Disruption Of Redox Homeostasis Research Articles

In situ-transition nanozyme triggered by tumor microenvironment boosts synergistic cancer radio-/chemotherapy through disrupting redox homeostasis

Disrupting redox homeostasis in the tumor microenvironment (TME), like excessive H2O2, glutathione (GSH) and weak acidity, has been proved as an effective tumor therapeutic strategy. Herein, we constructed a TME-responsive nanozyme, DOX@HMSN/Mn3O4(R), with reversible Mn3+/Mn2+ transition in situ triggered by TME to perturb the intrinsic redox homeostasis and catalyze reactive oxygen species (ROS) overproduction. In addition, this nanozyme could react with excess GSH in TME to produce GSSG, resulting in the consumption of reducing agents to suppress ROS clearance. Density functional theory calculations further confirmed that the nanozyme mainly exhibited the oxidase-like activity to catalyze the formation of hydroxyl radicals from O2, thus strengthening the oxidation environment in the TME. Combined with radiotherapy, the high-energy X-ray could excite the outer-layer electrons in the nanozyme, forming photoelectrons that participate in the oxidase-like enzymatic reaction, thus intensifying ROS accumulation and amplifying the radio-/chemotherapeutic efficacy.

Sleep deprivation induces corneal epithelial progenitor cell over-expansion through disruption of redox homeostasis in the tear film

Sleep deprivation induces corneal epithelial progenitor cell over-expansion through disruption of redox homeostasis in the tear film

Disruption of Redox Homeostasis by Alterations in Nitric Oxide Synthase Activity and Tetrahydrobiopterin along with Melanoma Progression.

Cutaneous melanoma emerges from the malignant transformation of melanocytes and is the most aggressive type of skin cancer. The progression can occur in different stages: radial growth phase (RGP), vertical growth phase (VGP), and metastasis. Reactive oxygen species contribute to all phases of melanomagenesis through the modulation of oncogenic signaling pathways. Tetrahydrobiopterin (BH4) is an important cofactor for NOS coupling, and an uncoupled enzyme is a source of superoxide anion (O2•−) rather than nitric oxide (NO), altering the redox homeostasis and contributing to melanoma progression. In the present work, we showed that the BH4 amount varies between different cell lines corresponding to distinct stages of melanoma progression; however, they all presented higher O2•− levels and lower NO levels compared to melanocytes. Our results showed increased NOS expression in melanoma cells, contributing to NOS uncoupling. BH4 supplementation of RGP cells, and the DAHP treatment of metastatic melanoma cells reduced cell growth. Finally, Western blot analysis indicated that both treatments act on the PI3K/AKT and MAPK pathways of these melanoma cells in different ways. Disruption of cellular redox homeostasis by the altered BH4 concentration can be explored as a therapeutic strategy according to the stage of melanoma.

Dietary consumption of polypropylene microplastics alter the biochemical parameters and histological response in freshwater benthic mollusc Pomacea paludosa

One of the most common environmental pollutant in aquatic ecosystems are polypropylene microplastics and their impacts on aquatic organisms are still scarce. The study aimed to prepare polypropylene microplastics using organic solvent (spherical and 11.86–44.62 μm) and then test their toxicity on the freshwater benthic mollusc grazer Pomaceae paludosa. The present study investigated chronic (28 days) exposure of polypropylene microplastics via dietary supplements (250 mg kg−1, 500 mg kg−1 & 750 mg kg−1) in P. paludosa, and the toxic effect was evaluated in digestive gland tissue. The FTIR results revealed no change in polypropylene microplastics during ingestion or after egestion. On the other hand, Ingestion causes accumulation in their bodies and disrupts redox homeostasis. Meanwhile, alteration occurs in oxidative stress-related biomarkers such as increased reactive oxygen species level (ROS), impaired the biochemical parameters of antioxidant system catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), and glutathione – S- transferase (GST), deterioration of oxidative stress effects in lipid peroxidation (LPO) and carbonyl protein (CP) and changed the digestive enzymes such as amylase, pepsin, esterase and alkaline phosphatase that are measured in hepatopancreas tissue. The histology results revealed that ingesting these microplastics caused severe damage to the digestive gland cells. According to the findings, ingestion of polypropylene microplastics in benthic freshwater mollusc causes more serious harm and impacts energy acquisition. This finding represents the ecological risk of polypropylene microplastic pollution in the freshwater ecosystem.

Sleep deprivation induces corneal epithelial progenitor cell over-expansion through disruption of redox homeostasis in the tear film.

SummarySleep deficiency, a common public health problem, causes ocular discomfort and affects ocular surface health. However, the underlying mechanism remains unclear. Herein, we identified that short-term sleep deprivation (SD) resulted in hyperproliferation of corneal epithelial progenitor cells (CEPCs) in mice. The expression levels of p63 and Keratin 14, the biomarkers of CEPCs, were upregulated in the corneal epithelium after short-term SD. In addition, SD led to elevated levels of reactive oxygen species (ROS), and subsequent decrease in antioxidant capacity, in the tear film. Exogenous hydrogen peroxide (H2O2) could directly stimulate the proliferation of CEPCs in vivo and in vitro. Topical treatment of antioxidant L-glutathione preserved the over-proliferation of CEPCs and attenuated corneal epithelial defects in SD mice. Moreover, the activation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway is essential to ROS-stimulated cell proliferation in CEPCs. However, long-term SD ultimately led to early manifestation of limbal stem cell deficiency.

182P Therapeutic activity of thiostrepton in patient-derived malignant pleural effusions

Malignant pleural effusion (MPE) is a common complication of many tumor types, arising at the onset of terminal cancer with a median survival of 3-12 months. Herein, we have characterized and evaluated the activity of thiostrepton (TS) on malignant and immune cell types present in MPE from patients diagnosed with primary lung, breast, prostate, pancreatic and ovarian cancers. TS targets mitochondrial peroxiredoxin 3 (PRX3) and disrupts redox homeostasis preferentially in malignant tissues, presenting a promising therapeutic approach currently under investigation in the MITOPE clinical trial.

Homeostasis Imbalance of YY2 and YY1 Promotes Tumor Growth by Manipulating Ferroptosis.

Ferroptosis is a type of programmed cell death caused by disruption of redox homeostasis and is closely linked to amino acid metabolism. Yin Yang 2 (YY2) and its homolog Yin Yang 1 (YY1) are highly homologous, especially in their zinc‐finger domains. Furthermore, they share a consensus DNA binding motif. Increasing evidences have demonstrated the tumor suppressive effect of YY2, in contrast with the oncogenic YY1; however, little is known about the biological and pathological functions of YY2. Here, it is determined that YY2 induces tumor cell ferroptosis and subsequently suppresses tumorigenesis by inhibiting solute carrier family 7 member 11 (SLC7A11) transcription, leading to the decreased glutathione biosynthesis. Furthermore, YY2 and YY1 bind competitively to the same DNA binding site in the SLC7A11 promoter and antagonistically regulate tumor cell ferroptosis, thus suggesting the molecular mechanism underlying their opposite regulation on tumorigenesis. Moreover, mutations of YY2 zinc‐finger domains in clinical cancer patients abrogate YY2/SLC7A11 axis and tumor cell ferroptosis. Together, these results provide a new insight regarding the regulatory mechanism of ferroptosis, and a mechanistic explanation regarding the tumor suppressive effect of YY2. Finally, these findings demonstrate that homeostasis between YY1 and YY2 is crucial for maintaining redox homeostasis in tumor cells.

Exercise decreases PP2A-specific reversible thiol oxidation in human erythrocytes: Implications for redox biomarkers

New readily accessible systemic redox biomarkers are needed to understand the biological roles reactive oxygen species (ROS) play in humans because overtly flawed, technically fraught, and unspecific assays severely hamper translational progress. The antibody-linked oxi-state assay (ALISA) makes it possible to develop valid ROS-sensitive target-specific protein thiol redox state biomarkers in a readily accessible microplate format. Here, we used a maximal exercise bout to disrupt redox homeostasis in a physiologically meaningful way to determine whether the catalytic core of the serine/threonine protein phosphatase PP2A is a candidate systemic redox biomarker in human erythrocytes. We reasoned that: constitutive oxidative stress (e.g., haemoglobin autoxidation) would sensitise erythrocytes to disrupted ion homeostasis as manifested by increased oxidation of the ion regulatory phosphatase PP2A. Unexpectedly, an acute bout of maximal exercise lasting ~16 min decreased PP2A-specific reversible thiol oxidation (redox ratio, rest: 0.46; exercise: 0.33) without changing PP2A content (rest: 193 pg/ml; exercise: 191 pg/ml). The need for only 3–4 μl of sample to perform ALISA means PP2A-specific reversible thiol oxidation is a capillary—fingertip blood—compatible candidate redox biomarker. Consistent with biologically meaningful redox regulation, thiol reductant-inducible PP2A activity was significantly greater (+10%) at rest compared to exercise. We establish a route to developing new readily measurable protein thiol redox biomarkers for understanding the biological roles ROS play in humans.

Honokiol inhibits growth and improves control efficiency against Phytophthora nicotianae through disrupting redox homeostasis and energy metabolism

Tobacco black shank, caused by Phytophthora nicotianae, is one of the most destructive fungal diseases affecting tobacco plants and is responsible for significant economic losses. Honokiol, as a botanical fungicide, is preferred over chemical fungicides to control tobacco black shank due to it being less toxic to the environment. This study evaluated the in vivo and in vitro antifungal activity of honokiol against Phytophthora nicotianae. Compared with the control, significant growth inhibition was observed upon honokiol treatment from 45% to 76%, respectively, at different concentrations. In vitro experiments indicated that honokiol disrupted hyphal morphology and increased membrane permeability in Phytophthora nicotianae. Honokiol treatment disrupted the cell membrane structure and resulted in increased sugar, protein, and relative conductivity-related contents. In addition, honokiol treatment reduced catalase and adenosine triphosphatase activity and increased superoxide dismutase activity, resulting in reactive oxygen species accumulation. The maximum inhibition of adenosine triphosphatase activity (3.98 mol/g protein) was achieved at 120 min with 54 µg/mL of honokiol. Moreover, in vivo analyses showed that honokiol protected tobacco seedlings from Phytophthora nicotianae and reduced the abundance of Fusarium pathogens; the highest control efficiency was recorded as 91.67% on day 5. Results suggest that honokiol can suppress tobacco black shank development, possibly by directly suppressing pathogen growth, and it possesses a remarkable biocontrol potential for Phytophthora nicotianae.

Chronic thioredoxin reductase deficiency disrupts redox homeostasis and impairs beta-cell function

Chronic thioredoxin reductase deficiency disrupts redox homeostasis and impairs beta-cell function

Plinia trunciflora Extract Administration Prevents HI-Induced Oxidative Stress, Inflammatory Response, Behavioral Impairments, and Tissue Damage in Rats.

The disruption of redox homeostasis and neuroinflammation are key mechanisms in the pathogenesis of brain hypoxia–ischemia (HI); medicinal plants have been studied as a therapeutic strategy, generally associated with the prevention of oxidative stress and inflammatory response. This study evaluates the neuroprotective role of the Plinia trunciflora fruit extract (PTE) in neonatal rats submitted to experimental HI. The HI insult provoked a marked increase in the lipoperoxidation levels and glutathione peroxidase (GPx) activity, accompanied by a decrease in the brain concentration of glutathione (GSH). Interestingly, PTE was able to prevent most of the HI-induced pro-oxidant effects. It was also observed that HI increased the levels of interleukin-1β in the hippocampus, and that PTE-treatment prevented this effect. Furthermore, PTE was able to prevent neuronal loss and astrocyte reactivity induced by HI, as demonstrated by NeuN and GFAP staining, respectively. PTE also attenuated the anxiety-like behavior and prevented the spatial memory impairment caused by HI. Finally, PTE prevented neural tissue loss in the brain hemisphere, the hippocampus, cerebral cortex, and the striatum ipsilateral to the HI. Taken together our results provide good evidence that the PTE extract has the potential to be investigated as an adjunctive therapy in the treatment of brain insult caused by neonatal hypoxia–ischemia.

Inhibition of NPC1L1 disrupts adaptive responses of drug‐tolerant persister cells to chemotherapy

Entering a drug‐tolerant persister (DTP) state of cancer cells is a transient self‐adaptive mechanism by which a residual cell subpopulation accelerates tumor progression. Here, we identified the acquisition of a DTP phenotype in multidrug‐resistant (MDR) cancer cells as a tolerance response to routine combination treatment. Characterization of MDR cancer cells with a DTP state by RNA‐seq revealed that these cells partially prevented chemotherapy‐triggered oxidative stress by promoting NPC1L1‐regulated uptake of vitamin E. Treatment with the NPC1L1 inhibitor ezetimibe further enhanced the therapeutic effect of combinatorial therapy by inducing methuosis. Mechanistically, we demonstrated that NRF2 was involved in transcriptional regulation of NPC1L1 by binding to the −205 to −215 bp site on its promoter. Decreased DNA methylation was also related partially to this process. Furthermore, we confirmed that a triple‐combination of chemotherapeutic agents, verapamil, and ezetimibe, had a significant anti‐tumor effect and prevented tumor recurrence in mice. Together, our study provides a novel insight into the role of DTP state and emphasizes the importance of disrupting redox homeostasis during cancer therapy.

Peroxide Antimalarial Drugs Target Redox Homeostasis in Plasmodium falciparum Infected Red Blood Cells.

Plasmodium falciparum causes the most lethal form of malaria. Peroxide antimalarials based on artemisinin underpin the frontline treatments for malaria, but artemisinin resistance is rapidly spreading. Synthetic peroxide antimalarials, known as ozonides, are in clinical development and offer a potential alternative. Here, we used chemoproteomics to investigate the protein alkylation targets of artemisinin and ozonide probes, including an analogue of the ozonide clinical candidate, artefenomel. We greatly expanded the list of proteins alkylated by peroxide antimalarials and identified significant enrichment of redox-related proteins for both artemisinins and ozonides. Disrupted redox homeostasis was confirmed by dynamic live imaging of the glutathione redox potential using a genetically encoded redox-sensitive fluorescence-based biosensor. Targeted liquid chromatography-mass spectrometry (LC-MS)-based thiol metabolomics also confirmed changes in cellular thiol levels. This work shows that peroxide antimalarials disproportionately alkylate proteins involved in redox homeostasis and that disrupted redox processes are involved in the mechanism of action of these important antimalarials.

A carrier free photodynamic oxidizer for enhanced tumor therapy by redox homeostasis disruption.

Abnormal tumor microenvironments play important roles in cancer progression. In general, tumor cells are capable of upregulating glutathione (GSH) levels to maintain aberrant redox homeostasis and cause resistance to oxidative damage. Herein, we develop a photodynamic oxidizer to disrupt the redox homeostasis of tumor cells for enhanced photodynamic tumor therapy. Based on pyropheophorbide-a (Pyro) and naphthazarin (Nap), a carrier free photodynamic oxidizer (named PyroNap) is prepared by the self-assembly technique through hydrophobic interactions. It is confirmed that nanosized PyroNap has high drug contents as well as favorable dispersity and stability. Besides, the photodynamic property of Pyro has obviously improved after self-assembly into the nanomedicine of PyroNap, which facilitates the production of reactive oxygen species (ROS) for robust photodynamic therapy (PDT). More importantly, the Nap induced GSH decrease could disrupt the redox homeostasis of tumor cells to further improve the PDT efficacy on tumor suppression. Consequently, after intravenous administration, PyroNap was able to significantly inhibit tumor growth and cause minimal side effects. This study might shed light on developing translational nanomedicine for tumor precision therapy.

The oxidative and inflammatory nature of age-related macular degeneration

The understanding of the effects of oxidation and inflammation on age-related macular degeneration (AMD) genesis has been of utmost importance for the advancement of preventive and therapeutical measures adopted in this disease. Several studies have been conducted on lifestyles, dietary antioxidants, expression of antioxidant enzymes, naturally found in the retina, as well as expression of cytokines, enzymes, and growth factors, with an ultimate goal to prevent or mitigate the visual damage induced by AMD. This article details the disruption of redox homeostasis associated with the increase of cells and inflammatory markers, major factors in triggering and/or aggravating the degenerative macular disease. The data sources used in this review study include Cochrane Database of Systematic Reviews, PubMed, MedlinePlus Health Information, and Elsevier Science.

One‐Pot Synthesis of Multifunctional Carbon‐Based Nanoparticle‐Supported Dispersed Cu2+Disrupts Redox Homeostasis to Enhance CDT

AbstractIn chemodynamic therapy (CDT), the levels of reactive oxygen species (ROS) production plays an important role for evaluating the therapeutic efficacy. However, the high levels of glutathione (GSH) in tumor cells consume the ROS, directly reducing the therapeutic efficiency. Herein, we synthesized carbon‐based nanoparticle (Cu‐cys CBNPs) using one‐pot strategy, which consume GSH via redox reactions to produce Cu+that catalyze H2O2to produce.OH, thus the ROS level was observably increased through this synergistic effect. In vivo experiments further revealed that Cu‐cys CBNPs could effectively inhibit tumor growth. Additionally, Cu‐cys CBNPs can affect the activity of some protein sulfhydryl groups in cells, which was assessed by rdTOP‐ABPP assay. In general, this study not only provides a potential CDT drug, but also provides a strategy for one‐pot synthesis of multifunctional nanomaterials.

One‐Pot Synthesis of Multifunctional Carbon‐Based Nanoparticle‐Supported Dispersed Cu2+Disrupts Redox Homeostasis to Enhance CDT

In chemodynamic therapy (CDT), the levels of reactive oxygen species (ROS) production plays an important role for evaluating the therapeutic efficacy. However, the high levels of glutathione (GSH) in tumor cells consume the ROS, directly reducing the therapeutic efficiency. Herein, we synthesized carbon-based nanoparticle (Cu-cys CBNPs) using one-pot strategy, which consume GSH via redox reactions to produce Cu+ that catalyze H2 O2 to produce . OH, thus the ROS level was observably increased through this synergistic effect. In vivo experiments further revealed that Cu-cys CBNPs could effectively inhibit tumor growth. Additionally, Cu-cys CBNPs can affect the activity of some protein sulfhydryl groups in cells, which was assessed by rdTOP-ABPP assay. In general, this study not only provides a potential CDT drug, but also provides a strategy for one-pot synthesis of multifunctional nanomaterials.

ROS-responsive fluorinated polyethyleneimine vector to co-deliver shMTHFD2 and shGPX4 plasmids induces ferroptosis and apoptosis for cancer therapy

Ferroptosis is a newly discovered non-apoptotic cell death form but its therapeutic efficacy triggered by traditional iron-based nanomaterials or classic drug inducers has been far from satisfactory due to the high glutathione (GSH) level in cancer cells and insufficient lipid peroxide production. Here we reported a ferroptosis/apoptosis combinational therapy by depleting GSH and downregulating GPX4 to disrupt redox homeostasis and amplify ferroptosis-related oxidation effect. In this study, we developed reactive oxygen species (ROS)-responsive serum-resistant nanoparticles with thioketal-crosslinked fluorinated polyethyleneimine 1.8K (TKPF) as the core, which were wrapped with hyaluronic acid (HA) as the shell (TKPFH NP) to co-deliver shGPX4 and shMTHFD2 plasmids for cancer treatment. The highly efficient and tumor-selective gene carrier TKPFH NPs revealed outstanding transfection efficiency (∼100 %) and sustained the efficiency (∼50 %) even in media containing 90 % FBS. Mediated by HA, TKPFH NPs actively targeted CD44 receptors, thus enabling efficient uptake by tumor cells and experiencing surface charge conversion to induce subsequent lysosomal escape. Then the TKPF NPs were effectively disintegrated by the abundant ROS in cancer cells, which facilitated the release of plasmids and avoided the cytotoxicity of cationic polymers. shGPX4 plasmid induced ferroptosis by producing ROS and lipid peroxides via downregulating GPX4, while shMTHFD2 triggered apoptosis by modulating NADPH/NADP and depleting GSH of the cancer cells. Moreover, GSH consumption caused by shMTHFD2 indirectly suppressed GPX4 and further augmented ferroptosis, showing synergistic anticancer effect against B16-F10 cells. Taken together, the rationally designed dual-gene loaded TKPFH NPs provided a safe and high-performance platform for enhanced ferroptosis-apoptosis combined anticancer efficacy based on gene therapy. Statement of significanceThe therapeutic efficacy of ferroptosis has been far from satisfactory due to high GSH level and insufficient lipid peroxide production in cancer cells. Herein, we reported a ferroptosis/apoptosis combinational therapy by depleting GSH and downregulating GPX4 to disrupt redox homeostasis and amplify ferroptosis-related oxidation effect. ROS-responsive serum-resistant nanoparticles were fabricated with thioketal-crosslinked fluorinated PEI 1.8K (TKPF) as the core and hyaluronic acid (HA) as the shell (TKPFH NP) to co-deliver shGPX4 and shMTHFD2 plasmids. The shGPX4 plasmid induced ferroptosis by producing ROS and lipid peroxides via downregulating GPX4, while shMTHFD2 triggered apoptosis by modulating NADPH/NADP and depleting GSH. The rationally designed dual-gene loaded TKPFH NPs provided a safe and high-performance platform aimed for enhanced ferroptosis-apoptosis combined anticancer efficacy.

Disruption of metabolic function and redox homeostasis as antibacterial mechanism of Lindera glauca fruit essential oil against Shigella flexneri

Current trend in food safety and public health is focusing on the use of natural antimicrobials. The Lindera glauca fruit with rich resource and essential oil has emerged as potential application in China. This work aimed to detect chemical compounds of L. glauca fruit essential oil (LGFEO) and to evaluate antimicrobial activity and mechanism of LGFEO for develop natural antimicrobials. A total of 70 volatile compounds were identified, and the major groups were monoterpene (56.62%) and sesquiterpene (39.71%). The analysis of antimicrobial activity indicated that LGFEO could effectively inhibit the growth of all tested 13 food-borne pathogens, of which Shigella flexneri had the highest inhibition zone diameter (DIZ, 25.45 nm), and the lowest minimum inhibitory concentration (MIC, 0.156 μg/mL) and bactericidal concentration (MBC, 0.312 μg/mL). To unravel antibacterial mechanism of LGFEO on S. flexneri , the dynamic changes for bacterial growth curve, material release, and the levels of intracellular mallondialdehyde (MDA), hydrogen peroxide (H 2 O 2 ), and ROS-detoxifying enzymes were analyzed in S. flexneri cells exposed to LGFEO at different concentrations (1/2 × MIC, 1 × MIC and 2 × MIC) and times (0–24 h), revealing that LGFEO could cause cell material leakage, antioxidant enzyme inactivation, H 2 O 2 and MDA accumulation, and bacterial growth inhibition. Also, antibacterial action of LGFEO was conducted on key enzymes of respiratory metabolic (glycolysis, oxidative pentose phosphate pathway, tricarboxylic acid cycle, and respiratory chain), and the levels of intracellular ATP, ADP, nicotinamide adenine dinucleotide (NAD + and NADH), nicotinamide adenine dinucleotide phosphate (NADP + and NADPH), and oxidized and reduced glutathione (GSSG and GSH) in LGFEO-treated S. flexneri cells, indicating a role of LGFEO in repressing respiratory pathway and electron transport with low redox potential. All these revealed that LGFEO could effectively induce H 2 O 2 accumulation and lipid peroxidation, resulting in cell membrane damage and metabolic function disruption, giving rise to a disturbance of redox homeostasis, which may be the main cause of growth inhibition or cell death for S. flexneri . • Essential oil contains 70 volatile compounds with good antimicrobial activity. • The first time for antibacterial mechanism from energy and respiratory metabolism. • Antibacterial action of essential oil involves in H2O2-mediated oxidative stress. •Essential oil-induced disruption of redox homeostasis as main antibacterial action.

Age-related accumulation of advanced oxidation protein products promotes osteoclastogenesis through disruption of redox homeostasis

Enhanced osteoclastogenesis is one of the major causes of age-related bone loss. Aging is accompanied by accumulation of advanced oxidation protein products (AOPPs). However, whether AOPPs accumulation contributing to the osteoclastogenesis with aging remains unclear. Here, we showed that AOPPs accumulation was associated with the enhanced osteoclastogenesis and deterioration of bone microstructure in aged mice. In vitro, AOPPs directly induced osteoclastogenesis by interaction with receptor activator of nuclear factor κ B (RANK) and the receptor for advanced glycation end products (RAGE) in the primary bone marrow monocytes. Bindings of AOPPs to RANK and RAGE were able to activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, trigger generation of reactive oxygen species, then induce phosphorylation of mitogen-activated protein kinases and c-fos, upregulation of the nuclear factor of activated T cell c1, eventually induce bone marrow monocytes to differentiate into mature osteoclasts. Chronic exposure to AOPPs enhanced osteoclastogenesis and bone loss in mice, which could be alleviated by NADPH oxidase inhibitor apocynin. Local injection of AOPPs into subperiosteal area induced bone resorption at the site of administration, which was similar to the effect of RANK ligand. Together, these results suggested that AOPPs could serve as a novel regulator of osteoclastogenesis and AOPPs accumulation might play an important role in the development of age-related bone loss.