with the identified 3 key targets. Collectively, this study elucidated the potential of 6-G in ameliorating UC by inhibiting ferroptosis. The integrated strategy also provided a theoretical basis for 6-G in treating UC.

Ginsenoside Rg1 Attenuates Eccentric Exercise-Induced Muscle Damage via the Modulation of Lipid Peroxidation and Inflammation

Eccentric exercise (EE) may lead to skeletal muscle injury, including oxidative stress and inflammation induction. Ginsenoside Rg1, a glycosylated triterpene present in the traditional Chinese medicine ginseng, was previously shown to prevent the development of multiple diseases through the attenuation of oxidative stress and inflammation. Therefore, this article hopes to investigate whether Rg1 exhibits anti-oxidant and anti-inflammatory effects in eccentric exercise-induced muscle damage (EEIMD). Additionally, Adult male Wistar rats were intraperitoneally injected with Rg1 (20 or 40 mg/kg) every day before EE for 5 consecutive days. The impact of Rg1 administration on levels of serum creatine kinase was evaluated, followed by observation of histological muscle damage through H&E staining. To assess protein nitrotyrosylation, lipid peroxidation and leukocyte infiltration in rat skeletal muscles, the levels of nitrotyrosine, MDA and MPO protein were analysed through western blotting analysis. The inflammatory response was evaluated by detecting iNOS, COX-2, IL-1β, IL-6, MCP-1 and TNF-α mRNA and protein levels in rat skeletal muscles. The regulation of Rg1 on the NF-κB pathway was examined through the analysis of phosphorylated NF-κB p65 and IκBα protein levels. Result display, EE resulted in elevated serum creatine kinase levels, widespread leukocyte infiltration, and notable muscle cell vacuolization and fragmentation in muscles. Furthermore, EE increased nitrotyrosine, MDA, MPO, iNOS, COX-2, IL-1β, IL-6, MCP-1, and TNF-α levels in rats. However, these changes were reversed by Rg1 treatment. Furthermore, EE-induced upregulation in phosphorylated NF-κB p65 and IκBα levels was counteracted by Rg1. Overall, ginsenoside Rg1 plays an anti-oxidant and anti-inflammatory role in EEIMD through suppressing this NF-κB signaling pathway.

Butin prevent liver damage triggered by D-galactosamine via regulating lipid peroxidation and proinflammatory cytokines in rodents

ObjectivesLiver damage is becoming a more severe problem around the world. Unfortunately, there is still a great need for clinically effective pharmacological therapy for liver injury. The investigation aimed to assess the favorable outcome of butin hepatoprotective efficacy against D-galactosamine (D-GalN)-produced liver damage in experimental rats. MethodsA single dose of D-GalN 400 mg/kg b. wt. was injected intraperitoneally, 24 hr prior to scarification of rats to cause liver damage. The liver injury was assessed biochemically, investigating parameters like aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT), γ-glutamyl transferase (GGT), total-bilirubin, -albumin and -protein. Butin (25 and 50 mg/kg b. wt.) was managed for 21st days and at the end of the experimental period, normal control, D-GalN control, and butin treatment group rats for further biochemical as well as histopathological consideration. ResultsButin pretreatment significantly attenuated D-GalN-induced hepatocytes damage by reducing hepatic markers and its ability in attenuating oxidative damage (MDA, GSH, SOD, CAT) and pro-inflammatory cytokine (TNF-α, IL-6, IL-1β) and MPO. Histopathological assessment of the liver and biochemical estimation confirmed the hepatoprotective effects of butin. Conclusions: These results demonstrated that butin protects experimental rats against D-GalN-induced liver injury by modulating lipid peroxidation and pro-inflammatory cytokine. Current research will give preliminary experimental evidence for butin, and possible therapeutic effects in liver disorders.

Hepatoprotective effects of ethnic cabbage dishes: a comparison study on kimchi and pao cai

Consuming ethnic vegetable dishes, that has been an integral part in the food culture of many countries, is suggested to bring health benefits to humans. Kimchi from Korea and pao cai from China are two distinct vegetable dishes made from Chinese cabbage (Brassica rapa) through different processes. While kimchi is a fermented food, pao cai is produced by pickling in brine or vinegar. The present study aimed to investigate and compare the hepatoprotective effects of kimchi and pao cai in vivo using animal model and in vitro using a cell line. Despite having similar nutritional profiles, kimchi and pao cai exhibited different chemical and microbiological properties. Compared to pao cai, the pH during fermentation of kimchi dropped more rapidly and the antioxidant activity of kimchi was also stronger. In addition, total microorganisms and lactic acid bacteria were consistently higher in kimchi than in pao cai. In vivo, the hepatoprotective properties of kimchi and pao cai were associated with the increase in expression and activity of major liver antioxidant enzymes, particularly glutathione reductase, glutathione peroxidase, glutathione S-transferase, catalase, and superoxide dismutase. In vitro, both kimchi and pao cai promoted the formation of glutathione. Upon exposure to chemically induced oxidative stress, kimchi protected liver cells by inhibiting glutathione depletion and limiting lipid peroxidation. In general, kimchi demonstrated stronger hepatoprotective properties compared to pao cai. Thus, the present study provides promising insights into the development of ethnic foods, particularly kimchi and pao cai, as functional foods beneficial for human health.

Prolyl oligopeptidase inhibition ameliorates experimental pulmonary fibrosis both in vivo and in vitro

BackgroundPulmonary fibrosis is a progressive disease characterized by lung remodeling due to excessive deposition of extracellular matrix. Although the etiology remains unknown, aberrant angiogenesis and inflammation play an important role in the development of this pathology. In this context, recent scientific research has identified new molecules involved in angiogenesis and inflammation, such as the prolyl oligopeptidase (PREP), a proteolytic enzyme belonging to the serine protease family, linked to the pathology of many lung diseases such as pulmonary fibrosis. Therefore, the aim of this study was to investigate the effect of a selective inhibitor of PREP, known as KYP-2047, in an in vitro and in an in vivo model of pulmonary fibrosis.MethodsThe in vitro model was performed using human alveolar A549 cells. Cells were exposed to lipopolysaccharide (LPS) 10 μg/ml and then, cells were treated with KYP-2047 at the concentrations of 1 μM, 10 μM and 50 μM. Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide colorimetric assay, while inflammatory protein expression was assessed by western blots analysis. The in vivo model was induced in mice by intra-tracheal administration of bleomycin (1 mg/kg) and then treated intraperitoneally with KYP-2047 at doses of 1, 2.5 and 5 mg/kg once daily for 12 days and then mice were sacrificed, and lung tissues were collected for analyses.ResultsThe in vitro results demonstrated that KYP-2047 preserved cell viability, reduced inflammatory process by decreasing IL-18 and TNF-α, and modulated lipid peroxidation as well as nitrosative stress. The in vivo pulmonary fibrosis has demonstrated that KYP-2047 was able to restore histological alterations reducing lung injury. Our data demonstrated that KYP-2047 significantly reduced angiogenesis process and the fibrotic damage modulating the expression of fibrotic markers. Furthermore, KYP-2047 treatment modulated the IκBα/NF-κB pathway and reduced the expression of related pro-inflammatory enzymes and cytokines. Moreover, KYP-2047 was able to modulate the JAK2/STAT3 pathway, highly involved in pulmonary fibrosis.ConclusionIn conclusion, this study demonstrated the involvement of PREP in the pathogenesis of pulmonary fibrosis and that its inhibition by KYP-2047 has a protective role in lung injury induced by BLM, suggesting PREP as a potential target therapy for pulmonary fibrosis. These results speculate the potential protective mechanism of KYP-2047 through the modulation of JAK2/STAT3 and NF-κB pathways.Graphical abstract

Inhibition of Ferroptosis Enables Safe Rewarming of HEK293 Cells following Cooling in University of Wisconsin Cold Storage Solution

The prolonged cooling of cells results in cell death, in which both apoptosis and ferroptosis have been implicated. Preservation solutions such as the University of Wisconsin Cold Storage Solution (UW) encompass approaches addressing both. The use of UW improves survival and thus extends preservation limits, yet it remains unclear how exactly organ preservation solutions exert their cold protection. Thus, we explored cooling effects on lipid peroxidation and adenosine triphosphate (ATP) levels and the actions of blockers of apoptosis and ferroptosis, and of compounds enhancing mitochondrial function. Cooling and rewarming experiments were performed in a cellular transplantation model using Human Embryonic Kidney (HEK) 293 cells. Cell viability was assessed by neutral red assay. Lipid peroxidation levels were measured by Western blot against 4-Hydroxy-Nonenal (4HNE) and the determination of Malondialdehyde (MDA). ATP was measured by luciferase assay. Cooling beyond 5 h in Dulbecco’s Modified Eagle Medium (DMEM) induced complete cell death in HEK293, whereas cooling in UW preserved ~60% of the cells, with a gradual decline afterwards. Cooling-induced cell death was not precluded by inhibiting apoptosis. In contrast, the blocking of ferroptosis by Ferrostatin-1 or maintaining of mitochondrial function by the 6-chromanol SUL150 completely inhibited cell death both in DMEM- and UW-cooled cells. Cooling for 24 h in UW followed by rewarming for 15 min induced a ~50% increase in MDA, while concomitantly lowering ATP by >90%. Treatment with SUL150 of cooled and rewarmed HEK293 effectively precluded the increase in MDA and preserved normal ATP in both DMEM- and UW-cooled cells. Likewise, treatment with Ferrostatin-1 blocked the MDA increase and preserved the ATP of rewarmed UW HEK293 cells. Cooling-induced HEK293 cell death from hypothermia and/or rewarming was caused by ferroptosis rather than apoptosis. UW slowed down ferroptosis during hypothermia, but lipid peroxidation and ATP depletion rapidly ensued upon rewarming, ultimately resulting in complete cell death. Treatment throughout UW cooling with small-molecule Ferrostatin-1 or the 6-chromanol SUL150 effectively prevented ferroptosis, maintained ATP, and limited lipid peroxidation in UW-cooled cells. Counteracting ferroptosis during cooling in UW-based preservation solutions may provide a simple method to improve graft survival following cold static cooling.

The Interplay of Exogenous and Endogenous Hydrogen Sulfide (H2S) in Maintaining Redox Homeostasis in Individuals with Low Ferritin Levels

The primary objective of this study was to investigate the influence of living near a thermal spring and being exposed to hydrogen sulfide (H2S) gas, which lingers in the surrounding atmosphere, on the redox and lipid peroxidation status of individuals with low ferritin levels. Participants in the study were divided into two groups based on their H2S exposure frequency and ferritin levels. Within Group A, individuals who did not experience occasional H2S exposure (2–3 h, 2–3 times per year) and had an average of normal ferritin levels of 87.5 ng/mL exhibited lower levels of oxidative stress and lipid peroxidation compared to those with low ferritin levels (average of 6.57 ng/mL) in the same group. Additionally, individuals with normal ferritin levels showed higher levels of thiol, H2S, and antioxidant capacity. However, it was observed that individuals with low ferritin levels had significantly lower levels of endogenous H2S and thiol and higher levels of oxidative stress and lipid peroxidation. In Group B, individuals who experienced occasional H2S exposure (2–3 h, 10–12 times per year) and had an average of normal ferritin levels of 91.65 ng/mL showed lower oxidative stress and lipid peroxidation, as well as higher thiol, H2S, and antioxidant capacity. Surprisingly, individuals in Group B with low ferritin levels (average of 6.18 ng/mL) showed increased endogenous levels of H2S, which resulted in lower oxidative stress, and lipid peroxidation. These findings suggest that inhaling environmental H2S emitted from thermal springs may serve as an adaptive and protective mechanism for individuals with low ferritin levels by enhancing antioxidant capacity and reducing oxidative stress and lipid peroxidation modification, thus mitigating the harmful effects of reactive oxygen species.

Deciphering the melatonin-mediated response andsignalling intheregulation ofheavy metal stress in plants.

Melatonin has a protective effect against heavy metal stress in plants by immobilizing HM in cell walls and sequestering them in root cell vacuoles, reducing HM's translocation from roots to shoots. It enhances osmolyte production, increases antioxidant enzyme activity, and improves photosynthesis, thereby improving cellular functions. Understanding the melatonin-mediated response and signalling can sustain crop production in heavy metal-stressed soils. Melatonin is a pleiotropic signal molecule that plays a critical role in plant growth and stress tolerance, particularly against heavy metals in soil. Heavy metals (HMs) are ubiquitously found in the soil-water environment and readily taken up by plants, thereby disrupting mineral nutrient homeostasis, osmotic balance, oxidative stress, and altered primary and secondary metabolism. Plants combat HM stress through inbuilt defensive mechanisms, such as metal exclusion, restricted foliar translocation, metal sequestration and compartmentalization, chelation, and scavenging of free radicals by antioxidant enzymes. Melatonin has a protective effect against the damaging effects of HM stress in plants. It achieves this by immobilizing HM in cell walls and sequestering them in root cell vacuoles, reducing HM's translocation from roots to shoots. This mechanism improves the uptake of macronutrients and micronutrients in plants. Additionally, melatonin enhances osmolyte production, improving the plant's water relations, and increasing the activity of antioxidant enzymes to limit lipid peroxidation and reactive oxygen species (ROS) levels. Melatonin also decreases chlorophyll degradation while increasing its synthesis, and enhances RuBisCO activity for better photosynthesis. All these functions contribute to improving the cellular functions of plants exposed to HM stress. This review aims to gain better insight into the melatonin-mediated response and signalling under HM stress in plants, which may be useful in sustaining crop production in heavy metal-stressed soils.

Stem bark methanolic extract of Bauhinia thonningii (Schum) demonstrates gastroprotective properties against in vivo ethanol-induced injury

Background: Stomach ulcer is one of the diseases that many patients suffer from all over the world, and it causes damage to the intestinal wall. Some research has shown that Bauhinia thonningii extract, which has been traditionally used to treat a variety of ailments, including stomach ulcers, has powerful antioxidant and mucus-increasing properties. Objective:This research is aimed at studying the mechanism(s) through which methanolic (MBST) and chloroform (CBST) extracts of B. thonningii stem bark protects against ethanol-induced stomach damage in rats. Material and Methods: MBST and CBST were evaluated in vivo for their cytoprotective qualities employing stomach acidity, mucus content, macroscopic and microscopic methods, lipid peroxidation, nitric oxide, mass spectroscopy, 2D gel electrophoresis, and biochemical indicators. These extracts were tested in vitro on lipopolysaccharide/interferon-stimulated rat cells. Additionally, in-vivo, and in-vitro toxicity investigations were conducted. FRAP, DPPH, and ORAC tests were used to determine the antioxidant activity of MBST and CBST. Chemical and spectroscopic approaches were used to analyze the phytochemistry of MBST and CBST.Results: The gross and histological characteristics of B. thonningii proved its anti-ulcerogenic effects. MBST has gastroprotective effects by modulating lipid peroxidation and proteomics indicators [heat shock protein (Hsp60), disulfide isomerase (ERp60), protein disulfide-isomerase, creatine kinase B, cytosolic malate dehydrogenase, peroxiredoxin-6, and ATP synthase]. MBST and CBST have substantial impacts on nitric oxide both in-vitro and in-vivo. In comparison to CBST, methanolic extract (MBST) demonstrated greater gastroprotective properties, polyphenolic content, and antioxidant activity. The plant extracts did not show any toxicity in-vitro or in-vivo. MBST shows anti-ulcer action, which may be ascribed to its ability to reduce ethanol-triggered oxidative injury, to intervene in proteomic mechanisms, and to modulate nitric oxide.Conclusion:The present study found that stem bark extracts of Bauhinia thonningii Schum have cytoprotective activities against in vivo ethanol-induced damage due to its powerful antioxidant and mucus-increasing capabilities. Bauhinia thonningii warrants more attention since it may provide an exciting novel medication for the treatment of acute erosive gastropathy.Keywords: Bauhinia thonningii Schum;polar and non-polar extraction; peptic ulcer; nitric oxide; proteomics

Excessive Production of Hydrogen Peroxide in Mitochondria Contributes to Atopic Dermatitis

Atopic dermatitis (AD) is a complex disease characterized by chronic recurring eczema and pruritus. In addition, AD patients display increased cutaneous and systemic levels of oxidative damage markers, whose source remains elusive. In this study, we investigated oxidative and mitochondrial stress in AD epidermis. The levels of SOD2 and hydrogen peroxide are augmented in mitochondria of flaky tail (ft/ft) mouse keratinocytes, which is associated with inhibition of the glutathione system and catalase. Furthermore, reduced amounts of Gpx4 are associated with accumulation of malondialdehyde, 4-hydroxy-2-nonenal, and oxidized phosphatidylcholines in ft/ft epidermis. Cytochrome c is markedly increased in ft/ft epidermis, hence demonstrating mitochondrial stress. Topical application of MitoQ, which is a mitochondrial targeting antioxidant, to ft/ft mouse skin reduced damage to macromolecules and inflammation and restored epidermal homeostasis. Absence of alteration in the expression of SOD2, catalase, Gpx4 and limited lipid peroxidation as well as oxidized phosphatidylcholines, in the epidermis of Flg-/- mice suggest that filaggrin deficiency marginally contributes to oxidative stress in ft/ft epidermis. Increased SOD2, lipid peroxidation and cytochrome c in the epidermis of AD patients, associated with reduced antioxidant response in primary AD keratinocytes, corroborate mitochondrial dysfunction and lack of cellular adjustment to oxidative stress in AD epidermis.

Magnetic water irrigation changes physiological traits and stress tolerance of Salvia virgata under saline conditions

In the present study, a pot experiment was conducted to evaluate the effect of magnetic water irrigation at different intensities and durations (non-magnetic water, 0.6 Tesla half an hour passed, 0.6 Tesla once passed, 0.3 Tesla half an hour passed and 0.3 Tesla once passed) on growth and physiological characteristics of Salvia virgata under salinity stress (0, 30, 60 and 90 mM NaCl). Accumulation of malondialdehyde, proline, soluble sugars, and total phenol as well as the antioxidant activity were increased with intensifying the salinity level. However, flavonoids, leaf water content, photosynthetic pigments, and plant growth showed a decrement trend under salt stress. Although magnetic water did not have a considerable effect on the growth and physiological traits of S. virgata under non-stress conditions irrigation of stressed plants with magnetic water especially at 0.6 T once passed was efficient in mitigation of salinity damages. Magnetic water irrigation increased the accumulation of phenolic compounds and stimulated the activity of peroxidase and polyphenol oxidase thereby limiting lipid peroxidation. Magnetic water increased the salt tolerance and water use efficiency of stressed S. virgata plants and consequently enhanced plant biomass. Generally, it can be concluded that magnetic water irrigation at 0.6 T once passed could alleviate the salinity disorders of S. virgata by improving the antioxidant capacity, especially in severe saline condition.

Coffee and lipid profile: from theory to everyday practice

Lipid disorders have been the most common cause of atherosclerotic cardiovascular diseases in Poland for years. The latest data indicate that about 20 million people in Poland have hypercholesterolemia. Nutritional habits have a very significant impact on the lipid profile. Therefore, taking into account the fact that coffee is an important component of the diet of Poles (on average, 1–2 cups of coffee are consumed in our country per inhabitant per day, and 66% of Poles declare regular consumption), its impact on the lipid profile cannot be overlooked. Coffee contains over 1000 chemical compounds, of which kahweol and cafestol are the most important in the context of lipidology. These are compounds that can have a hyperlipidemic effect. On the other hand, compounds such as caffeine, chlorogenic acid, trigonelline, and melanoidins are characterized by antioxidant activity, which can limit lipid peroxidation. The effect of consuming coffee prepared in different ways has been analyzed in numerous clinical studies. This article summarizes the current knowledge on the effects of coffee on the lipid profile and risk of atherosclerosis.

Hydrogen peroxide and iron ions can modulate lipid peroxidation, apoptosis, and the cell cycle, but do not have a significant effect on DNA double-strand break

Hydroxyl radical (·OH) generated by the Fenton reaction between transition metal ions and hydrogen peroxide (H2O2) can induce significant cellular damage. However, the specific mechanism of ·OH-induced cell death has not been systematically studied. In this study, we reacted FeSO4 and Fe3O4 magnetic nanoparticles with H2O2 and found that ·OH generated from the intracellular Fenton reaction can lead to significant cell death. The Fenton reaction between Fe2+ with H2O2 resulted in a shift in lipid peroxidation and cell cycle arrest. It is noteworthy that the ·OH generated from the Fenton reaction triggered severe apoptosis but did not lead to DNA double-strand breakage. Our results suggest that the Fenton reaction had acute cytotoxicity, which was primarily due to ·OH produced from the Fenton reaction inducing lipid peroxidation and apoptosis and modulating the cell cycle, but not by inducing DNA damage.

Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7

Coenzyme Q (or ubiquinone) is a redox-active lipid that serves as universal electron carrier in the mitochondrial respiratory chain and antioxidant in the plasma membrane limiting lipid peroxidation and ferroptosis. Mechanisms allowing cellular coenzyme Q distribution after synthesis within mitochondria are not understood. Here we identify the cytosolic lipid transfer protein STARD7 as a critical factor of intracellular coenzyme Q transport and suppressor of ferroptosis. Dual localization of STARD7 to the intermembrane space of mitochondria and the cytosol upon cleavage by the rhomboid protease PARL ensures the synthesis of coenzyme Q in mitochondria and its transport to the plasma membrane. While mitochondrial STARD7 preserves coenzyme Q synthesis, oxidative phosphorylation function and cristae morphogenesis, cytosolic STARD7 is required for the transport of coenzyme Q to the plasma membrane and protects against ferroptosis. A coenzyme Q variant competes with phosphatidylcholine for binding to purified STARD7 in vitro. Overexpression of cytosolic STARD7 increases ferroptotic resistance of the cells, but limits coenzyme Q abundance in mitochondria and respiratory cell growth. Our findings thus demonstrate the need to coordinate coenzyme Q synthesis and cellular distribution by PARL-mediated STARD7 processing and identify PARL and STARD7 as promising targets to interfere with ferroptosis.

Modulation of lipid peroxidation and energy metabolism in the gastric mucosa as a mechanism ofantiulcer activity of placental cryoextract in the healing of stress-induced ulcers

Background. Peptic ulcer disease has a leading place in the overall structure of digestive diseases: its prevalence is 6.00–10.0% of the population in developed countries, and mortality ranges from 6 to 9.7 per 100 thousand population. An important etiological factor of this pathology is the neuropsychological background, primarily stress, which under repeated exposure becomes the initiating factor of physiological imbalance between the elements of aggression and protection of the gastric mucosa. The purpose was to establish the mechanisms of the protective activity of placental cryoextract based on the biochemical indicators of lipid peroxidation and antioxidant protection in the gastric mucosa on a model of stress-induced erosive-ulcerative damage. Materials and methods. Studies were performed on 28 nonlinear laboratory male rats weighing 200–220g. Stress-induced gastric ulcer was modeled under water-immobilization stress in rats according to the K.Y. Takagi etal. In the gastric mucosa, the content of reactants with thiobarbituric acid was determined spectrophotometrically by the method of T. Asakawa etal., catalase activity— spectrophotometrically by the method of M.A.Korolyuk etal., the content of reduced glutathione— spectrophotometrically by the method of E.D. Beutler etal., the level of adenyl nucleotides was determined using chromatographic method. Energy charge was calculated by D.E. Atkinson equation. Results.The prophylactic five-day use of placental cryoextract led to a decrease in the severity of stress-induced lipid peroxidation and energy imbalance in the gastric mucosa. Thus, it was found that rats who received placental cryoextract had a statistically significant (p<0.001) increase in adenosine triphosphate content by 73.3%, an increase in adenosine diphosphate (p<0.001) by 37.3% and a decrease in adenosine monophosphate (p<0.001) by 47.6% that led to an increase in energy charge (p<0.001) by 35.1% compared to rats exposed to water-immobilization stress without correction (control group). It was shown that the use of placental cryoextract led to a statistically significant (p<0.001) increase in the antioxidant-prooxidant index by 3.1 times versus control group, which was (26.60±0.96) and (8.60±0.43), respectively. Conclusions. Prophylactic five-day administration of placental cryoextract leads to the restoration of balance in the system of adenyl nucleotides and, accordingly, to a statistically significant (p<0.001) increase in the energy charge by 35.1% compared to the control animals. Inhibition of stress-induced hyperactivation of lipid peroxidation in the gastric mucosa is one of the mechanisms of its antiulcer activity.

Mutant p53K120R expression enables a partial capacity to modulate metabolism.

The TP53 tumor suppressor gene is one of the most studied gene in virtue of its ability to prevent cancer development by regulating apoptosis, cell cycle arrest, DNA repair, autophagy and senescence. Furthermore, the modulation of metabolism by P53 is fundamental for tumor suppressor activity. Studies in mouse models showed that mice carrying TP53 mutations affecting the acetylation in the DNA binding domain still retain the ability to transactivate genes involved in metabolism. Noteworthy, mice expressing the triple 3KR or the single K117R mutant do not show early on-set tumor development in contrast to TP53 −/− mice. Interestingly, the mouse K117R mutation corresponds to the human tumor-derived K120R modification, which abrogates P53-dependent activation of apoptosis without affecting growth arrest. In this study, we investigated the property of the human P53 K120R mutant in the regulation of metabolism by analyzing the transcriptional specificity in yeast- and mammalian-based reporter assays, the metabolic phenotype associated to its expression in colon cancer HCT116 TP53−/− cells and the induction of P53 targets and proteins involved in the antioxidant response. These properties were analyzed in comparison to wild type P53 protein, the human triple mutant corresponding to mouse 3KR and the cancer hot-spot R273H mutant. We confirm the selective functionality of P53 K120R mutant, which shows a transcriptional activity on cell cycle arrest but not on apoptotic targets. Interestingly, this mutant shows a partial transactivation activity on p53 response element belonging to the metabolic target TIGAR. Moreover, we observe a significant uncoupling between oxygen consumption and ATP production associated with higher lipid peroxidation level in all P53 mutants carrying cells with respect to wild type P53 expressing cells. Noteworthy, in the absence of a pro-oxidative challenge, cells expressing K120R mutant retain a partial capacity to modulate glucose metabolism, limiting lipid peroxidation with respect to the other P53 mutants carrying cells. Lastly, especially in presence of human 3KR mutant, a high expression of proteins involved in the antioxidant response is found. However, this response does not avoid the increased lipid peroxidation, confirming that only wild type P53 is able to completely counteract the oxidative stress and relative damages.