Intracellular Redox Imbalance Research Articles

Nanoparticle-mediated synergistic disruption of tumor innervation and redox homeostasis for potent antineoplastic therapy

Innervation is closely linked to several biological processes that promote tumor growth, making it an increasingly promising therapeutic target. In this study, biomimetic hollow MnO2 nanocarriers camouflaged with tumor cell membranes (HMLC) are developed to encapsulate lidocaine, an innervation inhibitor, for effective antineoplastic therapy. This approach aims to suppress nerve fiber growth and induce intracellular redox imbalance. Benefiting from the tumor-homing effect, HMLC accumulates in cancerous tissue during circulation and is endocytosed by tumor cells through homologous membrane fusion. Once inside the cells, MnO2 can be degraded by the overproduced glutathione and H2O2, leading to the tumor-specific release of Mn2+ and lidocaine. The Mn2+-mediated Fenton-like reaction promotes the accumulation of reactive oxygen species, and the resulting oxidative stress, combined with glutathione depletion, exacerbates redox imbalance. Simultaneously, the released lidocaine downregulates nerve growth factor and neuronatin. The reduction in nerve growth factor significantly inhibits nerve fiber formation and infiltration in tumor tissue, while the decrease in neuronatin reduces intracellular Ca2+, which helps prevent metastasis. Overall, this strategy highlights the potential of nanoparticle-based tumor innervation disruptors in antineoplastic therapy.

Prophylactic supplementation with selenium nanoparticles protects against foodborne toxin zearalenone-induced intestinal barrier dysfunction

Selenium nanoparticles (SeNPs) have been used as a potential alternative to other forms of selenium in nutritional supplements for the treatment and prevention of inflammatory and oxidative stress-related diseases. Zearalenone (ZEA) is a foodborne mycotoxin present in grains that poses a health threat. Here, we investigated the adverse impacts of ZEA on intestinal homeostasis and explored the protective effects of probiotic-synthesized SeNPs against its damage. Results showed that ZEA reduced mucin and tight junction proteins expression in jejunum, induced inflammatory process and oxidative stress which in turn increased intestinal permeability in mice. ZEA-induced intestinal toxicity was further verified in vitro. Intracellular redox imbalance triggered endoplasmic reticulum (ER) stress in intestinal epithelial cells, which caused structural damage to the ER. Remarkably, SeNPs exhibited a counteractive effect by inducing a decrease in intracellular levels of Inositol 1,4,5-trisphosphate (IP3) and Ca2+, along with a reduction in the expression level of IP3 receptor. SeNPs effectively mitigated ZEA-induced ER stress was related to the increased activity of selenium-dependent antioxidant enzymes and the expression of ER-resident selenoproteins. Furthermore, SeNPs significantly inhibited the activation of PERK/eIF2α/ATF4/CHOP pathway in vitro and in vivo. In addition, SeNPs effectively reversed ZEA-induced gut microbiota dysbiosis and increased the abundance of short-chain fatty acid-producing beneficial bacteria (Alloprevotella and Muribaculaceae). The Spearman correlation analysis suggested that the structure of gut microbiota was closely related to the SeNPs attenuation of ZEA-induced intestinal toxicity. This study provides new insights into ZEA-induced intestinal toxicity and identifies a novel potential nutrient SeNPs to overcome adverse effects.

Donor-Acceptor-Donor Strategy Rouses the Photodynamic Therapy Anticancer Activity of a Bis-terpyridyl Ru(II) Complex.

Photodynamic therapy has been regarded as a noninvasive treatment for cancer with spatiotemporal control over drug activation. Bis-terpyridyl Ru(II) complexes exhibit a promising achiral structure but suffer from low photoreactivity due to deviation from the ideal octahedral geometry. Herein, we introduce the donor-acceptor-donor motif to construct a dinuclear bis-terpyridyl Ru(II) complex (Ru2). Ru2 exhibits superior light absorption properties compared with mononuclear complex Ru1. Importantly, upon 595 nm light excitation, Ru2 shows promising synergetic type I/II photosensitization and photocatalytic activity, while Ru1 is inactive. Anticancer mechanistic studies reflect that Ru2 induces intracellular redox imbalance and affects the biosynthetic and metabolic processes, leading to cell apoptosis. Overall, this work provides a simple strategy to rouse the PDT efficiency of bis-terpyridyl Ru(II) complexes.

Self-assembling gelatin based delivery of multienzyme activity nanozyme and photosensitizer for ROS storm based cancer therapy

Nanozymes with multienzyme activity for reactive oxygen species (ROS) generation and intracellular redox imbalance are attractive strategy for cancer therapy. However, it is severely limited by low biocompatibility and catalytic efficiency, hypoxic and high levels of GSH in the tumor microenvironment. To address these issues, a copper doping carbon nanozyme (CC) with multienzyme activity was designed and integrated with photosensitizer Ce6 and gelatin to fabricate ROS amplifier (CCC). Gelatin endowed CCC with good biocompatibility, low hemolysis, and enzyme responsive degradation. CCC with high CAT-like, POD-like, OXD-like, and GSHox-like activities can induce the intracellular ROS storm formation to eliminate the cancer cells. The OXD-like activity and PDT performance mediated 1O2 generation was markedly potentiated by the CAT-like activity of CCC via catalyzing high expression of H2O2 to generate O2. At the same time, a large amount of ·OH were produced through POD-like activity of CCC and GSH was depleted by the GSHox-like activities of CCC, resulting in a destructive ROS storm formation and cellular redox homeostasis disruption. Both in vivo and in vitro experiments showed that CCC displayed satisfactory anti-tumor activity and biocompatibility. Our work provides a novel strategy for the development of nanozyne enhanced photodynamic therapy of cancer.

Dinuclear Tridentate Ru(II) Complex with Strong Near-Infrared Light-Triggered Anticancer Activity.

The design of the dinuclear Ru(II) complex (Ru2) with strong near-infrared (NIR) absorption properties has been reported for efficient anticancer phototherapy. Under 700 nm LED light excitation, Ru2 exhibited remarkable synergistic type I/II photosensitization ability and photocatalytic activity toward intracellular biomolecules. Ru2 showed impressive 700 nm light-triggered anticancer activity under normoxia and hypoxia compared with the clinically used photosensitizer Chlorin e6. The mechanistic studies showed that Ru2 induced intracellular redox imbalance and perturbed the energy metabolism and biosynthesis in A549 cancer cells. Overall, this work provides a new strategy for developing efficient metal-based complexes for anticancer phototherapy under NIR light.

The role of nitro oxidative factors in metabolic dysfunctions: A link between severe obesity and weight-loss treatment – a narrative review

Abstract Introduction: Metabolic syndrome (MS) is linked to oxidative stress and intracellular redox imbalance, both triggered by chronic inflammatory conditions. The aim of our research was to figure out if bariatric surgery changes the production of free radicals in obese people. In addition, the relationship between metabolic syndrome(MS) and associated conditions is represented by oxidative stress (OS) and intracellular redox imbalance, both of which are induced by the chronic inflammatory conditions that define MS. Methods: The literature search was conducted on PubMed, Cochrane Library, and ScienceDirect, using terms related to severe obesity, nitro-oxidative factors, pro-inflammatory status and reactive oxygen species. Six studies were included. We included papers published till 2022, with a concentration on more recent publications (January 2019 to December 2022). Results: Studies that analyzed the status of the patient after bariatric surgery at 1, 2, 3, 6, 12 months were included in the review, regarding inflammation: CRP levels,IL-6, and regarding oxidative stress: MPO serum activity, blood plasma proteins: dityrosine, kynurenine, glycophore, amyloid and Amadori products, had been found strongly statistically significant decreased at each periodic analyze, the same thing applied to regulatory hormones such as leptin, and due to the fact that these patients have the possibility to keep their weight stable for a longer period, all these factors kept their levels low even 4 years after the intervention. Conclusion: Bariatric surgery is an efficient and quick solution in increasing the quality of life.

Self-assembled metal-phenolic nanocomplexes comprised of green tea catechin for tumor-specific ferroptosis

Ferroptosis, a newly discovered form of regulated cell death, has garnered significant attention in the field of tumor therapy. However, the presence of overexpressed glutathione (GSH) and insufficient levels of H2O2 in the tumor microenvironment (TME) hinders the occurrence of ferroptosis. In response to these challenges, here we have constructed the self-assembled nanocomplexes (FeE NPs) utilizing epigallocatechin-3-gallate (EGCG) from green tea polyphenols and metal ions (Fe3+) as components. After grafting PEG, the nanocomplexes (FeE@PEG NPs) exhibit good biocompatibility and synergistically enhanced tumor-inhibitory properties. FeE@PEG NPs can be disassembled by H2O2 in the TME, leading to the rapid release of Fe3+ and EGCG. The released Fe3+ produces large amounts of toxic •OH by the Fenton reactions while having minimal impact on normal cells. The generated •OH effectively induces lipid peroxidation, which leads to ferroptosis in tumor cells. Meanwhile, the released EGCG can autoxidize to produce H2O2, which further promotes the production of •OH radicals and increases lipid peroxide levels. Moreover, EGCG also depletes the high levels of intracellular GSH, leading to an intracellular redox imbalance and triggering ferroptosis. This study provides new insights into advancing anticancer ferroptosis through rational material design, offering promising avenues for future research.

Targeted Liposomes Sensitize Plastic Melanoma to Ferroptosis via Senescence Induction and Coenzyme Depletion.

Ferroptotic cancer therapy has been extensively investigated since the genesis of the ferroptosis concept. However, the therapeutic efficacy of ferroptosis induction in heterogeneous and plastic melanoma has been compromised, because the melanocytic and transitory cell subpopulation is resistant to iron-dependent oxidative stress. Here, we report a phenotype-altering liposomal nanomedicine to enable the ferroptosis-resistant subtypes of melanoma cells vulnerable to lipid peroxidation via senescence induction. The strategy involves the ratiometric coencapsulation of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (palbociclib) and a ferroptosis inducer (auranofin) within cRGD peptide-modified targeted liposomes. The two drugs showed a synergistic anticancer effect in the model B16F10 melanoma cells, as evidenced by the combination index analysis (<1). The liposomes could efficiently deliver both drugs into B16F10 cells in a targeted manner. Afterward, the liposomes potently induced the intracellular redox imbalance and lipid peroxidation. Palbociclib significantly provoked cell cycle arrest at the G0/G1 phase, which sensitized auranofin-caused ferroptosis through senescence induction. Meanwhile, palbociclib depleted intracellular glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), further boosting ferroptosis. The proof-of-concept was also demonstrated in the B16F10 tumor-bearing mice model. The current work offers a promising ferroptosis-targeting strategy for effectively treating heterogeneous melanoma by manipulating the cellular plasticity.

Construction of a plasmid-free l-leucine overproducing Escherichia coli strain through reprogramming of the metabolic flux

Backgroundl-Leucine is a high-value amino acid with promising applications in the medicine and feed industries. However, the complex metabolic network and intracellular redox imbalance in fermentative microbes limit their efficient biosynthesis of l-leucine.ResultsIn this study, we applied rational metabolic engineering and a dynamic regulation strategy to construct a plasmid-free, non-auxotrophic Escherichia coli strain that overproduces l-leucine. First, the l-leucine biosynthesis pathway was strengthened through multi-step rational metabolic engineering. Then, a cooperative cofactor utilization strategy was designed to ensure redox balance for l-leucine production. Finally, to further improve the l-leucine yield, a toggle switch for dynamically controlling sucAB expression was applied to accurately regulate the tricarboxylic acid cycle and the carbon flux toward l-leucine biosynthesis. Strain LEU27 produced up to 55 g/L of l-leucine, with a yield of 0.23 g/g glucose.ConclusionsThe combination of strategies can be applied to the development of microbial platforms that produce l-leucine and its derivatives.

Physicochemical stability of lichenan (Usnea longissima) decorated-selenium nanoparticles for cancer chemoprevention

The biological activity of amorphous selenium nanoparticles (SeNPs) was limited by their poor stability and rapid spontaneous phase transformation. Herein, we prepared amorphous SeNPs by decorating them with lichenan (LC), a natural random coil conformation polysaccharide, through C–O⋯Se bonds or O–H⋯Se bonds. The synthesized amorphous spherical LC-SeNPs maintained their amorphous phase and zero valence state after being stored for 60 days at 4 °C. This stability can be also maintained under different heating treatment temperatures (37, 55, 75, and 95 °C), pH conditions (pH 3–10), and ionic strength (10–200 mM). Furthermore, LC-SeNPs displayed potential anticancer efficacy based on their ROS-triggered selenium release property and variable redox potential in the ROS model. The underlying antiproliferative mechanism was related to cell cycle arrest, intracellular redox imbalance, and mitochondrial dysfunction. This work provides a promising strategy for using LC-SeNPs in diet supplements or cancer chemoprevention.

Multifunctional nanoadjuvant-driven microenvironment modulation for enhanced photothermal immunotherapy in breast cancer

Intracellular redox imbalance, achieved by exploiting the tumor microenvironment (TME), has emerged as a promising strategy for cancer therapy. In this study, we developed a multifunctional nanoadjuvant, termed GITFe/Z-HA, by modified a metal-organic backbone Fe/ZIF-8 with hyaluronic acid (HA) targeting. The nanocarriers were loaded with glucose oxidase (Gox), neoindocyanine green (IR820) and tilazamine (TPZ). This design aimed to achieve a cascade reaction within tumor cells, mediated by Gox, Fe3+, and IR820, which consumes intrinsic glucose and oxygen, leading to an elevated production of reactive oxygen species (ROS). This cascade reaction creates a hypoxic environment conducive for TPZ to exert its therapeutic action. Consequently, the combination of photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy demonstrates a good synergistic effect. Moreover, the imbalanced ROS/glutathione (GSH) induced by this treatment approach, along with PTT, promote immunogenic cell death (ICD). This ICD triggers the release of damage-related molecular patterns and CD8+ lymphocyte infiltration sensitizes the immune checkpoint blockade (αPD-L1) response, thereby eliciting a systemic anti-tumor immune response. Collectively, this comprehensive treatment regimen, driven by environmentally stimulated multiple pathways, overcomes the limitations of single therapeutic modalities, thereby improving tumor outcomes. Additionally, these findings provide valuable insights for strategies aimed at modulating the tumor immune microenvironment.

Destroying pathogen-tumor symbionts synergizing with catalytic therapy of colorectal cancer by biomimetic protein-supported single-atom nanozyme

The crucial role of intratumoral bacteria in the progression of cancer has been gradually recognized with the development of sequencing technology. Several intratumoral bacteria which have been identified as pathogens of cancer that induce progression, metastasis, and poor outcome of cancer, while tumor vascular networks and immunosuppressive microenvironment provide shelters for pathogens localization. Thus, the mutually-beneficial interplay between pathogens and tumors, named “pathogen-tumor symbionts”, is probably a potential therapeutic site for tumor treatment. Herein, we proposed a destroying pathogen-tumor symbionts strategy that kills intratumoral pathogens, F. nucleatum, to break the symbiont and synergize to kill colorectal cancer (CRC) cells. This strategy was achieved by a groundbreaking protein-supported copper single-atom nanozyme (BSA-Cu SAN) which was inspired by the structures of native enzymes that are based on protein, with metal elements as the active center. BSA-Cu SAN can exert catalytic therapy by generating reactive oxygen species (ROS) and depleting GSH. The in vitro and in vivo experiments demonstrate that BSA-Cu SAN passively targets tumor sites and efficiently scavenges F. nucleatum in situ to destroy pathogen-tumor symbionts. As a result, ROS resistance of CRC through elevated autophagy mediated by F. nucleatum was relieved, contributing to apoptosis of cancer cells induced by intracellular redox imbalance generated by BSA-Cu SAN. Particularly, BSA-Cu SAN experiences renal clearance, avoiding long-term systemic toxicity. This work provides a feasible paradigm for destroying pathogen-tumor symbionts to block intratumoral pathogens interplay with CRC for antitumor therapy and an optimized trail for the SAN catalytic therapy by the clearable protein-supported SAN.

Uncovering the Differential Growth of Microcystis aeruginosa Cultivated under Nitrate and Ammonium from a Photophysiological Perspective

Cyanobacteria have a relatively high affinity for NH4+, yet a NO3–-rich environment is comparatively conducive to their proliferation. To date, little information is available on why NO3–-N favors cyanobacterial biomass accumulation. This study investigated the dependence of biomass, nitrogen assimilation characteristics, and photophysiological performance of Microcystis aeruginosa on the forms of nitrogen supply, including NO3–-N-only, NH4+-N-only, and NO3–-N + NH4+-N. The results indicated that despite the retarded growth of M. aeruginosa, cells supplied with NO3–-N-only maintained a simultaneous promotion in the growth rate, nitrogen assimilation efficiency, and photosynthetic capacity, resulting in high biomass production. Cells supplied with NH4+-N-only and NO3–-N + NH4+-N were able to rapidly assimilate nitrogen during initial cell proliferation, showing a preferential use of NH4+-N and the inhibition of NO3– uptake by NH4+. However, growth repression occurred as cultivation time was prolonged when NH4+-N was excessively supplied, mainly due to PSII photodamage, intracellular redox imbalance, and increased electron energy accumulation. Thus, cells supplied with NH4+-N-only had to reduce light energy capture, increase photoprotection, and consume excess electrons to mitigate the damage. These findings are critical for improving our understanding of the role of different nitrogen forms in the regulation of cyanobacterial photophysiological performance and growth.

Engineering of a GSH activatable photosensitizer for enhanced photodynamic therapy through disrupting redox homeostasis.

Although disrupted redox homeostasis has emerged as a promising approach for tumor therapy, most existing photosensitizers are not able to simultaneously improve the reactive oxygen species level and reduce the glutathione (GSH) level. Therefore, designing photosensitizers that can achieve these two aspects of this goal is still urgent and challenging. In this work, an organic activatable near-infrared (NIR) photosensitizer, CyI-S-diCF3, is developed for GSH depletion-assisted enhanced photodynamic therapy. CyI-S-diCF3, composed of an iodinated heptamethine cyanine skeleton linked with a recognition unit of 3,5-bis(trifluoromethyl)benzenethiol, can specifically react with GSH by nucleophilic substitution, resulting in intracellular GSH depletion and redox imbalance. Moreover, the activated photosensitizer can produce abundant singlet oxygen (1O2) under NIR light irradiation, further heightening the cellular oxidative stress. By this unique nature, CyI-S-diCF3 exhibits excellent toxicity to cancer cells, followed by inducing earlier apoptosis. Thus, our study may propose a new strategy to design an activatable photosensitizer for breaking the redox homeostasis in tumor cells.

The Chemistry and the Anti-Inflammatory Activity of Polymethoxyflavonoids from Citrus Genus.

Polymethoxyflavonoids (PMFs) are a large group of compounds belonging to the more general class of flavonoids that possess a flavan carbon framework decorated with a variable number of methoxy groups. Hydroxylated polymethoxyflavonoids (HPMFs), instead, are characterized by the presence of both hydroxyl and methoxy groups in their structural unities. Some of these compounds are the aglycone part in a glycoside structure in which the glycosidic linkage can involve the -OH at various positions. These compounds are particular to Citrus genus plants, especially in fruits, and they are present mainly in the peel. A considerable number of PMFs and HPMFs have shown promising biological activities and they are considered to be important nutraceuticals, responsible for some of the known beneficial effects on health associated with a regular consumption of Citrus fruits. Among their several actions on human health, it is notable that the relevant contribution in controlling the intracellular redox imbalance is associated with the inflammation processes. In this work, we aim to describe the status concerning the chemical identification and the anti-inflammatory activity of both PMFs and HPMFs. In particular, all of the chemical entities unambiguously identified by isolation and complete NMR analysis, and for which a biochemical evaluation on the pure compound was performed, are included in this paper.

Inhibitory Effect and Mechanism of Dill Seed Essential Oil on Neofusicoccum parvum in Chinese Chestnut

The chestnut postharvest pathogen Neofusicoccum parvum (N. parvum) is an important postharvest pathogen that causes chestnut rot. Chestnut rot in postharvest reduces food quality and causes huge economic losses. This study aimed to evaluate the inhibitory effect of dill seed essential oil (DSEO) on N. parvum and its mechanism of action. The chemical characterization of DSEO by gas chromatography/mass spectrometry (GC/MS) showed that the main components of DSEO were apiole, carvone, dihydrocarvone, and limonene. DSEO inhibited the growth of mycelium in a dose-dependent manner. The antifungal effects are associated with destroying the fungal cell wall (cytoskeleton) and cell membrane. In addition, DSEO can induce oxidative damage and intracellular redox imbalance to damage cell function. Transcriptomics analysis showed DSEO treatment induced differently expressed genes most related to replication, transcription, translation, and lipid, DNA metabolic process. Furthermore, in vivo experiments showed that DSEO and DSEO emulsion can inhibit the growth of fungi and prolong the storage period of chestnuts. These results suggest that DSEO can be used as a potential antifungal preservative in food storage.

Heterocyclic aromatic amines induce Neuro-2a cells cytotoxicity through oxidative stress-mediated mitochondria-dependent apoptotic signals.

Heterocyclic aromatic amines (HAAs) are a class of hazardous compounds produced in food thermal processing. These compounds raise concerns because they have mutagenic and carcinogenic properties. However, the neurotoxicity of these compounds has received limited attention. Here, the toxic effects of three HAAs, i.e. 9H-pyrido[3,4-b]indole (Norharman), 1-methyl-9H-pyrido[3,4-b]indole (Harman), and 2-amino-3-methylimidazole[4,5-f]quinoline (IQ) were investigated in Neuro-2a cells model. The results showed that the survival rate of cells decreased in a dose-dependent manner and apoptosis occurred after exposure to the three HAAs for 24h and 48h. Their neurotoxicity was ranked as Harman>Norharman>IQ. Further, treatment of Harman, Norharman, or IQ at 50 and 100μM for 48h led to intracellular REDOX imbalance, which was manifested as increased ROS and malondialdehyde (MDA) levels, decreased GSH/GSSG ratio, and reduced SOD and CAT activities. Moreover, Norharman and Harman up-regulated the expression level of nuclear factor erythroid 2-related factor 2 (Nrf2), as well as the mRNA levels of Heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoredutase1 (NQO1), while IQ had no significant effect on the levels of Nrf2, HO-1, and NQO1. Additionally, Harman, Norharman, or IQ exposure significantly reduced mitochondrial membrane potential and intracellular ATP levels and up-regulated the levels of apoptosis-related genes and proteins. Collectively, our finding suggested that HAAs were neurotoxic, with mechanisms related to induction of oxidative stress and mitochondrial dysfunction.

A Comprehensive Review on Beneficial Effects of Catechins on Secondary Mitochondrial Diseases.

Mitochondria are the main sites for oxidative phosphorylation and synthesis of adenosine triphosphate in cells, and are known as cellular power factories. The phrase “secondary mitochondrial diseases” essentially refers to any abnormal mitochondrial function other than primary mitochondrial diseases, i.e., the process caused by the genes encoding the electron transport chain (ETC) proteins directly or impacting the production of the machinery needed for ETC. Mitochondrial diseases can cause adenosine triphosphate (ATP) synthesis disorder, an increase in oxygen free radicals, and intracellular redox imbalance. It can also induce apoptosis and, eventually, multi-system damage, which leads to neurodegenerative disease. The catechin compounds rich in tea have attracted much attention due to their effective antioxidant activity. Catechins, especially acetylated catechins such as epicatechin gallate (ECG) and epigallocatechin gallate (EGCG), are able to protect mitochondria from reactive oxygen species. This review focuses on the role of catechins in regulating cell homeostasis, in which catechins act as a free radical scavenger and metal ion chelator, their protective mechanism on mitochondria, and the protective effect of catechins on mitochondrial deoxyribonucleic acid (DNA). This review highlights catechins and their effects on mitochondrial functional metabolic networks: regulating mitochondrial function and biogenesis, improving insulin resistance, regulating intracellular calcium homeostasis, and regulating epigenetic processes. Finally, the indirect beneficial effects of catechins on mitochondrial diseases are also illustrated by the warburg and the apoptosis effect. Some possible mechanisms are shown graphically. In addition, the bioavailability of catechins and peracetylated-catechins, free radical scavenging activity, mitochondrial activation ability of the high-molecular-weight polyphenol, and the mitochondrial activation factor were also discussed.

Biogenic Selenium Nanoparticles Alleviate Intestinal Epithelial Barrier Damage through Regulating Endoplasmic Reticulum Stress-Mediated Mitophagy.

The intestinal barrier plays a fundamental role in body health. Intracellular redox imbalance can trigger endoplasmic reticulum stress (ERS) and mitophagy, leading to intestinal barrier damage. Our previous studies demonstrated that mitophagy is closely associated with the protective effects of biogenic selenium nanoparticles (SeNPs) on intestinal epithelial barrier function. Thus, we hypothesize that ERS and mitophagy are likely involved in the regulatory effects of SeNPs on oxidative stress-induced intestinal epithelial barrier dysfunction. The results showed that oxidative stress or ERS caused the increase of intestinal epithelial permeability. SeNPs effectively alleviated hydrogen peroxide (H2O2-)-induced structural damage of endoplasmic reticulum (ER) and mitochondria of porcine jejunal epithelial cells (IPEC-J2). SeNPs significantly decreased intracellular inositol triphosphate (IP3) and Ca2+ concentration, down-regulated inositol trisphosphate receptor (IP3R) expression level, and up-regulated ER-resident selenoproteins mRNA levels in IPEC-J2 cells exposed to H2O2. In addition, SeNPs pretreatment significantly decreased the intracellular Ca2+, IP3, IP3R, and reactive oxygen species (ROS) levels; protected the structure and function of ER and mitochondria; and effectively alleviated the increase of intestinal epithelial permeability of IPEC-J2 cells exposed to tunicamycin (TM). Moreover, SeNPs significantly inhibited the colocalization of mitochondria and lysosomes. Furthermore, compared with TM model group, SeNPs significantly inhibited the activation of PERK/eIF2α/ATF4 and AMPK/mTOR/PINK1 signaling pathway. The PERK agonist (CCT020312) and the AMPK agonist (AICAR) could reverse the protective effects of SeNPs on IPEC-J2 cells. The PERK inhibitor (GSK2656157) and the AMPK inhibitor (compound C) had a similar effect on IPEC-J2 cells as that of SeNPs. In summary, the protective effects of SeNPs on intestinal barrier dysfunction are closely associated with ERS-related PERK and mitophagy-related AMPK signaling pathway.

Physicochemical and Colon Cancer Cell Inhibitory Properties of Theabrownins Prepared by Weak Alkali Oxidation of Tea Polyphenols.

Existing studies on the biological activity of theabrownins are not based on their free state but on the complexes of theabrownins, polysaccharides, proteins, and flavonoids. In this study, theabrownins (TBs-C) were prepared by weak alkali oxidation of tea polyphenols. The ultraviolet-visible scanning spectrum of TBs-C showed two characteristic absorption peaks at 203 and 270nm. The zeta potential of the TBs-C aqueous solution was negative, and the values varied from - 6.26 to -19.55 mV with a solution pH of 3-9. Storage conditions of pH 5.0-7.0 and around 25°C were beneficial for the physical and chemical stability of the TBS-C solution. Cells were treated with series concentrations and examined by MTT, HE staining, PI immunofluorescence staining, flow cytometry, and real-time PCR to investigate the antiproliferative effect of TBs-C on human colon cancer HT-29 cells. The results showed that TBs-C, particularly at 500µg/mL, inhibited cell growth. TBs-C induced HT-29 cell apoptosis, as confirmed by morphological changes, nucleus propidium iodide staining, and distributions of the cell cycle. The apoptotic mechanism may be due to the intracellular redox imbalance induced by TBs-C.