bims-redobi 2024-09-29 papers

bims-redobi

Biomed News

on Redox biology

Issue of 2024–09–29
nineteen papers selected by
Vanesa Cepas López, Candiolo Cancer Institute

Sodium stress-induced oxidative damage and antioxidant responses during grain filling in Indica rice.
Oxidative stress and atrial fibrillation.
Redox, cysteines, and kinases-A triad sustaining myeloid leukemia.
Transcriptome profiling reveals ethylene production by reactive oxygen species in trichloroisocyanuric acid-treated rice seeds.
Hydrogen sulfide mitigates mitochondrial dysfunction and cellular senescence in diabetic patients: Potential therapeutic applications.
RIPK4 promotes oxidative stress and ferroptotic death through the downregulation of ACSM1.
The colonic polyphenol catabolite dihydroferulic acid (DHFA) regulates macrophages activated by oxidized LDL, 7-ketocholesterol, and LPS switching from pro- to anti-inflammatory mediators.
Enhanced photodynamic therapy of curcumin using biodegradable PLGA coated mesoporous silica nanoparticles.
Redox remodeling of central metabolism as a driving force for cellular protection, proliferation, differentiation, and dysfunction.
Reactive Oxygen species dependent increase in H3K27 acetylation by intermittent hypoxia is regulated by H3S28 phosphorylation.
RGS5+ lymphatic endothelial cells facilitate metastasis and acquired drug resistance of breast cancer through oxidative stress-sensing mechanism.
Enhanced release of volatile halocarbons of microalgae in response to antibiotic-induced stress: Based on laboratory and ship-field experiments.
Non-thermal atmospheric pressure plasma induces selective cancer cell apoptosis by modulating redox homeostasis.
Unlocking the in vitro and in vivo antioxidant and anti-inflammatory activities of polysaccharide fractions from Lepidium sativum seed-coat mucilage.
Effect of Bis (methyl glycol) Phthalate on Endoplasmic Reticulum Stress in Endothelial Cells.
Study on the mechanism of ROS-induced oxidative stress injury and the broad-spectrum antimicrobial performance of nickel ion-doped V6O13 powder.
Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in heavy metals-induced oxidative stress.
Biliverdin improved angiogenesis and suppressed apoptosis via PI3K/Akt-mediated Nrf2 antioxidant system to promote ischemic flap survival.
FTH1P8 induces and transmits docetaxel resistance by inhibiting ferroptosis in prostate cancer.

Plant Cell Rep. 2024 Sep 24. 43(10): 239

Sodium stress-induced oxidative damage and antioxidant responses during grain filling in Indica rice.

Tushar Khare, Chandra Shekhar Seth, Vinay Kumar.

   KEY MESSAGE: Sodium treatment caused the sodium ion accumulation at the milk stage of immature rice grains which in turn triggered the overproduction of reactive oxygen species and oxidative damage. The tolerant cultivar showed an enhanced antioxidative response and induced expressions of OsNHX and OsHKT ion-transporters. Sodium chloride-(NaCl) induced soil salinity is a major constraint hindering global rice production. Amongst its constituent ions, sodium (Na+) is known to be the main driver of toxicity under salt stress. The present investigation aims to measure the impacts of excess Na+ during rice grain filling using two Indica rice cultivars with opposite tolerances to salt (salt tolerant: Panvel-3, salt-sensitive: Sahyadri-3) mainly via oxidative and responsive antioxidative pathways. Plants were treated with Na+-specific treatments and NaCl with equimolar Na+ levels (100 mM) at the initiation of the reproductive phase. Stressed and control plants were harvested at three different grain-filling stages- early milk, milk, and dough and assessed for ion accumulation and oxidative damage/antioxidant responses under Na+ stress. Na+ toxicity triggered reactive oxygen species (ROS) production and upregulated the responsive enzymatic antioxidants. Na+ stress also increased the nitric oxide (NO) levels and the activity of nitrate reductase in immature grains. Differential expression levels of OsNHX and OsHKT transporters were observed in response to Na+ stress. Mature grains displayed a high accumulation of Na+ along with reduced K+ content and elevated Na+/K+ under high Na+ availability. The alterations in mature grains' sugar, starch, and protein content were also observed in response to the Na+ stress. Overall, the salt-tolerant cultivar displayed higher antioxidant activities and a lower rate of ROS generation in response to the Na+ stress. Results suggested a link between Na+ accumulation, Na+-mediated stress responses via anti/-oxidant pathways, and the grain-filling process in both rice cultivars.

Keywords:  Agronomic yield; Antioxidants; Grain filling; Reactive oxygen species; Salinity; Sodium

DOI:  https://doi.org/10.1007/s00299-024-03319-3
J Mol Cell Cardiol. 2024 Sep 20. pii: S0022-2828(24)00160-3. [Epub ahead of print]

Oxidative stress and atrial fibrillation.

Anna Pfenniger, Shin Yoo, Rishi Arora.

  Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice. Though the pathogenesis of AF is complex and is not completely understood, many studies suggest that oxidative stress is a major mechanism in pathophysiology of AF. Through multiple mechanisms, reactive oxygen species (ROS) lead to the formation of an AF substrate that facilitates the development and maintenance of AF. In this review article, we provide an update on the different mechanisms by which oxidative stress promotes atrial remodeling. We then discuss several therapeutic strategies targeting oxidative stress for the prevention or treatment of AF. Considering the complex biology of ROS induced remodeling, and the evolution of ROS sources and compartmentalization during AF progression, there is a definite need for improvement in timing, targeting and reduction of off-target effects of therapeutic strategies targeting oxidative injury in AF.

Keywords:  Atrial fibrillation; Autonomic remodeling; Calcium handling remodeling; Electrical remodeling; Molecular mechanisms; Oxidative stress; Structural remodeling

DOI:  https://doi.org/10.1016/j.yjmcc.2024.09.011
Adv Cancer Res. 2024 ;pii: S0065-230X(24)00008-3. [Epub ahead of print]164 1-68

Redox, cysteines, and kinases-A triad sustaining myeloid leukemia.

Vanessa Marensi.

  Reactive oxygen species (ROS) work as a second messenger, modulating cell response and establishing homeostasis. Abrupt changes in ROS are used to modulate transient cell response to different stimuli, from viral infection to inflammation. Chronic exposure to high ROS concentration can cause cellular damage and promote the development of diseases. Leukemogenesis is adapted to high concentrations of ROS, hijacking the ROS system, and uses kinase cascades to promote survival advantages. The oxidation-reduction (redox) machinery is composed of enzymes that orchestrate all classes of protein and use available Cys as transmitters and sensors, to disseminate stress signals through cells via kinase cascades. Myeloid leukemias (MLs) are known for being a heterogeneous disease, and clonal diversity is remarkably characterized by differences in the activation of kinase-regulated signaling cascades to provide survival advantage. Stress-activated kinase cascades and other cascades are regulated by the ROS system. Several studies present nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and the ER-resident NOX4 as key elements of ROS activity in healthy myeloid cells and myeloid leukemia. Targeting ROS presents an attractive therapeutic strategy for (MLs) patients, but the boundaries between pro-apoptotic and anti-apoptotic ROS concentrations are not well established. Detailed understanding of the signaling switches that determine cell fate needs to be well understood. This work explores several aspects of the redox system and thiol-mediated reactions with focus on kinase signaling in myeloid cancers and highlights some of the challenges.

Keywords:  Cysteines; Kinases; Myeloid leukemia; Post-translational modification; Reactive oxygen species; Redox

DOI:  https://doi.org/10.1016/bs.acr.2024.04.008
Physiol Plant. 2024 Sep-Oct;176(5):176(5): e14548

Transcriptome profiling reveals ethylene production by reactive oxygen species in trichloroisocyanuric acid-treated rice seeds.

Zhang Jinshi, Li Mei, Lian Jinjin, Zhu Yizhengnan, Jin Yannan, Yang Jing, Hu Wenfan, Zhang Weilin.

Reactive oxygen species (ROS) have been extensively suggested to stimulate ethylene production. However, the molecular mechanism by which ROS stimulate ethylene production remains largely unclear. Here, transcriptome profiling was used to verify if ROS could stimulate ethylene production via direct formation of ethylene from ROS. Trichloroisocyanuric acid (TCICA) can stimulate seed germination in rice. When transcriptome profiling was performed to determine the molecular responsiveness of rice seeds to TCICA, TCICA was initially proven to be a ROS-generating reagent. A total of 300 genes potentially responsive to TCICA treatment were significantly annotated to cysteine, and the expression of these genes was significantly upregulated. Nonetheless, the levels of cystine did not exhibit significant changes upon TCICA exposure. Cystine was then proven to be a substrate that reacted with TCICA to form ethylene under FeSO4 conditions. Moreover, 7 of 22 genes responsive to TCICA were common with the hydrogen peroxide (H2O2)-responsive genes. Ethylene was then proven to be produced from cysteine or cystine by reacting with H2O2 under FeSO4 condition, and the hydroxyl radical (OH-) was proposed to be the free radical species responsible for ethylene formation under FeSO4 condition. These results provide the first line of evidence that ethylene can be produced from ROS in a non-enzymatic manner, thereby unveiling one new molecular mechanism by which ROS stimulate ethylene production and offering novel insights into the crosstalk between ethylene and ROS.

DOI: https://doi.org/10.1111/ppl.14548
Biochem Pharmacol. 2024 Sep 25. pii: S0006-2952(24)00556-2. [Epub ahead of print] 116556

Hydrogen sulfide mitigates mitochondrial dysfunction and cellular senescence in diabetic patients: Potential therapeutic applications.

Ting Chen, Dacheng Bai, Changyong Gong, Yu Cao, Xiaoqing Yan, Renyi Peng.

  Diabetes induces a pro-aging state characterized by an increased abundance of senescent cells in various tissues, heightened chronic inflammation, reduced substance and energy metabolism, and a significant increase in intracellular reactive oxygen species (ROS) levels. This condition leads to mitochondrial dysfunction, including elevated oxidative stress, the accumulation of mitochondrial DNA (mtDNA) damage, mitophagy defects, dysregulation of mitochondrial dynamics, and abnormal energy metabolism. These dysfunctions result in intracellular calcium ion (Ca2+) homeostasis disorders, telomere shortening, immune cell damage, and exacerbated inflammation, accelerating the aging of diabetic cells or tissues. Hydrogen sulfide (H2S), a novel gaseous signaling molecule, plays a crucial role in maintaining mitochondrial function and mitigating the aging process in diabetic cells. This article systematically explores the specific mechanisms by which H2S regulates diabetes-induced mitochondrial dysfunction to delay cellular senescence, offering a promising new strategy for improving diabetes and its complications.

Keywords:  Anti-aging; Cell senescence; Diabetes; Hydrogen sulfide; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.bcp.2024.116556
Proc Natl Acad Sci U S A. 2024 Oct;121(40): e2410628121

RIPK4 promotes oxidative stress and ferroptotic death through the downregulation of ACSM1.

Jing Zhang, Yuehan Wei, Yangbo Yue, Huike Jiao, Yan Wu, Wan Fu, Keng-Mean Lin, Christopher Lu, Shan Mou, Qing Zhong.

  One of the most critical axes for cell fate determination is how cells respond to excessive reactive oxygen species (ROS)-oxidative stress. Extensive lipid peroxidation commits cells to death via a distinct cell death paradigm termed ferroptosis. However, the molecular mechanism regulating cellular fates to distinct ROS remains incompletely understood. Through siRNA against human receptor-interacting protein kinase (RIPK) family members, we found that RIPK4 is crucial for oxidative stress and ferroptotic death. Upon ROS induction, RIPK4 is rapidly activated, and the kinase activity of RIPK4 is indispensable to induce cell death. Specific ablation of RIPK4 in kidney proximal tubules protects mice from acute kidney injury induced by cisplatin and renal ischemia/reperfusion. RNA sequencing revealed the dramatically decreased expression of acyl-CoA synthetase medium-chain (ACSM) family members induced by cisplatin treatment which is compromised in RIPK4-deficient mice. Among these ACSM family members, suppression of ACSM1 strongly augments oxidative stress and ferroptotic cell death with induced expression of ACS long-chain family member 4, an important component for ferroptosis execution. Our lipidome analysis revealed that overexpression of ACSM1 leads to the accumulation of monounsaturated fatty acids, attenuation of polyunsaturated fatty acid (PUFAs) production, and thereby cellular resistance to ferroptosis. Hence, knockdown of ACSM1 resensitizes RIPK4 KO cells to oxidative stress and ferroptotic death. In conclusion, RIPK4 is a key player involved in oxidative stress and ferroptotic death, which is potentially important for a broad spectrum of human pathologies. The link between the RIPK4-ASCM1 axis to PUFAs and ferroptosis reveals a unique mechanism to oxidative stress-induced necrosis and ferroptosis.

Keywords:  acute kidney injury; acyl-CoA synthetase medium-chain family; ferroptosis; oxidative stress; receptor interacting protein kinase

DOI:  https://doi.org/10.1073/pnas.2410628121
Food Funct. 2024 Sep 25.

The colonic polyphenol catabolite dihydroferulic acid (DHFA) regulates macrophages activated by oxidized LDL, 7-ketocholesterol, and LPS switching from pro- to anti-inflammatory mediators.

Oscar J Lara-Guzmán, Ángela Arango-González, Diego A Rivera, Katalina Muñoz-Durango, Jelver A Sierra.

Macrophage activation plays a central role in the development of atherosclerotic plaques. Interaction with oxidized low-density lipoprotein (oxLDL) leads to macrophage differentiation into foam cells and oxylipin production, contributing to plaque formation. 7-Ketocholesterol (7KC) is an oxidative byproduct of cholesterol found in oxLDL particles and is considered a factor contributing to plaque progression. During atherosclerotic lesion regression or stabilization, macrophages undergo a transformation from a pro-inflammatory phenotype to a reparative anti-inflammatory state. Interleukin-10 (IL-10) and PGE1 appear to be crucial in resolving both acute and chronic inflammatory processes. After coffee consumption, the gut microbiota processes non-absorbed chlorogenic acids producing various lower size phenolic acids. These colonic catabolites, including dihydroferulic acid (DHFA), may exert various local and systemic effects. We focused on DHFA's impact on inflammation and oxidative stress in THP-1 macrophages exposed to oxLDL, 7KC, and lipopolysaccharides (LPS). Our findings reveal that DHFA inhibits the release of several pro-inflammatory mediators induced by LPS in macrophages, such as CCL-2, CCL-3, CCL-5, TNF-α, IL-6, and IL-17. Furthermore, DHFA reduces IL-18 and IL-1β secretion in an inflammasome-like model. DHFA demonstrated additional benefits: it decreased oxLDL uptake and CD36 expression induced by oxLDL, regulated reactive oxygen species (ROS) and 8-isoprostane secretion (indicating oxidative stress modulation), and selectively increased IL-10 and PGE1 levels in the presence of inflammatory stimuli (LPS and 7KC). Finally, our study highlights the pivotal role of PGE1 in foam cell inhibition and inflammation regulation within activated macrophages. This study highlights DHFA's potential as an antioxidant and anti-inflammatory agent, particularly due to its ability to induce PGE1 and IL-10.

DOI: https://doi.org/10.1039/d4fo02114b
Eur J Pharm Biopharm. 2024 Sep 18. pii: S0939-6411(24)00329-1. [Epub ahead of print] 114503

Enhanced photodynamic therapy of curcumin using biodegradable PLGA coated mesoporous silica nanoparticles.

Muhammad Umair Amin, Sajid Ali, Konrad H Engelhardt, Usman Nasrullah, Eduard Preis, Jens Schaefer, Josef Pfeilschifter, Udo Bakowsky.

  Since the available treatments are not highly effective to combat cancer, therefore, the alternative strategies are unavoidable. Photodynamic therapy (PDT) is one of the emerging approaches which is target specific and minimally invasive. This study explores the successful development of Poly (D,L-lactide-co-glycolide) (PLGA) coated mesoporous silica nanoparticles (MSNs) and their augmented effects achieved by integrating curcumin (Cur) and cetyltrimethylammonium bromide (CTAB) in the polymeric layer and silica's pores, respectively. The synthesized nanocarriers (Cur-PLGA-cMSNs) have shown preferential targeting to the cellular organelles facilitated by CTAB's and Cur's affinity to mitochondria. CTAB and Cur-based PDT induced oxidative stress and generation of reactive oxygen species (ROS), resulting in dysfunctional mitochondria and triggered apoptotic pathways. PLGA coating has produced multifunctional effects, including; gatekeeping effects at pore openings, providing an extra loading site, enhancing the hemocompatibility of MSNs, and masking the free cur-related prolonged coagulation time. Cur-PLGA-cMSNs, as a multifaceted and combative approach with synergistic effects demonstrate promising potential to enhance outcomes in cancer treatment.

Keywords:  Drug delivery; Mesoporous silica nanoparticles; Nanomedicine; Photodynamic therapy; Polymer coating; Reactive oxygen species; Surface modification

DOI:  https://doi.org/10.1016/j.ejpb.2024.114503
Free Radic Res. 2024 Sep 24. 1-24

Redox remodeling of central metabolism as a driving force for cellular protection, proliferation, differentiation, and dysfunction.

Junichi Fujii.

  The production of reactive oxygen species (ROS) is elevated via metabolic hyperactivation in response to a variety of stimuli such as growth factors and inflammation. Tolerable amounts of ROS moderately inactivate enzymes via oxidative modification, which can be reversed back to the native form in a redox-dependent manner. The excessive production of ROS, however, causes cell dysfunction and death. Redox-reactive enzymes are present in primary metabolic pathways such as glycolysis and the tricarboxylic acid cycle, and these act as floodgates for carbon flux. Oxidation of a specific form of cysteine inhibits glyceraldehyde-3-phosphate dehydrogenase, which is reversible, and causes an accumulation of upstream intermediary compounds that increases the flux of glucose-6-phosphate to the pentose phosphate pathway. These reactions increase the NADPH and ribose-5-phosphate that are available for reductive reactions and nucleotide synthesis, respectively. On the other hand, oxidative inactivation of mitochondrial aconitase increases citrate, which is then recruited to synthesize fatty acids in the cytoplasm. Decreases in the use of carbohydrate for ATP production can be compensated via amino acid catabolism, and this metabolic change makes nitrogen available for nucleic acid synthesis. Coupling of the urea cycle also converts nitrogen to urea and polyamine, the latter of which supports cell growth. This metabolic remodeling stimulates the proliferation of tumor cells and fibrosis in oxidatively damaged tissues. Oxidative modification of these enzymes is generally reversible in the early stages of oxidizing reactions, which suggests that early treatment with appropriate antioxidants promotes the maintenance of natural metabolism.

Keywords:  Glycolysis; TCA cycle; metabolic remodeling; reactive sulfhydryl; urea cycle

DOI:  https://doi.org/10.1080/10715762.2024.2407147
bioRxiv. 2024 Sep 09. pii: 2024.09.09.612097. [Epub ahead of print]

Reactive Oxygen species dependent increase in H3K27 acetylation by intermittent hypoxia is regulated by H3S28 phosphorylation.

Ning Wang, Matthew Hildreth, Nanduri R Prabhakar, Jayasri Nanduri.

Histones play a crucial role in regulating gene expression through post -translational modifications (PTMS) which include acetylation, methylation and phosphorylation. We have previously identified histone 3 acetylation (H3Kac) and methylation (H3Kme) as an early epigenetic mechanism associated with intermittent hypoxia (IH), a hallmark feature of sleep apnea. The goal of the present study was to determine the molecular mechanisms underlying IH increased H3 acetylation. IH-induced H3 acetylation was blocked by an antioxidant. Conversely, reactive oxygen species (ROS) mimetics, increased H3 acetylated protein expression similar to IH, suggesting a role for ROS. Trichostatin A (TSA), an HDAC (histone deacetylase) inhibitor mimicked IH-induced H3 acetylation under normoxic conditions, while pharmacological blockade of p300/CBP (HAT, histone acetylase) with CTK7A abolished IH-induced H3 acetylation. These results suggest that interplay between HATs and HDACs regulate ROS-dependent H3 acetylation by IH. Lysine 27 (H3K27) on H3 was one of the lysines specifically acetylated by IH and this acetylation was associated with dephsophorylation of H3 at serine 28 (H3S28). Inhibition of S28 dephosphorylation by protein phosphatase inhibitors (PIC or Calyculin A), prevented H3K27 acetylation by IH. Conversely, inhibiting K27 acetylation with CTK7A, increased S28 phosphorylation in IH-exposed cells. These findings highlight the intricate balance between H3 acetylation and phosphorylation in response to IH, shedding light on epigenetic mechanism regulating gene expression. (Supported by NIH-PO1-HL90554).

DOI: https://doi.org/10.1101/2024.09.09.612097
Drug Resist Updat. 2024 Sep 06. pii: S1368-7646(24)00107-9. [Epub ahead of print]77 101149

RGS5+ lymphatic endothelial cells facilitate metastasis and acquired drug resistance of breast cancer through oxidative stress-sensing mechanism.

Caixin Qiu, Chaoyi Tang, Yujun Tang, Ka Su, Xiao Chai, Zexu Zhan, Xing Niu, Jiehua Li.

   AIMS: Oxidative stress reflected by elevated reactive oxygen species (ROS) in the tumor ecosystem, is a hallmark of human cancers. The mechanisms by which oxidative stress regulate the metastatic ecosystem and resistance remain elusive. This study aimed to dissect the oxidative stress-sensing machinery during the evolvement of early dissemination and acquired drug resistance in breast cancer.
METHODS: Here, we constructed single-cell landscape of primary breast tumors and metastatic lymph nodes, and focused on RGS5+ endothelial cell subpopulation in breast cancer metastasis and resistance.
RESULTS: We reported on RGS5 as a master in endothelial cells sensing oxidative stress. RGS5+ endothelial cells facilitated tumor-endothelial adhesion and transendothelial migration of breast cancer cells. Antioxidant suppressed oxidative stress-induced RGS5 expression in endothelial cells, and prevented adhesion and transendothelial migration of cancer cells. RGS5-overexpressed HLECs displayed attenuated glycolysis and oxidative phosphorylation. Drug-resistant HLECs with RGS5 overexpression conferred acquired drug resistance of breast cancer cells. Importantly, genetic knockdown of RGS5 prevented tumor growth and lymph node metastasis.
CONCLUSIONS: Our work demonstrates that RGS5 in lymphatic endothelial cells senses oxidative stress to promote breast cancer lymph node metastasis and resistance, providing a novel insight into a potentially targetable oxidative stress-sensing machinery in breast cancer treatment.

Keywords:  Acquired drug resistance; Breast cancer; G-protein signaling 5; Lymphatic endothelial cells; Metastasis; Oxidative stress

DOI:  https://doi.org/10.1016/j.drup.2024.101149
Mar Environ Res. 2024 Sep 16. pii: S0141-1136(24)00415-X. [Epub ahead of print]202 106754

Enhanced release of volatile halocarbons of microalgae in response to antibiotic-induced stress: Based on laboratory and ship-field experiments.

Xiao-Yu Zhang, Li-Jing Yin, Xiao-Ping Lang, Zhen He, Gui-Peng Yang.

  This study investigated the impacts of sulfamethazine (SMZ) and oxytetracycline (OTC) antibiotics on the marine microalgae Nitzschia closterium and its release of volatile halocarbons (VHCs), which contribute to ozone depletion and climate change. High concentrations of SMZ and OTC suppressed cell density, reduced chlorophyll a content, and hindered Fv/Fm elevation in N. closterium, indicating its growth was inhibited. The exposure of N. closterium to antibiotics led to increased reactive oxygen species (ROS), reduced soluble protein content, and heightened catalase (CAT) activity, indicative of increased oxidative stress. This stress increased the release of three VHCs (CHBrCl2, CHBr2Cl, and CHBr3). Ship-borne experiments showed that high phytoplankton biomass was linked to high VHC release. Notably, the production and release of VHCs were significantly higher in the high-concentration antibiotic group (100 μg/L) than the low-concentration group (0.1 μg/L). These findings suggested that antibiotics induce excess ROS in algal cells, stimulating VHC production and release.

Keywords:  Antibiotic addition; N. closterium; Oxidative stress; Reactive oxygen species; Toxicity; Volatile halocarbons

DOI:  https://doi.org/10.1016/j.marenvres.2024.106754
Cell Commun Signal. 2024 Sep 26. 22(1): 452

Non-thermal atmospheric pressure plasma induces selective cancer cell apoptosis by modulating redox homeostasis.

Ju Hyun Yun, Yoon Hee Yang, Chang Hak Han, Sung Un Kang, Chul-Ho Kim.

   BACKGROUND: Anticancer treatments aim to selectively target cancer cells without harming normal cells. While non-thermal atmospheric pressure plasma (NTAPP) has shown anticancer potential across various studies, the mechanisms behind its selective action on cancer cells remain inadequately understood. This study explores the mechanism of NTAPP-induced selective cell death and assesses its application in cancer therapy.
METHODS: We treated HT1080 fibrosarcoma cells with NTAPP and assessed the intracellular levels of mitochondria-derived reactive oxygen species (ROS), mitochondrial function, and cell death mechanisms. We employed N-acetylcysteine to investigate ROS's role in NTAPP-induced cell death. Additionally, single-cell RNA sequencing was used to compare gene expression in NTAPP-treated HT1080 cells and human normal fibroblasts (NF). Western blotting and immunofluorescence staining examined the expression and nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), a key antioxidant gene transcription factor. We also evaluated autophagy activity through fluorescence staining and transmission electron microscopy.
RESULTS: NTAPP treatment increased ROS levels and induced mitochondrial dysfunction, leading to apoptosis in HT1080 cells. The involvement of ROS in selective cancer cell death was confirmed by N-acetylcysteine treatment. Distinct gene expression patterns were observed between NTAPP-treated NF and HT1080 cells, with NF showing upregulated antioxidant gene expression. Notably, NRF2 expression and nuclear translocation increased in NF but not in HT1080 cells. Furthermore, autophagy activity was significantly higher in normal cells compared to cancer cells.
CONCLUSIONS: Our study demonstrates that NTAPP induces selective cell death in fibrosarcoma cells through the downregulation of the NRF2-induced ROS scavenger system and inhibition of autophagy. These findings suggest NTAPP's potential as a cancer therapy that minimizes damage to normal cells while effectively targeting cancer cells.

Keywords:  Autophagy; Fibrosarcoma; NRF2; Non-thermal atmospheric pressure plasma; Reactive oxygen species

DOI:  https://doi.org/10.1186/s12964-024-01810-8
Heliyon. 2024 Sep 15. 10(17): e36797

Unlocking the in vitro and in vivo antioxidant and anti-inflammatory activities of polysaccharide fractions from Lepidium sativum seed-coat mucilage.

Imdad Ullah Khan, Yusra Jamil, Fareeha Shams, Salman Farsi, Muhammad Humayun, Anwar Hussain, Ayaz Ahmad, Amjad Iqbal, Abdulwahed Fahad Alrefaei, Sajid Ali.

  Inflammation coupled with oxidative stress contribute to the pathogenicity of various clinical disorders. Oxidative stress arises from an imbalance between production of reactive oxygen species (ROS) and antioxidant defense system, leading to cellular damages. The study investigated the antioxidant and anti-inflammatory effects of polysaccharides isolated from Lepidium sativum seed-coat mucilage. The water-soluble polysaccharides were extracted from mucilage and fractionated using gel permeation chromatography. The radical scavenging potential of various fractions was determined using DPPH, H2O2, and lipid peroxidation assays. The most effective EC50 was recorded for F53 (57.41 ± 1.34 μg/mL), followed by F20 (69.19 ± 0.61 μg/mL) and F52 (75.06 ± 0.45 μg/mL). In vitro anti-inflammatory effect was determined through human membrane stabilization assay while the in vivo effect was evaluated using a carrageenan-induced paw edema in mouse model where F53 demonstrated significant (P = 0.05) anti-inflammatory potential (92.60 % compared to diclofenac sodium 91.46 %). GC-MS analysis revealed the presence of galacturonic acid and glucuronic acid as main acidic monosaccharides along with varying quantities of rhamnose, arabinose, and maltose as prominent neutral monosaccharides. The study concludes that cress seed mucilage contains potent antioxidant and anti-inflammatory polysaccharides. Further studies on the mode of action of these polysaccharides could provide deeper insights into their potential use as antioxidant and anti-inflammatory agents.

Keywords:  Antioxidants; GC-MS; Inflammation; Lepidium sativum; Oxidative stress; Polysaccharides

DOI:  https://doi.org/10.1016/j.heliyon.2024.e36797
Environ Toxicol Pharmacol. 2024 Sep 24. pii: S1382-6689(24)00209-6. [Epub ahead of print] 104569

Effect of Bis (methyl glycol) Phthalate on Endoplasmic Reticulum Stress in Endothelial Cells.

Verma Nishitha-Hiresha, Raghavan Varsha, S Srinidhi, Ravichandran Jayasuriya, Kannan Harithpriya, Paromita Chakraborty, Kunka Mohanram Ramkumar.

  Phthalate-based polymeric plasticizers are widely used for their durability, transparency, and odorless nature, resulting in human exposure through inhalation, ingestion, or contaminated water. Epidemiological studies have identified bis-phthalate as a potential cardiovascular disease risk factor, though its mechanisms remain unclear. This study investigates the effects of bis-phthalate on endothelial dysfunction (ED), an early event in cardiovascular complications, with a focus on Endoplasmic Reticulum (ER) stress pathways. We observed dose- and time-dependent cytotoxicity in endothelial cells exposed to bis-phthalate, accompanied by elevated expression of ER stress markers (GRP78, IRE-1α, CHOP) and oxidative stress markers (TXNIP, P22phox), as measured by qPCR. Reactive oxygen species (ROS) levels also increased dose-dependently, as determined by H2DCFDA using flow cytometry. These findings suggest that bis-phthalate exposure induces both oxidative and ER stress, leading to the development of ED, providing insights into its potential role in cardiovascular disease progression.

Keywords:  ED; ER Stress; Phthalate; Plasticizer; Toxicity; oxidative stress

DOI:  https://doi.org/10.1016/j.etap.2024.104569
Sci Rep. 2024 Sep 27. 14(1): 22374

Study on the mechanism of ROS-induced oxidative stress injury and the broad-spectrum antimicrobial performance of nickel ion-doped V6O13 powder.

Li Liu, Siyu Li, Wei Zhu, Qifu Bao, Yan Liang, Tiangui Zhao, Xiaolong Li, Jianer Zhou.

  In this study, pure V6O13 and nickel ion-doped V6O13 powders were synthesized by a simple hydrothermal-calcination method, and their broad-spectrum antimicrobial properties and mechanisms were investigated. The crystal structure, morphology, and chemical state of the powders were thoroughly analyzed by XRD, SEM, TEM, XPS, and UV-Vis. Their antimicrobial properties and mechanisms were evaluated by the ring of inhibition, bio-SEM, live-dead cell staining, ROS detection, and protein leakage experiments. The results showed that nickel ion doping modulated the oxygen defects of V6O13, generating more reactive oxygen species and leading to more severe oxidative stress, resulting in a broad-spectrum and highly efficient antimicrobial effect. This study also revealed the antimicrobial mechanism based on oxygen defect -induced ROS production, which caused cellular oxidative stress damage, leading to leakage of intracellular substances and cell death. This study not only demonstrates the potential of V6O13 as an efficient antimicrobial agent but also provides a strong experimental basis and theoretical support for the engineering design and optimization of novel antimicrobial materials by modulating material defects through ion doping.

Keywords:  Broad-spectrum antimicrobial; Ni-doped; Oxygen vacancy; V6O13

DOI:  https://doi.org/10.1038/s41598-024-71959-2
Heliyon. 2024 Sep 30. 10(18): e37545

Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in heavy metals-induced oxidative stress.

Swapnil Tripathi, Gitika Kharkwal, Rajeev Mishra, Gyanendra Singh.

  Organisms encounter reactive oxidants through intrinsic metabolism and environmental exposure to toxicants. Reactive oxygen and nitrogen species (ROS, RNS) are generally considered detrimental because they induce oxidative stress. In order to combat oxidative stress, a potential modulator of cellular defense nuclear factor erythroid 2-related factor 2 (Nrf2) and its endogenous inhibitor Kelch-like ECH-associated protein 1 (Keap1) operate as a common, genetically preserved intrinsic defense system. There has been a significant increase in the amount of harmful metalloids and metals that individuals are exposed to through their food, water, and air, primarily due to human activities. Many studies have looked at the connection between the emergence of different ailments in humans and ecological exposure to metalloids, i.e., arsenic (As) and metals viz., chromium (Cr), mercury (Hg), cadmium (Cd), cobalt (Co), and lead (Pb). It is known that they can produce ROS in several organs by both direct and indirect means. Studies suggest that Nrf2 signaling is a crucial mechanism in maintaining antioxidant balance and can have two roles, depending on the particular biological setting. From one perspective, Nrf2 is an essential defense mechanism against metal-induced toxicity. Still, it may also operate as a catalyst for metal-induced carcinogenesis in situations involving protracted exposure and persistent activation. Therefore, this review aims to provide an overview of the antioxidant defense mechanism of Nrf2-Keap1 signaling and the interrelation between Nrf2 signaling and the toxic elements.

Keywords:  Cellular defense system; Metal-induced toxicity; Nrf2-Keap1 signaling; Oxidative stress; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.heliyon.2024.e37545
Free Radic Biol Med. 2024 Sep 25. pii: S0891-5849(24)00689-0. [Epub ahead of print]

Biliverdin improved angiogenesis and suppressed apoptosis via PI3K/Akt-mediated Nrf2 antioxidant system to promote ischemic flap survival.

Zhe Yao, Kaikai Xue, Jinghao Chen, Yu Zhang, Guojian Zhang, Zimin Zheng, Zihao Li, Zi Li, Fulin Wang, Xiaoqi Sun, Liyan Shen, Cong Mao, Cai Lin.

  Plastic and reconstructive surgeons frequently utilize random skin flap transplantation to repair skin defects. However, the procedure carries a substantial risk of necrosis. Previous research has suggested that Biliverdin (Bv), the main component of Calculus Bovis, possessed potent anti-ischemic properties, making it a potential therapeutic agent for skin flap survival. Hence, in this study, the potential of Bv in promoting flap survival has been comprehensively investigated. Network pharmacology analysis revealed that the pharmacological effects of Bv on ischemic diseases may be attributed to its modulation of various signaling molecules, including the PI3K-Akt pathway. In vitro results demonstrated that Bv treatment significantly promoted angiogenesis in human umbilical vein endothelial cells (HUVEC), even in the presence of H2O2. This was evident by the increased cell proliferation, enhanced migration, and improved tube formation. Bv also effectively attenuated the intracellular generation of reactive oxygen species (ROS) induced by H2O2, which was achieved by suppressing mitochondrial ROS production through the PI3K/Akt-mediated activation of Nrf2/HO-1 signaling pathway. Consequently, Bv treatment led to a significant reduction in apoptosis and an increase in cell viability of HUVEC. Furthermore, in vivo experiment demonstrated that Bv treatment vastly elevated flap survival through enhancing angiogenesis while decreasing oxidative stress and apoptosis, which was comparable to the results of positive control of N-acetylcysteine (Nac). In conclusion, this study not only established a solid foundation for future study on therapeutic potential of Bv, but also proposed a promising treatment approach for enhancing the success rate of flap transplants and other ischemic-related tissue repair.

Keywords:  Biliverdin; PI3K/Akt; angiogenesis; oxidative stress; random skin flaps

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.042
Biomed Pharmacother. 2024 Sep 26. pii: S0753-3322(24)01358-1. [Epub ahead of print]180 117472

FTH1P8 induces and transmits docetaxel resistance by inhibiting ferroptosis in prostate cancer.

Junhong Lu, Qingrong Zou, Yang Li, Chuanwei Xiong, Lin Tao, Jiayuan Wu, Mei Qin, Jie Yang, Linhong He, Meichun Qin, Min Dong, Yingxin Li, Sisi Cao.

  Overcoming docetaxel resistance remains a significant challenge in the management of prostate cancer. Previous studies have confirmed a link between ferroptosis and the development of docetaxel resistance. This study revealed that docetaxel-resistant prostate cancer cells presented increased FTH1P8 expression compared with docetaxel-sensitive cells. Decreasing the level of FTH1P8 counteracted docetaxel resistance and facilitated docetaxel-induced ferroptosis, which is characterized by an increase in intracellular Fe2+ concentration, lipid peroxidation levels (lipid ROS), reactive oxygen species (ROS) accumulation, malondialdehyde (MDA) production and mitochondrial damage, a decrease in the Fe3+ concentration and glutathione (GSH) content, and the ability to inhibit hydroxyl radical (·OH) and the mitochondrial membrane potential (MMP). Conversely, increasing the level of FTH1P8 had the opposite effect. A positive correlation was revealed between the expression of FTH1P8 and its parental gene FTH1 in prostate cancer tissues in The Cancer Genome Atlas (TCGA) database. Molecular investigations revealed that FTH1P8 expression increased through miR-1252-5p. Furthermore, rescue experiments confirmed that FTH1 mediated the inhibitory effect of FTH1P8 on ferroptosis. Moreover, FTH1P8 was discovered to play a role in the spread of docetaxel resistance via exosomes. Docetaxel-siRNA targeting FTH1P8 (siFTH1P8)-nanoliposomes (DOC-siFTH1P8-LIP), which can codeliver docetaxel and siFTH1P8, significantly inhibited docetaxel resistance in cells. These results indicated that FTH1P8 can function as both an indicator and a treatment target for docetaxel resistance. The use of DOC-siFTH1P8-LIP demonstrated promising therapeutic effects on docetaxel-resistant cells, suggesting a novel option for treating docetaxel-resistant prostate cancer.

Keywords:  Docetaxel; FTH1P8; Ferroptosis; Prostate cancer; Resistance

DOI:  https://doi.org/10.1016/j.biopha.2024.117472