ROS Elimination Research Articles

ΔNp63α promotes radioresistance in esophageal squamous cell carcinoma through the PLEC-KEAP1-NRF2 feedback loop.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is highly prevalent in China, exhibiting resistance to current treatments. ΔNP63α, the main isoform of p63, is frequently amplified in ESCC and contributes to therapeutic resistance, although the molecular mechanisms remain unknown. Here, we report that ΔNP63α is highly expressed in ESCC and is associated with radioresistance by reducing ROS level. Furthermore, ΔNP63α plays a critical role in radioresistance by directly transactivating the expression of PLEC. PLEC competitively interacts with KEAP1, resulting in the release of NRF2 from KEAP1 and its translocation from the cytosol to the nucleus, where it activates gene expression to facilitate ROS elimination. Additionally, radiotherapy-induced ROS also activates ΔNP63α expression via NRF2. Pharmacologic inhibition of NRF2 effectively improves radiosensitivity in nude mice. Collectively, our results strongly suggest that the ΔNp63α/PLEC/NRF2 axis plays a key role in radioresistance in ESCC, indicating that targeting NRF2 is a promising therapeutic approach for ESCC treatment.

New Insights into Mitochondria in Health and Diseases.

Mitochondria are a unique type of semi-autonomous organelle within the cell that carry out essential functions crucial for the cell's survival and well-being. They are the location where eukaryotic cells carry out energy metabolism. Aside from producing the majority of ATP through oxidative phosphorylation, which provides essential energy for cellular functions, mitochondria also participate in other metabolic processes within the cell, such as the electron transport chain, citric acid cycle, and β-oxidation of fatty acids. Furthermore, mitochondria regulate the production and elimination of ROS, the synthesis of nucleotides and amino acids, the balance of calcium ions, and the process of cell death. Therefore, it is widely accepted that mitochondrial dysfunction is a factor that causes or contributes to the development and advancement of various diseases. These include common systemic diseases, such as aging, diabetes, Parkinson's disease, and cancer, as well as rare metabolic disorders, like Kearns-Sayre syndrome, Leigh disease, and mitochondrial myopathy. This overview outlines the various mechanisms by which mitochondria are involved in numerous illnesses and cellular physiological activities. Additionally, it provides new discoveries regarding the involvement of mitochondria in both disorders and the maintenance of good health.

Multiomics Analysis of the Mechanism by Which Gibberellin Alleviates S-Metolachlor Toxicity in Rice Seedlings.

S-metolachlor is a selective pre-emergence herbicide used in dryland. However, it is challenging to employ in paddy fields due to its phytotoxic effects on rice. As a common phytohormone, Gibberellin-3 (GA3) is inferred to have the ability to alleviate herbicide phytotoxicity. This study first quantitatively verified the phytotoxicity of s-metolachlor to rice and then demonstrated the mitigative effect of GA3 on these adverse reactions. Furthermore, a transcriptome of rice seedlings subjected to different treatments was constructed to assemble the reference genes, followed by comparative metabolomics and proteomics analyses. Metabolomics revealed an enrichment of flavonoid metabolites in the group of adding GA3, and these flavonoids can eliminate ROS in plants. Proteomics analysis indicated that differential proteins were enriched in the phenylpropanoid biosynthesis pathway responsible for the synthesis of flavonoids and that the functions of most differential proteins are associated with peroxidase. The proteome, combined with the transcriptome, revealed that the expressions of proteins and genes was related to the POD activity in the group of adding GA3. It was speculated that the elimination of ROS is key to alleviating the stress of s-metolachlor on rice growth. It was inferred that the mechanism of GA3 in alleviating the phytotoxicity of the substance s-metolachlor is by increasing the activity of the POD and influencing the growth of rice seedlings through the restoration of flavonoid synthesis. In this study, we screened GA3 as a safener to alleviate the phytotoxicity of s-metolachlor on rice. On this basis, the mechanism of alleviating phytotoxicity was studied. The application range of s-metolachlor might be expanded, providing a new supplementary method for weed control and herbicide resistance management.

Structurally Oriented Carbon Dots as ROS Nanomodulators for Dynamic Chronic Inflammation and Infection Elimination.

The selective elimination of cytotoxic ROS while retaining essential ones is pivotal in the management of chronic inflammation. Co-occurring bacterial infection further complicates the conditions, necessitating precision and an efficacious treatment strategy. Herein, the dynamic ROS nanomodulators are rationally constructed through regulating the surface states of herbal carbon dots (CDs) for on-demand inflammation or infection elimination. The phenolic OH containing CDs derived from honeysuckle (HOCD) and dandelion (DACD) demonstrated appropriate redox potentials, ensuring their ability to scavenge cytotoxic ROS such as ·OH and ONOO-, while invalidity toward essential ones such as O2·-, H2O2, and NO. This enables efficient treatment of chronic inflammation without affecting essential ROS signal pathways. The surface C-N/C═N of CDs derived from taxus leaves (TACD) and DACD renders them with suitable band structures, facilitating absorption in the red region and efficient generation of O2·- upon light irradiation for sterilization. Specifically, the facilely prepared DACD demonstrates fascinating dynamic ROS modulating ability, making it highly suitable for addressing concurrent chronic inflammation and infection, such as diabetic wound infection. This dynamic ROS regulation strategy facilitates the realization of the precise and efficient treatment of chronic inflammation and infection with minimal side effects, holding immense potential for clinical practice.

Enhancement of Bone Tissue Regeneration with Multi-Functional Nanoparticles by Coordination of Immune, Osteogenic, and Angiogenic Responses.

Inorganic nanoparticles are promising materials for bone tissue engineering due to their chemical resemblance to the native bone structure. However, most studies are unable to capture the entirety of the defective environment, providing limited bone regenerative abilities. Hence, this study aims to develop a multifunctional nanoparticle to collectively control the defective bone niche, including immune, angiogenic, and osteogenic systems. The nanoparticles, self-assembled by biomimetic mineralization and tannic acid (TA)-mediated metal-polyphenol network (MPN), are released sustainably after the incorporation within a gelatin cryogel. The released nanoparticles display a reduction in M1 macrophages by means of reactive oxygen species (ROS) elimination. Consequently, osteoclast maturation is also reduced, which is observed by the minimal formation of multinucleated cells (0.4%). Furthermore, the proportion of M2 macrophages, osteogenic differentiation, and angiogenic potential are consistently increased by the effects of magnesium from the nanoparticles. This orchestrated control of multiple systems influences the in vivo vascularized bone regeneration in which 80% of the critical-sized bone defect is regenerated with new bones with mature lamellar structure and arteriole-scale micro-vessels. Altogether, this study emphasizes the importance of the coordinated modulation of immune, osteogenic, and angiogenic systems at the bone defect site for robust bone regeneration.

Hyperosmotic Stress Induces Inflammation and Excessive Th17 Response to Blunt T-Cell Immunity in Tilapia.

Despite the advances in study on osmotic physiology in bony fish, the mechanism by which the immune system, especially T-cell immunity, adapts and responds to osmotic stress remains unknown. In the current study, we investigated the response of T cells to hyperosmotic stress in the bony fish Nile tilapia (Oreochromis niloticus). As a euryhaline fish, tilapia was able to adapt to a wide range of salinities; however, hypertonic stress caused inflammation and excessive T-cell activation. Furthermore, hypertonic stress increased the expression of IL-17A in T cells, upregulated the transcription factor RORα, and activated STAT3 signaling, along with IL-6- and TGF-β1-mediated pathways, revealing an enhanced Th17 response in this early vertebrate. These hypertonic stress-induced events collectively resulted in an impaired antibacterial immune response in tilapia. Hypertonic stress elevated the intracellular ROS level, which in turn activated the p38-MK2 signaling pathway to promote IL-17A production by T cells. Both ROS elimination and the p38-MK2 axis blockade diminished the increased IL-17A production in T cells under hypertonic conditions. Moreover, the produced proinflammatory cytokines further amplified the hypertonic stress signaling via the MKK6-p38-MK2 axis-mediated positive feedback loop. To our knowledge, these findings represent the first description of the mechanism by which T-cell immunity responds to hypertonic stress in early vertebrates, thus providing a novel perspective for understanding the adaptive evolution of T cells under environmental stress.

Retracted: Rhodiola Rosea Extract Counteracts Stress in an Adaptogenic Response Curve Manner via Elimination of ROS and Induction of Neurite Outgrowth.

[This retracts the article DOI: 10.1155/2022/5647599.].

Tropical postbiotics alleviate the disorders in the gut microbiota and kidney damage induced by ochratoxin A exposure.

Ochratoxin A (OTA), commonly found in various foods, significantly impacts the health of humans and animals, especially their kidneys. Our study explores OTA's effects on the gut microbiota and kidney damage while examining how postbiotics offer protection. Using metagenomic sequencing, we observed that OTA increased the potential gut pathogens such as Alistipes, elevating detrimental metabolites and inflammation. Also, OTA inhibited the Nrf2/HO-1 pathway, reducing kidney ROS elimination and leading to cellular ferroptosis and subsequent kidney damage. Postbiotics mitigate OTA's effects by downregulating the abundance of the assimilatory sulfate reduction IV pathway and virulence factors associated with iron uptake and relieving the inhibition of OTA on Nrf2/HO-1, restoring ROS-clearing capabilities and thereby alleviating chronic OTA-induced kidney damage. Understanding the OTA-gut-kidney link provides new approaches for preventing kidney damage, with postbiotics showing promise as a preventive treatment.

A copper-loaded self-assembled nanoparticle for disturbing the tumor redox balance and triple anti-tumor therapy.

Both chemodynamic therapy and photodynamic therapy, based on the production of reactive oxygen (ROS), have excellent potential in cancer therapy. However, the abnormal redox homeostasis in tumor cells, especially the overexpressed glutathione (GSH) could scavenge ROS and reduce the anti-tumor efficiency. Therefore, it is essential to develop a simple and effective tumor-specific drug delivery system for modulating the tumor microenvironment (TME) and achieving synergistic therapy at the tumor site. In this study, self-assembled nanoparticles (named CDZP NPs) were developed using copper ion (Cu2+), doxorubicin (Dox), zinc phthalocyanine (ZnPc) and a trace amount of poly(2-(di-methylamino)ethylmethacrylate)-poly[(R)-3-hydroxybutyrate]-poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA-PHB-PDMAEMA) through chelation, π-π stacking and hydrophobic interaction. These triple factor-responsive (pH, laser and GSH) nanoparticles demonstrated unique advantages through the synergistic effect. Highly controllable drug release ensured its effectiveness at the tumor site, Dox-induced chemotherapy and ZnPc-mediated fluorescence (FL) imaging exhibited the distribution of nanoparticles. Meanwhile, Cu2+-mediated GSH-consumption not only reduced the intracellular ROS elimination but also produced Cu+ to catalyze hydrogen peroxide (H2O2) and generated hydroxyl radicals (˙OH), thereby enhancing the chemodynamic and photodynamic therapy. Herein, this study provides a green and relatively simple method for preparing multifunctional nanoparticles that can effectively modulate the TME and improve synergetic cancer therapy.

Organelle-Mediated Dissipative Self-Assembly of Peptides in Living Cells.

Implementing dissipative assembly in living systems is meaningful for creation of living materials or even artificial life. However, intracellular dissipative assembly remains scarce and is significantly impeded by the challenges lying in precisely operating chemical reaction cycles under complex physiological conditions. Here, we develop organelle-mediated dissipative self-assembly of peptides in living cells fueled by GSH, via the design of a mitochondrion-targeting and redox-responsive hexapeptide. While the hexapeptide undergoes efficient redox-responsive self-assembly, the addition of GSH into the peptide solution in the presence of mitochondrion-biomimetic liposomes containing hydrogen peroxide allows for transient assembly of peptides. Internalization of the peptide by LPS-stimulated macrophages leads to the self-assembly of the peptide driven by GSH reduction and the association of the peptide assemblies with mitochondria. The association facilitates reversible oxidation of the reduced peptide by mitochondrion-residing ROS and thereby dissociates the peptide from mitochondria to re-enter the cytoplasm for GSH reduction. The metastable peptide-mitochondrion complexes prevent the thermodynamically equilibrated self-assembly, thus establishing dissipative assembly of peptides in stimulated macrophages. The entire dissipative self-assembling process allows for elimination of elevated ROS and decrease of pro-inflammatory cytokine expression. Creating dissipative self-assembling systems assisted by internal structures provides new avenues for the development of living materials or medical agents in the future.

Low-Se Diet Increased Mitochondrial ROS to Suppress Myoblasts Proliferation and Promote Apoptosis in Broilers via miR-365-3p/SelT Signaling Axis.

microRNA (miRNA) controls the post-transcriptional translation of mRNA to affect the expression of many genes participating in functional interaction pathways. Selenoproteins are characterized by their antioxidant activity, wherein selenoprotein T (SelT) is an essential membrane-bound selenoprotein serving as a guardian of intracellular homeostasis. During muscle development and regeneration, myoblasts enter the cell cycle and rapidly proliferate. However, the role of SelT in muscle development and selenium (Se) deficiency-induced muscle damage remains poorly investigated. This study established Se deficient broiler models, chicken embryos models, and cultured chicken primary myoblasts in vitro. We showed that Se deficiency induced skeletal muscle damage in broilers, promoted miR-365-3p expression, and downregulated the level of SelT, significantly. The absence of SelT led to the accumulation of mitochondrial superoxide and downregulated mitochondrial dynamics gene expression, which, in turn, induced the disruption of mitochondria potential and blocked the oxidative phosphorylation (OXPHOS) process. Limited ATP production rate caused by mitochondrial ROS overproduction went along with cell cycle arrest, cell proliferation slowness, and myocyte apoptosis increase. Using Mito-TEMPO for mitochondrial ROS elimination could effectively mitigate the above adverse reactions and significantly restore the proliferation potential of myoblasts. Moreover, we identified miR-365-3p, a miRNA that targeted SelT mRNA to inhibit myoblast proliferation by disrupting intracellular redox balance. The omics analysis results showed that Se deficiency led to the significant enrichment of "cell cycle", "oxidative stress response", and "oxidative phosphorylation" pathway genes. Finally, we proved that the effect of the miR-365-3p/SelT signaling axis on muscle development did exist in the chicken embryo stage. In summary, our findings revealed that miR-365-3p was involved in broiler skeletal muscle damage in Se deficiency by targeting SelT, and SelT, serving as an intracellular homeostasis guardian, resisted mitochondrial oxidative stress, and protected ATP generation, promoting myoblast proliferation and inhibiting apoptosis. This study provides an attractive target for the cultivated meat industry and regenerative medicine.

Hepatocyte-targeted hyaluronic acid-polyethyleneimine conjugates for acute liver injury therapy by ROS elimination and inflammation modulation

Acute liver injury (ALI) is one of the most important causes of liver failure, and there are no FDA-approved drugs that could therapy late-stage ALI. It has been shown in this study that HA-PEI, a molecule formed by covalently combining HA and PEI, can effectively treat advanced ALI. Through the CD44 receptor, HA-PEI could target the liver actively, with the highest liver-targeting effect confirmed at 1000 K. The underlying mechanism of protection of HA-PEI is by increasing oxygen content, reducing ROS, and maintaining mitochondrial membrane potential. HA-PEI also inhibits the secretion of inflammatory factors and blocks the migration of immune cells to the liver, protecting the hepatocytes not suffer from secondary damage. More importantly, for late-stage ALI, NAC, as the only FDA-approved drug, is completely ineffective, whereas HA-PEI has an excellent therapeutic effect. This work provides a new safe therapeutic agent for ALI, which has a bright application prospect.

Alleviation of acetaminophen-induced liver failure using silibinin nanoliposomes: An in vivo study

BackgroundAcetaminophen (Act) overdose is a known inducer of liver failure in both children and adults. Cell annihilation ensues following acetaminophen overdose and its toxic metabolites by depleting cellular GSH storage and increasing ROS levels. Silymarin extract and its major compound silibinin (SLB) possess robust antioxidant properties by inducing ROS elimination; however, low bioavailability and rapid metabolism limit their applications. Herein, we aimed at using SLB liposomes to combat acetaminophen-induced acute liver toxicity. MethodsWe have developed a SLB-lipid complex to improve SLB loading efficiency within nanoliposome by using the lipid film method. Liposomes were characterized by using DLS and TEM analysis, and the release pattern, and toxicity profile on the normal cells as well as histopathological and serum analysis were investigated to reveal relevant enzyme activities in an animal model. ResultsData demonstrated that negatively-charged SLB liposomes of 115 nm had homogeneous spherical morphology, and entrapped a considerable quantity of SLB of almost 40%. Liposomes shows a favorable release pattern and were not toxic against NIH3T3 mouse fibroblast cells. The animal study revealed that treatment of mice with SLB nanoliposomes could significantly preserve liver function as revealed by the reduced levels of ALT and AST hepatic enzymes as well as ALP in the serum. Our data indicated that intraperitoneal administration of SLB Lip could significantly reduce ALT enzyme levels (p < 0.05) compared to N-acetylcysteine, while i.v administration resulted in no significant difference compared to control animals with no treatment. ConclusionThe results of this study support the significant hepatoprotective effect of SLB nanoliposomes against acetaminophen-induced toxicity depending on the route of administration.

Nrf2/HO-1 blocks TXNIP/NLRP3 interaction via elimination of ROS in oxygen-glucose deprivation-induced neuronal necroptosis

Acute ischemic stroke (AIS) is known to trigger a cascade of inflammatory events that induces secondary tissue damages. As a type of regulated inflammatory cell death, necroptosis is associated with AIS, whilst its regulation during neuroinflammation is not well understood. In particular, the actual function of NOD-like-receptor family pyrin domain-containing-3(NLRP3) inflammasome in cortical neuronal necroptosis still not clear. Herein, we explored the function of nuclear factor erythroid-2 related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) in oxygen-glucose deprivation (OGD) induced neuronal necroptosis and its underlying mechanism. To establish an in vitro model of neuronal necrosis, we used OGD/caspase-8 inhibitors (Q-VD-OPh, QVD) to treat rat primary cortical neurons (PCNs) after reoxygenation, wherein we found that the model cause an elevated ROS levels by mediating TXNIP/NLRP3 interactions, which in turn activated the NLRP3 inflammasome. Also, we observed that regulation of nuclear factor erythroid-2 related factor-2 (Nrf2) promoted heme oxygenase-1 (HO-1) expression and decreased TXNIP (a protein that relate oxidative stress to activation of inflammasome) and ROS levels, which negatively regulated the expression of OGD-induced activation of NLRP3 inflammasomes. In addition, HO-1 weakened NLRP3 inflammation body activation, which suggests that Nrf2-regulated HO-1 could block the interaction between TXNIP and NLRP3 in OGD/R-treated cortical neurons by inhibiting ROS production. Our study has discovered the importance of Nrf2/HO-1 signaling cascade for inhibiting inflammasome of NLRP3, which negatively regulated necrosis. Therefore, NLRP3 is considered a potential target for a novel neuroprotective approach, which can expand the therapeutic windows of stroke drugs.

Enhancing tolerance of Kluyveromyces marxianus to lignocellulose-derived inhibitors and its ethanol production from corn cob via overexpression of a nitroreductase gene

Despite its potential as a sustainable feedstock for producing renewable fuels and chemicals, lignocellulosic biomass (LCB) remains largely untapped due to problems associated with its deconstruction and the toxicity of its sugar-rich hydrolysates in microbial conversion processes. Using genetic modification to facilitate inhibitor tolerance, the present study aimed to construct a robust yeast cell factory for cellulosic ethanol bioproduction from non-detoxified LCB. To this effect, two putative nitroreductase genes (KmHBN1 and KmFRM2) hypothesized to be possible mediators of oxidative stress response were separately overexpressed and disrupted in Kluyveromyces marxianus. In contrast to KmFRM2 modified strains (disrupted or overexpressed) with no significant change, the inhibitor tolerance to phenols, furfural, and acetic acid cocktail was improved in YKmHBN1-URA3 strain overexpressing KmHBN1. Although the recombinant KmHBN1 and KmFRM2 had nitroreductase activity, they did not degrade or convert inhibitors. The change of intracellular reactive oxygen species level (ROS) of KmHBN1 disrupted or overexpressed strains indicated that KmHBN1 affected intracellular ROS elimination. Cells with disrupted KmHBN1 failed to respond to ROS created during inhibitor metabolism, and this disruption also led to reduced expression of respiratory chain genes which translates to a decreased inhibitor tolerance. The overexpression of KmHBN1 not only enhanced the ethanol production from glucose in the presence of inhibitors but also improved ethanol productivity (18.75%) from simultaneously-saccharified and co-fermented inhibitor-ladened corn cob. These findings unlock a new pathway for the creation of robust yeast strains to aid in the biorefinery conversion of lignocellulosic feedstock.

Potent pigmentation inhibitory activity of incensole-enriched frankincense volatile oil-identification, efficacy and mechanism.

Frankincense volatile oil (FVO) has long been considered a side product in pharmaceutical industry since frankincense of large molecular weight is the prime target. However, the volatile oil recycled in the extract process might contain a series of functional actives, serving as promising ingredients in the cosmetic field. Gas chromatography-mass spectrometer was utilized to determine the species and amount of active ingredients in FVO. Subsequently, zebrafish models were used to evaluate pigmentation inhibition, ROS elimination and neutrophil activation. In vitro DPPH test was also conducted to consolidate the anti-oxidation efficacy. Based on the test results, network pharmacology was incorporated, where GO and KEGG enrichment analyses were performed to discover the interrelations between active ingredients. About 40 actives molecules were identified, including incensole, acetate incensole, and acetate incensole oxide. The FVO demonstrated great depigmentation activity by suppressing melanin synthesis, as well as providing free radical scavenging and anti-inflammation effect. In network pharmacology analysis, 192 intersected targets were identified. By enrichment analysis and network construction, a series of whitening signal pathways, and hub genes, containing STAT3，MAPK3，MAPK1 were identified. The current study quantified the components of FVO, evaluated its efficacy in skin depigmentation, and give pioneering insights on the possible mechanism. The results confirmed that the FVO could serve as whitening agent in topical uses.

Caffeoylquinic acids isolated from Lonicera japonica Thunb. as TAK1 inhibitors protects against LPS plus IFN-γ-stimulated inflammation by interacting with KEAP1-regulated NRF2 activation

The transforming growth factor-β-activated kinase 1 (TAK1) phosphorylation promotes inflammation occurrence. Meanwhile, TAK1 directly interacts with KEAP1 and strenghtenes NRF2/HO-1 pathway downregulated-inflammation. Recently, we found that caffeoylquinic acids not only possessed powderful anti-inflammation function, but also attenuated oxidative damage through KEAP1/NRF2 pathway. Whereas it’s rarely understood whether the anti-inflammatory activity were regulated by their interaction between TAK1 and NRF2. Herein, 34 caffeoylquinic acids including five new (2, 4-7) were systematically isolated and identified on the basis of spectroscopic evidence from Lonicera japonica Thunb. flower buds. Their inhibitory effects on inflammation induced by LPS plus IFN-γ were exerted substantial NO scavenging activity, and inhibited massive production of inflammatory cytokines and related proteins. Compound 3 (4F5C-QAME) exhibited the best anti-inflammation activity. 4F5C-QAME down-regulated the phosphorylation of TAK1, JNK, and c-JUN, thereby alleviated inflammation stimulated by LPS plus IFN-γ. Meanwhile, 4F5C-QAME could alleviate the interaction between TAK1 and KEAP1, inhibit the ubiquitination degradation of NRF2, activate NRF2/HO-1 signaling pathway, result in the increase in ROS elimination. Furthermore, 4F5C-QAME effectively protected against inflammation through direct inhibition of TAK1 phosphorylation. Based on these findings, 4F5C-QAME directly targeting TAK1 could be represented as a potential drug candidate for preventing/treating inflammatory diseases that regulated NRF2 activation through alleviating the interaction between TAK1 and KEAP1. Moreover, the regulatory mechanism of TAK1 on NRF2 activation under exogenous oxidative stress was revealed for the first time.

Opioids Alleviate Oxidative Stress via the Nrf2/HO-1 Pathway in LPS-Stimulated Microglia

Opioids are known to have antioxidant effects and to modulate microglial function under certain conditions. It has been previously shown that opioid ligands can effectively inhibit the release of proinflammatory cytokines when stimulated with lipopolysaccharide (LPS) and convert microglia to an anti-inflammatory polarization state. Here, we used C8-B4 cells, the mouse microglial cell line activated by LPS as a model to investigate the anti-inflammatory/antioxidant potential of selected opioid receptor agonists (DAMGO, DADLE, and U-50488). We found that all of these ligands could exert cytoprotective effects through the mechanism affecting LPS-induced ROS production, NADPH synthesis, and glucose uptake. Interestingly, opioids elevated the level of reduced glutathione, increased ATP content, and enhanced mitochondrial respiration in microglial cells exposed to LPS. These beneficial effects were associated with the upregulation of the Nrf2/HO-1 pathway. The present results indicate that activation of opioid signaling supports the preservation of mitochondrial function with concomitant elimination of ROS in microglia and suggest that an Nrf2/HO-1 signaling pathway-dependent mechanism is involved in the antioxidant efficacy of opioids. Opioid receptor agonists may therefore be considered as agents to suppress oxidative stress and inflammatory responses of microglia.

Glucocorticoid nanoformulations relieve chronic pelvic pain syndrome and may alleviate depression in mice

BackgroundChronic pelvic pain syndrome (CPPS) is a typical symptom of chronic prostatitis (CP) in males that may cause abnormal urination, sexual dysfunction, or depression and significantly affect the quality of life of the patient. Currently, there is no effective treatment for CPPS due to its recurrence and intractability. For synergistic CPPS therapy, we developed pH/reactive oxygen species (ROS) dual-responsive dexamethasone (Dex) nanoformulations using a ROS-responsive moiety and phytochemical modified α-cyclodextrin (α-CD) as the carrier.ResultsDex release from the nanoformulations can be controlled in acidic and/or ROS-rich microenvironments. The fabricated Dex nanoformulations can also be efficiently internalized by lipopolysaccharide (LPS)-stimulated macrophages, prostatic epithelial cells, and stromal cells. Moreover, the levels of proinflammatory factors (e.g., TNF-α, IL-1β, and IL-17 A) in these cells were significantly decreased by Dex nanoformulations treatment through the release of Dex, phytochemical and elimination of ROS. In vivo experiments demonstrated notable accumulation of the Dex nanoformulations in prostate tissue to alleviate the symptoms of CPPS through the downregulation of proinflammatory factors. Interestingly, depression in mice may be relieved due to alleviation of their pelvic pain.ConclusionWe fabricated Dex nanoformulations for the effective management of CPPS and alleviation of depression in mice.

Novel insights on toxicology of ochratoxin A contaminated diets to skin: Residues, mucus disruption and barrier impairment in teleost model grass carp (Ctenopharyngodon idella)

Ochratoxin A (OTA), a notorious pollutant widely present worldwide, seriously pollutes aquafeeds. This paper aims to explore the toxicity effects of OTA by the way of diet on the skin barrier in grass carp (Ctenopharyngodon idella). Results were shown as follows in the skin: (1) OTA increased the mRNA abundances of uptake transporter proteins (e.g., OAT3) and decreased efflux transporter proteins (e.g., ABCG2), which caused the accumulation of OTA in the skin of grass carp. (2) OTA upregulated the gene expression related to ROS production by enhancing the NOX (1, 2, 4) signaling pathway and decreased the ability to ROS elimination with downregulation of GPx1 (a,b), Trx by inhibiting the PGC1-α/Nrf2 signaling pathway, which caused oxidative damage to the skin. (3) OTA exacerbated apoptosis in the skin by upregulating the expression of apoptosis-related proteins mediated by ways of endoplasmic reticulum stress and mitochondrial apoptosis. Moreover, OTA down-regulated the mRNA and protein abundances of tight junction-related proteins by inhibiting the MLCK signaling pathway, which in turn disrupted the tight junctions. (4) OTA reduced the number of mucous cup cells and decreased f LZ activities and IgM contents, and finally down-regulated the mRNA abundances of mucin (2, 3), LEAP-2 (A, B), and β-defensin (1, 2, 3), which in turn resulted in impairing skin chemical barrier. Moreover, based on the antimicrobial-related indexes (LZ activities and IgM contents), the OTA-safe upper doses were 814.827 and 813.601 μg/kg.