Mechanism of extracellular electron transport and reactive oxygen mediated Sb(III) oxidation by Klebsiella aerogenes HC10.

Microbial oxidation and the mechanism of Sb(III) are key governing elements in biogeochemical cycling. A novel Sb oxidizing bacterium, Klebsiella aerogenes HC10, was attracted early and revealed that extracellular metabolites were the main fractions driving Sb oxidation. However, linkages between the extracellular metabolite driven Sb oxidation process and mechanism remain elusive. Here, model phenolic and quinone compounds, i.e., anthraquinone-2,6-disulfonate (AQDS) and hydroquinone (HYD), representing extracellular oxidants secreted by K. aerogenes HC10, were chosen to further study the Sb(III) oxidation mechanism. N2 purging and free radical quenching showed that oxygen-induced oxidation accounted for 36.78% of Sb(III) in the metabolite reaction system, while hydroxyl free radicals (·OH) accounted for 15.52%. ·OH and H2O2 are the main driving factors for Sb oxidation. Radical quenching, methanol purification and electron paramagnetic resonance (EPR) analysis revealed that ·OH, superoxide radical (O2•-) and semiquinone (SQ-•) were reactive intermediates of the phenolic induced oxidation process. Phenolic-induced ROS are one of the main oxidants in metabolites. Cyclic voltammetry (CV) showed that electron transfer of quinone also mediated Sb(III) oxidation. Part of Sb(V) was scavenged by the formation of the secondary Sb(V)-bearing mineral mopungite [NaSb(OH)6] in the incubation system. Our study demonstrates the microbial role of oxidation detoxification and mineralization of Sb and provides scientific references for the biochemical remediation of Sb-contaminated soil.

4-Nitrophenol at environmentally relevant concentrations mediates reproductive toxicity in Caenorhabditis elegans via metabolic disorders-induced estrogen signaling pathway.

4-Nitrophenol (4-NP), as a toxic and refractory pollutant, has generated significant concern due to its adverse effects. However, the potential toxic effects and mechanism remained unclear. In this study, the reproduction, development, locomotion and reactive oxygen species (ROS) production of Caenorhabditis elegans were investigated to evaluate the 4-NP toxicity. We used metabolomics to assess the potential damage mechanisms. The role of metabolites in mediating the relationship between 4-NP and phenotypes was examined by correlation and mediation analysis. 4-NP (8 ng/L and 8 µg/L) caused significant reduction of brood size, ovulation rate, total germ cells numbers, head thrashes and body bends, and an increase in ROS. However, the oosperm numbers in uterus, body length and body width were decreased in 8 µg/L. Moreover, 36 differential metabolites were enriched in the significant metabolic pathways, including lysine biosynthesis, ß-alanine metabolism, tryptophan metabolism, pentose phosphate pathway, pentose and glucuronate interconversions, amino sugar and nucleotide sugar metabolism, starch and sucrose metabolism, galactose metabolism, propanoate metabolism, glycerolipid metabolism, and estrogen signaling pathway. The mechanism of 4-NP toxicity was that oxidative stress caused by the perturbation of amino acid, which had effects on energy metabolism through disturbing carbohydrate and lipid metabolism, and finally affected the estrogen signaling pathway to exert toxic effects. Moreover, correlation and mediation analysis showed glycerol-3P, glucosamine-6P, glucosamine-1P, UDP-galactose, L-aspartic acid, and uracil were potential markers for the reproduction and glucose-1,6P2 for developmental toxicity. The results provided insight into the pathways involved in the toxic effects caused by 4-NP and developed potential biomarkers to evaluate 4-NP toxicity.

A review on reactive oxygen species-induced mechanism pathways of pharmaceutical waste degradation: Acetaminophen as a drug waste model.

Innately designed to induce physiological changes, pharmaceuticals are foreknowingly hazardous to the ecosystem. Advanced oxidation processes (AOPs) are recognized as a set of contemporary and highly efficient methods being used as a contrivance for the removal of pharmaceutical residues. Since reactive oxygen species (ROS) are formed in these processes to interact and contribute directly toward the oxidation of target contaminant(s), a profound insight regarding the mechanisms of ROS leading to the degradation of pharmaceuticals is fundamentally significant. The conceptualization of some specific reaction mechanisms allows the design of an effective and safe degradation process that can empirically reduce the environmental impact of the micropollutants. This review mainly deliberates the mechanistic reaction pathways for ROS-mediated degradation of pharmaceuticals often leading to complete mineralization, with a focus on acetaminophen as a drug waste model.

Allicin inhibits the growth of HONE-1 and HNE1 human nasopharyngeal carcinoma cells by inducing ferroptosis.

Allicin (AL) is one of garlic-derived organosulfides and has a variety of pharmacological effects. Studies have reported that AL has notable inhibitory effects on liver cancer, gastric cancer, breast cancer, and other cancers. However, there are no relevant reports about its role in human nasopharyngeal carcinoma. Ferroptosis is an iron-dependent form of non-apoptotic regulated cell death. Increasing evidence indicates that induction of ferroptosis can inhibit the proliferation, migration, invasion, and survival of various cancer cells, which act as a tumor suppressor in cancer. In this study, we confirmed that AL can inhibit cell proliferation, migration, invasion, and survival in human nasopharyngeal carcinoma cells. Our finding shows that AL can induce the ferroptosis axis by decreasing the level of GSH and GPX4 and promoting the induction of toxic LPO and ROS. AL-mediated cytotoxicity in human nasopharyngeal carcinoma cells is dependent on ferroptosis. Therefore, AL has good anti-cancer properties and is expected to be a potential drug for the treatment of nasopharyngeal carcinoma.

Wireless Powered Microwave-Light Conversion Platform with Dual-Stimulus Nanoresponder Coating for Deep-Seated Photodynamic Therapy.

Traditional external field-assisted therapies, e.g., microwave (MW) therapy and phototherapy, cannot effectively and minimally damage eliminate deep-seated infection, owing to the poor penetrability of light and low reactive oxygen species (ROS) stimulation capability of MW. Herein, an implantable and wireless-powered therapeutic platform (CNT-FeTHQ-TS), in which external MW can be converted into internal light via MW wireless-powered light-emitting chips, is designed to eradicate deep-seated tissue infections by MW-induced deep-seated photodynamic therapy. In application, CNT-FeTHQ-TS is implanted at internal lesions, and the chip emits light under external MW irradiation. Subsequently, CNT-FeTHQ coating in the platform can respond to both MW and light simultaneously to generate ROS and MW-hyperthermia for rapid and precise sterilization at focus. Importantly, MW also improves the photodynamic performance of CNT-FeTHQ by introducing vacancies in FeTHQ to facilitate the photoexcitation process and changing the spin state of electrons to inhibit the complexation of photogenerated electron-hole pairs, which were confirmed by simulation calculations and in situ MW-irradiated photoluminescence experiments. In vivo, CNT-FeTHQ-TS can effectively cure mice with Staphylococcus aureus infection in dorsal subcutaneous tissue. This work overcomes the key clinical limitations of safe energy transmission and conversion for treating deep-seated infections.

Preventing loss of sirt1 lowers mitochondrial oxidative stress and preserves C2C12 myotube diameter in an in vitro model of cancer cachexia.

Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle atrophy. Increased skeletal muscle mitochondrial reactive oxygen species (ROS) is a contributing factor to loss of muscle mass in cachectic patients. Mice inoculated with Lewis lung carcinoma (LLC) cells lose weight, muscle mass, and have lower muscle sirtuin-1 (sirt1) expression. Nicotinic acid (NA) is a precursor to nicotinamide dinucleotide (NAD+) which is exhausted in cachectic muscle and is a direct activator of sirt1. Mice lost body and muscle weight and exhibited reduced skeletal muscle sirt1 expression after inoculation with LLC cells. C2C12 myotubes treated with LLC-conditioned media (LCM) had lower myotube diameter. We treated C2C12 myotubes with LCM for 24 h with or without NA for 24 h. C2C12 myotubes treated with NA maintained myotube diameter, sirt1 expression, and had lower mitochondrial superoxide. We then used a sirt1-specific small molecule activator SRT1720 to increase sirt1 activity. C2C12 myotubes treated with SRT1720 maintained myotube diameter, prevented loss of sirt1 expression, and attenuated mitochondrial superoxide production. Our data provides evidence that NA may be beneficial in combating cancer cachexia by maintaining sirt1 expression and decreasing mitochondrial superoxide production.

Andrographolide induces protective autophagy and targeting DJ-1 triggers reactive oxygen species-induced cell death in pancreatic cancer.

Background: Andrographolide (Andro), an extract of Andrographis paniculate (Burm.f.) Wall. ex Nees (Acanthaceae), possesses diverse biologically active properties. However, the precise mechanisms and effects of Andro on pancreatic cancer (PC) remain unclear. Methods: The cytotoxic potential of Andro and underlying mechanism towards PC cells was investigated through in vitro experiments and a xenograft mouse model. PC cells were first subjected to varying concentrations of Andro. The reactive oxygen species (ROS) was assessed using flow cytometry and DCFH-DA staining. The apoptosis rate was detected by flow cytometry. Additionally, western blot was applied to evaluate the expression levels of cleaved-caspase-3, DJ-1, LC3-I, LC3-II, and p62. To further elucidate the involvement of ROS accumulation and autophagy, we employed N-acetylcysteine as a scavenger of ROS and 3-Methyladenine as an inhibitor of autophagy. Results: Andro demonstrated potent anti-proliferative effects on PC cells and induced apoptosis, both in vitro and in vivo. The cytotoxicity of Andro on PC cells was counteracted by DJ-1 overexpression. The reduction in DJ-1 expression caused by Andro led to ROS accumulation, subsequently inhibiting the growth of PC cells. Furthermore, Andro stimulated cytoprotective autophagy, thus weakening the antitumor effect. Pharmacological blockade of autophagy further enhanced the antitumor efficacy of Andro. Conclusion: Our study indicated that ROS accumulation induced by the DJ-1 reduction played a key role in Andro-mediated PC cell inhibition. Furthermore, the protective autophagy induced by the Andro in PC cells is a mechanism that needs to be addressed in future studies.

Mitochondrial Targeted Cerium Oxide Nanoclusters for Radiation Protection and Promoting Hematopoiesis.

Purpose: Mitochondrial oxidative stress is an important factor in cell apoptosis. Cerium oxide nanomaterials show great potential for scavenging free radicals and simulating superoxide dismutase (SOD) and catalase (CAT) activities. To solve the problem of poor targeting of cerium oxide nanomaterials, we designed albumin-cerium oxide nanoclusters (TPP-PCNLs) that target the modification of mitochondria with triphenyl phosphate (TPP). TPP-PCNLs are expected to simulate the activity of superoxide dismutase, continuously remove reactive oxygen species, and play a lasting role in radiation protection. Methods: First, cerium dioxide nanoclusters (CNLs), polyethylene glycol cerium dioxide nanoclusters (PCNLs), and TPP-PCNLs were characterized in terms of their morphology and size, ultraviolet spectrum, dispersion stability and cellular uptake, and colocalization Subsequently, the anti-radiation effects of TPP-PCNLs were investigated using in vitro and in vivo experiments including cell viability, apoptosis, comet assays, histopathology, and dose reduction factor (DRF). Results: TPP-PCNLs exhibited good stability and biocompatibility. In vitro experiments indicated that TPP-PCNLs could not only target mitochondria excellently but also regulate reactive oxygen species (ROS)levels in whole cells. More importantly, TPP-PCNLs improved the integrity and functionality of mitochondria in irradiated L-02 cells, thereby indirectly eliminating the continuous damage to nuclear DNA caused by mitochondrial oxidative stress. TPP-PCNLs are mainly targeted to the liver, spleen, and other extramedullary hematopoietic organs with a radiation dose reduction factor of 1.30. In vivo experiments showed that TPP-PCNLs effectively improved the survival rate, weight change, hematopoietic function of irradiated animals. Western blot experiments have confirmed that TPP-PCNLs play a role in radiation protection by regulating the mitochondrial apoptotic pathway. Conclusion: TPP-PCNLs play a radiologically protective role by targeting extramedullary hematopoietic organ-liver cells and mitochondria to continuously clear ROS.

Breakthrough of Hypoxia Limitation by Tumor-Targeting Photothermal Therapy-Enhanced Radiation Therapy.

Purpose: To address the problem of suboptimal reactive oxygen species (ROS) production in Radiation therapy (RT) which was resulted from exacerbated tumor hypoxia and the heterogeneous distribution of radiation sensitizers. Materials and Methods: In this work, a novel nanomedicine, designated as PLGA@IR780-Bi-DTPA (PIBD), was engineered by loading the radiation sensitizer Bi-DTPA and the photothermal agent IR780 onto poly(lactic-co-glycolic acid) (PLGA). This design leverages the tumor-targeting ability of IR780 to ensure selective accumulation of the nanoparticles in tumor cells, particularly within the mitochondria. The effect of the photothermal therapy-enhanced radiation therapy was also examined to assess the alleviation of hypoxia and the enhancement of radiation sensitivity. Results: The PIBD nanoparticles exhibited strong capacity in mitochondrial targeting and selective tumor accumulation. Upon activation by 808 nm laser irradiation, the nanoparticles effectively alleviated local hypoxia by photothermal effect enhanced blood supplying to improve oxygen content, thereby enhancing the ROS production for effective RT. Comparative studies revealed that PIBD-induced RT significantly outperformed conventional RT in treating hypoxic tumors. Conclusion: This design of tumor-targeting photothermal therapy-enhanced radiation therapy nanomedicine would advance the development of targeted drug delivery system for effective RT regardless of hypoxic microenvironment.

Development of graphitic carbon nitride quantum dots-based oxygen self-sufficient platforms for enhanced corneal crosslinking.

Keratoconus, a disorder characterized by corneal thinning and weakening, results in vision loss. Corneal crosslinking (CXL) can halt the progression of keratoconus. The development of accelerated corneal crosslinking (A-CXL) protocols to shorten the treatment time has been hampered by the rapid depletion of stromal oxygen when higher UVA intensities are used, resulting in a reduced cross-linking effect. It is therefore imperative to develop better methods to increase the oxygen concentration within the corneal stroma during the A-CXL process. Photocatalytic oxygen-generating nanomaterials are promising candidates to solve the hypoxia problem during A-CXL. Biocompatible graphitic carbon nitride (g-C3N4) quantum dots (QDs)-based oxygen self-sufficient platforms including g-C3N4 QDs and riboflavin/g-C3N4 QDs composites (RF@g-C3N4 QDs) have been developed in this study. Both display excellent photocatalytic oxygen generation ability, high reactive oxygen species (ROS) yield, and excellent biosafety. More importantly, the A-CXL effect of the g-C3N4 QDs or RF@g-C3N4 QDs composite on male New Zealand white rabbits is better than that of the riboflavin 5'-phosphate sodium (RF) A-CXL protocol under the same conditions, indicating excellent strengthening of the cornea after A-CXL treatments. These lead us to suggest the potential application of g-C3N4 QDs in A-CXL for corneal ectasias and other corneal diseases.

Gut microbial metalloproteins and its role in xenobiotics degradation and ROS scavenging.

The gut microbial metalloenzymes play an important role in maintaining the balance between gut microbial ecosystem, human physiologically processes and immune system. The metals coordinated into active site contribute in various detoxification and defense strategies to avoid unfavourable environment and ensure bacterial survival in human gut. Metallo-ß-lactamase is a potent degrader of antibiotics present in periplasmic space of both commensals and pathogenic bacteria. The resistance to anti-microbial agents developed in this enzyme is one of the global threats for human health. The organophosphorus eliminator, organophosphorus hydrolases have evolved over a course of time to hydrolyze toxic organophosphorus compounds and decrease its effect on human health. Further, the redox stress responders namely superoxide dismutase and catalase are key metalloenzymes in reducing both endogenous and exogenous oxidative stress. They hold a great importance for pathogens as they contribute in pathogenesis in human gut along with reduction of oxidative stress. The in-silico study on these enzymes reveals the importance of point mutation for the evolution of these enzymes in order to enhance their enzyme activity and stability. Various mutation studies were conducted to investigate the catalytic activity of these enzymes. By using the "directed evolution" method, the enzymes involved in detoxification and defense system can be engineered to produce new variants with enhance catalytic features, which may be used to predict the severity due to multi-drug resistance and degradation pattern of organophosphorus compounds in human gut.

Cell Wall Binding Strategies Based on Cu3SbS3 Nanoparticles for Selective Bacterial Elimination and Promotion of Infected Wound Healing.

Utilizing nanomaterials as an alternative to antibiotics, with a focus on maintaining high biosafety, has emerged as a promising strategy to combat antibiotic resistance. Nevertheless, the challenge lies in the indiscriminate attack of nanomaterials on both bacterial and mammalian cells, which limits their practicality. Herein, Cu3SbS3 nanoparticles (NPs) capable of generating reactive oxygen species (ROS) are discovered to selectively adsorb and eliminate bacteria without causing obvious harm to mammalian cells, thanks to the interaction between O of N-acetylmuramic acid in bacterial cell walls and Cu of the NPs. Coupled with the short diffusion distance of ROS in the surrounding medium, a selective antibacterial effect is achieved. Additionally, the antibacterial mechanism is then identified: Cu3SbS3 NPs catalyze the generation of O2•-, which has subsequently been conversed by superoxide dismutase to H2O2. The latter is secondary catalyzed by the NPs to form •OH and 1O2, initiating an in situ attack on bacteria. This process depletes bacterial glutathione in conjunction with the disruption of the antioxidant defense system of bacteria. Notably, Cu3SbS3 NPs are demonstrated to efficiently impede biofilm formation; thus, a healing of MRSA-infected wounds was promoted. The bacterial cell wall-binding nanoantibacterial agents can be widely expanded through diversified design.

Myricetin mitigates motor disturbance and decreases neuronal ferroptosis in a rat model of Parkinson's disease.

Ferroptosis is an iron-dependent cell death form characterized by reactive oxygen species (ROS) overgeneration and lipid peroxidation. Myricetin, a flavonoid that exists in numerous plants, exhibits potent antioxidant capacity. Given that iron accumulation and ROS-provoked dopaminergic neuron death are the two main pathological hallmarks of Parkinson's disease (PD), we aimed to investigate whether myricetin decreases neuronal death through suppressing ferroptosis. The PD models were established by intraperitoneally injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into rats and by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+), respectively. Ferroptosis was identified by assessing the levels of Fe2+, ROS, malondialdehyde (MDA), and glutathione (GSH). The results demonstrated that myricetin treatment effectively mitigated MPTP-triggered motor impairment, dopamine neuronal death, and α-synuclein (α-Syn) accumulation in PD models. Myricetin also alleviated MPTP-induced ferroptosis, as evidenced by decreased levels of Fe2+, ROS, and MDA and increased levels of GSH in the substantia nigra (SN) and serum in PD models. All these changes were reversed by erastin, a ferroptosis activator. In vitro, myricetin treatment restored SH-SY5Y cell viability and alleviated MPP+-induced SH-SY5Y cell ferroptosis. Mechanistically, myricetin accelerated nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and subsequent glutathione peroxidase 4 (Gpx4) expression in MPP+-treated SH-SY5Y cells, two critical inhibitors of ferroptosis. Collectively, these data demonstrate that myricetin may be a potential agent for decreasing dopaminergic neuron death by inhibiting ferroptosis in PD.

Activation of PPAR-α attenuates myocardial ischemia/reperfusion injury by inhibiting ferroptosis and mitochondrial injury via upregulating 14-3-3η.

This study aimed to explore the effects of peroxisome proliferator-activated receptor α (PPAR-α), a known inhibitor of ferroptosis, in Myocardial ischemia/reperfusion injury (MIRI) and its related mechanisms. In vivo and in vitro MIRI models were established. Our results showed that activation of PPAR-α decreased the size of the myocardial infarct, maintained cardiac function, and decreased the serum contents of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and Fe2+ in ischemia/reperfusion (I/R)-treated mice. Additionally, the results of H&E staining, DHE staining, TUNEL staining, and transmission electron microscopy demonstrated that activation of PPAR-α inhibited MIRI-induced heart tissue and mitochondrial damage. It was also found that activation of PPAR-α attenuated MIRI-induced ferroptosis as shown by a reduction in malondialdehyde, total iron, and reactive oxygen species (ROS). In vitro experiments showed that intracellular contents of malondialdehyde, total iron, LDH, reactive oxygen species (ROS), lipid ROS, oxidized glutathione disulphide (GSSG), and Fe2+ were reduced by the activation of PPAR-α in H9c2 cells treated with anoxia/reoxygenation (A/R), while the cell viability and GSH were increased after PPAR-α activation. Additionally, changes in protein levels of the ferroptosis marker further confirmed the beneficial effects of PPAR-α activation on MIRI-induced ferroptosis. Moreover, the results of immunofluorescence and dual-luciferase reporter assay revealed that PPAR-α achieved its activity via binding to the 14-3-3η promoter, promoting its expression level. Moreover, the cardioprotective effects of PPAR-α could be canceled by pAd/14-3-3η-shRNA or Compound C11 (14-3-3η inhibitor). In conclusion, our results indicated that ferroptosis plays a key role in aggravating MIRI, and PPAR-α/14-3-3η pathway-mediated ferroptosis and mitochondrial injury might be an effective therapeutic target against MIRI.

Synthesis and characterization of novel histidine functionalized chitosan nanoformulations and its bioactivity in tomato plant.

The use of novel active ingredients for the functional modification of chitosan nanoformulations has attracted global attention. In this study, chitosan has been functionalized via histidine to craft novel chitosan-histidine nanoformulation (C-H NF) using ionic gelation method. C-H NF exhibited elite physico-biochemical properties, influencing physiological and biochemical dynamics in Tomato. These elite properties include homogenous-sized nanoparticles (314.4 nm), lower PDI (0.218), viscosity (1.43 Cps), higher zeta potential (11.2 mV), nanoparticle concentration/ml (3.53 × 108), conductivity (0.046 mS/cm), encapsulation efficiency (53%), loading capacity (24%) and yield (32.17%). FTIR spectroscopy revealed histidine interaction with C-H NF, while SEM and TEM exposed its porous structure. Application of C-H NF to Tomato seedling and potted plants through seed treatment and foliar spray positively impacts growth parameters, antioxidant-defense enzyme activities, reactive oxygen species (ROS) content, and chlorophyll and nitrogen content. We claim that the histidine-functionalized chitosan nanoformulation enhances physico-biochemical properties, highlighting its potential to elevate biochemical and physiological processes of Tomato plant.

Glutamate oxaloacetate transaminase 1 is dispensable in macrophage differentiation and anti-pathogen response.

Macrophages play a pivotal role in orchestrating the immune response against pathogens. While the intricate interplay between macrophage activation and metabolism remains a subject of intense investigation, the role of glutamate oxaloacetate transaminase 1 (Got1) in this context has not been extensively assessed. Here, we investigate the impact of Got1 on macrophage polarization and function, shedding light on its role in reactive oxygen species (ROS) production, pathogen defense, and immune paralysis. Using genetically modified mouse models, including both myeloid specific knockout and overexpression, we comprehensively demonstrate that Got1 depletion leads to reduced ROS production in macrophages. Intriguingly, this impairment in ROS generation does not affect the resistance of Got1 KO mice to pathogenic challenges. Furthermore, Got1 is dispensable for M2 macrophage differentiation and does not influence the onset of LPS-induced immune paralysis. Our findings underscore the intricate facets of macrophage responses, suggesting that Got1 is dispensable in discrete immunological processes.

Clotrimazole inhibits growth of multiple myeloma cells in vitro via G0/G1 arrest and mitochondrial apoptosis.

Patients with multiple myeloma (MM) experience relapse and drug resistance; therefore, novel treatments are essential. Clotrimazole (CTZ) is a wide-spectrum antifungal drug with antitumor activity. However, CTZ's effects on MM are unclear. We investigated CTZ's effect on MM cell proliferation and apoptosis induction mechanisms. CTZ's effects on MM.1S, NCI- H929, KMS-11, and U266 cell growth were investigated using Cell Counting Kit-8 (CCK-8) assay. The apoptotic cell percentage was quantified with annexin V-fluorescein isothiocyanate/7-amino actinomycin D staining. Mitochondrial membrane potential (MMP) and cell cycle progression were evaluated. Reactive oxygen species (ROS) levels were measured via fluorescence microscopy. Expression of apoptosis-related and nuclear factor (NF)-κB signaling proteins was analyzed using western blotting. The CCK-8 assay indicated that CTZ inhibited cell proliferation based on both dose and exposure time. Flow cytometry revealed that CTZ decreased apoptosis and MMP and induced G0/G1 arrest. Immunofluorescence demonstrated that CTZ dose-dependently elevated in both total and mitochondrial ROS production. Western blotting showed that CTZ enhanced Bax and cleaved poly ADP-ribose polymerase and caspase-3 while decreasing Bcl-2, p-p65, and p-IκBα. Therefore, CTZ inhibits MM cell proliferation by promoting ROS-mediated mitochondrial apoptosis, inducing G0/G1 arrest, inhibiting the NF-κB pathway, and has the potential for treating MM.

lncRNA FGD5-AS1 is required for gastric cancer proliferation by inhibiting cell senescence and ROS production via stabilizing YBX1.

BACKGROUND: The vast majority of lncRNAs have low expression abundance, which greatly limits their functional range and impact. As a high expression abundance lncRNA, FGD5-AS1's non-ceRNA biological function in cancer is unclear. METHODS: RNA-seq studies and chromatin immunoprecipitation (Chip) assays were performed to identify ZEB1-regulated lncRNAs. RNA sequencing, RNA pulldown, RNA Immunoprecipitation assays, and rescue assays were conducted to explore the molecular mechanisms of FGD5-AS1 in GC. RESULTS: As one of the most abundant lncRNAs in cells, FGD5-AS1 has been shown to be transcriptionally activated by ZEB1, thus closely related to epithelial-mesenchymal transition (EMT) signaling. Clinical analysis showed that FGD5-AS1 overexpression was clinically associated with lymph node metastasis, and predicted poor survival in GC. Loss-of-function studies confirmed that FGD5-AS1 knockdown inhibited GC proliferation and induced cisplatin chemosensibility, cell senescence, and DNA damage in GC cells. Mechanismically, FGD5-AS1 is a YBX1-binding lncRNA due to its mRNA contains three adjacent structural motifs (UAAUCCCA, ACCAGCCU, and CAGUGAGC) that can be recognized and bound by YBX1. And this RNA-protein interaction prolonged the half-life of the YBX1 protein in GC. Additionally, a rescue assay showed that FGD5-AS1 promotes GC by repressing cell senescence and ROS production via YBX1. CONCLUSION: FGD5-AS1 is a cellular high-abundant lncRNA that is transcriptionally regulated by ZEB1. FGD5-AS1 overexpression promoted GC progression by inhibiting cell senescence and ROS production through binding and stabilizing the YBX1 protein.

Network pharmacology and molecular-docking-based strategy to explore the potential mechanism of salidroside-inhibited oxidative stress in retinal ganglion cell.

BACKGROUND: Salidroside (SAL), the main component of Rhodiola rosea extract, is a flavonoid with biological activities, such as antioxidative stress, anti-inflammatory, and hypolipidemic. In this study, the potential therapeutic targets and mechanisms of SAL against oxidative stress in retinal ganglion cells (RGCs) were investigated on the basis of in-vitro experiments, network pharmacology, and molecular docking techniques. METHODS: RGC oxidative stress models were constructed, and cell activity, reactive oxygen species (ROS), and apoptosis levels were examined for differences. The genes corresponding to rhodopsin, RGCs, and oxidative stress were screened from GeneCards, TCMSP database, and an analysis platform. The intersection of the three was taken, and a Venn diagram was drawn. Protein interactions, GO functional enrichment, and KEGG pathway enrichment data were analyzed by STRING database, Cytohubba plugin, and Metascape database. The key factors in the screening pathway were validated using qRT-PCR. Finally, molecular docking prediction was performed using MOE 2019 software, molecular dynamic simulations was performed using Gromacs 2018 software. RESULTS: In the RGC oxidative stress model in vitro, the cell activity was enhanced, ROS was reduced, and apoptosis was decreased after SAL treatment. A total of 16 potential targets of oxidative stress in SAL RGCs were obtained, and the top 10 core targets were screened by network topology analysis. GO analysis showed that SAL retinal oxidative stress treatment mainly involved cellular response to stress, transcriptional regulatory complexes, and DNA-binding transcription factor binding. KEGG analysis showed that most genes were mainly enriched in multiple cancer pathways and signaling pathways in diabetic complications, nonalcoholic fatty liver, and lipid and atherosclerosis. Validation by PCR, molecular docking and molecular dynamic simulations revealed that SAL may attenuate oxidative stress and reduce apoptosis in RGCs by regulating SIRT1, NRF2, and NOS3. CONCLUSION: This study initially revealed the antioxidant therapeutic effects and molecular mechanisms of SAL on RGCs, providing a theoretical basis for subsequent studies.

Rhizoma coptidis can inhibit the excessive proliferation, inflammation, and transformation of lung fibroblasts into myofibroblasts.

BACKGROUND: Pulmonary fibrosis (PF) is a chronic, progressive, and irreversible heterogeneous disease of lung interstitial tissue. To combat progression of PF, new drugs are required to be developed. Rhizoma coptidis (COP), one of the main alkaloids of Coptis chinensis, is a traditional herbal medicine used to treat various inflammatory diseases. OBJECTIVE: To investigate the possible effects of Coptisine (Cop) on the growth, inflammation, as well as FMT of TNF-ß1-induced HFL1 cells and uncover the mechanism. MATERIAL AND METHODS: Human fetal lung fibroblast 1 (HFL1) was induced using 6ng/mL TGF-ß1 as a model of pulmonary fibrosis. CCK-8, Brdu, and transwell assays indicated the effects on cell growth as well as motility. qPCR and the corresponding kits indicted the effects on cell inflammation. Immunoblot showed the effects on FMT and further confirmed the mechanism. RESULTS: Coptisine inhibits excessive growth as well as motility of TNF-ß1-induced HFL1 cells. It further inhibits inflammation and ROS levels in TNF-ß1-induced HFL1 cells. Coptisine inhibits the FMT process of TNF-ß1-induced HFL1 cells. Mechanically, coptisine promotes the Nrf2/HO-1 pathway. CONCLUSION: Coptisine can inhibit the excessive growth, inflammation as well as FMT of lung fibroblasts into myofibroblasts. It could serve as a promising drug of PF.