IRF1 regulation of ZBP1 links mitochondrial DNA and chondrocyte damage in osteoarthritis.

BACKGROUND: Z-DNA binding protein 1 (ZBP1) is a nucleic acid sensor that is involved in multiple inflammatory diseases, but whether and how it contributes to osteoarthritis (OA) are unclear. METHODS: Cartilage tissues were harvested from patients with OA and a murine model of OA to evaluate ZBP1 expression. Subsequently, the functional role and mechanism of ZBP1 were examined in primary chondrocytes, and the role of ZBP1 in OA was explored in mouse models. RESULTS: We showed the upregulation of ZBP1 in articular cartilage originating from OA patients and mice with OA after destabilization of the medial meniscus (DMM) surgery. Specifically, knockdown of ZBP1 alleviated chondrocyte damage and protected mice from DMM-induced OA. Mechanistically, tumor necrosis factor alpha induced ZBP1 overexpression in an interferon regulatory factor 1 (IRF1)-dependent manner and elicited the activation of ZBP1 via mitochondrial DNA (mtDNA) release and ZBP1 binding. The upregulated and activated ZBP1 could interact with receptor-interacting protein kinase 1 and activate the transforming growth factor-beta-activated kinase 1-NF-κB signaling pathway, which led to chondrocyte inflammation and extracellular matrix degradation. Moreover, inhibition of the mtDNA-IRF1-ZBP1 axis with Cyclosporine A, a blocker of mtDNA release, could delay the progression of DMM-induced OA. CONCLUSIONS: Our data revealed the pathological role of the mtDNA-IRF1-ZBP1 axis in OA chondrocytes, suggesting that inhibition of this axis could be a viable therapeutic approach for OA.

Stimuli-responsive grating with a tunable period and a diffraction order.

The next-generation diffraction grating not only requires a nonmechanical control and a remote control to generate a diffraction pattern but also requires a tunable period. Here, we propose a stimuli-responsive liquid crystal (LC) phase grating with a tunable period and a diffraction order. The stimuli-responsive LC diffraction grating is composed of periodically arranged electrodes on a double-sided glass substrate. By adjusting the driving scheme, the pitch and diffraction order of the LC grating can be switched between three different modes. The experimental results show that the LC grating has a lower driving voltage (∼5 V). In addition, the tunable LC grating can achieve more diffraction orders, which can be applied to a holographic display to achieve a wide-viewing angle and an enlarged size.

Controllable switch of a transmittance signal via polarization combination manipulation.

We propose and experimentally demonstrate a process in which we can control the behavior of an atomic medium to switch on or off transmittance signals at multiple frequencies in ladder-type electromagnetically induced transparency (EIT) of 5S1/2-5P3/2-5D3/2 transition of Rb87 atoms. By adjusting the polarizations of the applied optical fields, the amplitudes of the transmittance spectra at multiple frequency channels can be controlled. This mechanism originates from the competition between EIT subsystems and single-photon absorption with a contribution from different transition strengths. Moreover, we also analyze the influences of the intensity and detuning of the coupling field on the transmitted signals when two lasers are perpendicular, linearly polarized lights, and observe electromagnetically induced absorption due to quantum constructive interference. Detailed theoretical analyses, including the different strengths in different transitions and Doppler broadening, agree with the experimental observations.

Effects of different-intensity laser acupuncture at two adjacent same-meridian acupoints on nitric oxide and soluble guanylate cyclase releases in human.

OBJECTIVES: The aim of this study was to detect the influences of LA at nonacupoint and two adjacent acupoints of pericardium meridian on the releases of NO and sGC in 20 healthy subjects. METHODS: Different intensities (12, 24, 48 mW) of infrared laser were used for irradiating Jianshi (PC5), Ximen (PC4) acupoints and nonacupoint for 20, 40 minutes, respectively. Semi-circular tubes were taped to the skin surface and filled with NO-scavenging compound for 20 minutes to capture NO and sGC, which were measured using spectrophotometry in a blinded fashion. RESULTS: As the increase in the intensity of LA stimulation, the levels of NO releases over acupoints all were significantly increased, NO releases in nonacupoints following the same treatment only changed slightly, sGC amounts were observably enhanced over acupoints, but did not any change in nonacupoint area. Different intensities of LA treatments can sensitively affect the NO and sGC releases over acupoints. This indicated that LA-induced releases of the NO and sGC were specific to acupoints. CONCLUSIONS: This is the first evidence reporting that LA induced significant elevations of NO-sGC releases over acupoints, and the enhanced signal molecules contribute to local circulation, which improves the beneficial effects of the therapy.

[Polypyrrole Functionalized Gold Nanorods as Novel Contrast Agents for Optical Coherence Tomography].

Polypyrrole (PPy) is easy-prepared with good biocompatibility and strong absorption in near-infrared (NIR) region which can serve as both the photothermal therapeutic agent and contrast agent of optical coherence tomography (OCT) imaging. Herein, gold nanorod (GNR) modified with PPy (GNR-PPy) as contrast agent for optical coherence tomography imaging was investigated. GNR-PPy was synthesized via one-pot facile oxidative polymerization by using pyrrole and GNR as starting materials. Nanoparticles were characterized using ultraviolet-visible absorbance spectroscopy, Raman spectroscopy and transmission electron microscopy. A xenograft tumor mouse model was fabricated to study the OCT contrast effect of GNR-PPy on breast tumor. An OCT system equipped with an 840 nm SLED was used for OCT imaging of the tumors injected with gold nanostructures. The experimental results indicated that the penetration depth of the OCT signals from tumors injected with GNR-PPy was lower than that from tumors injected with gold nanorods, which could be ascribed to the stronger light activity of GNR-PPy in NIR region. To quantitatively analyze the contrast effect, the attenuation coefficients were extracted from the OCT images of tumors injected with the nanostructures. In comparison with the attenuation coefficient extracted from the OCT images containing GNR, the attenuation coefficient of tumors injected with GNR-PPy was significant higher. It was concluded that gold nanorods modified with polypyrrole can enhance the light absorption in near-infrared much better, which would provide a possible detection means for enhancing the contrast effect of tumor tissues.

[Road Extraction in Remote Sensing Images Based on Spectral and Edge Analysis].

Roads are typically man-made objects in urban areas. Road extraction from high-resolution images has important applications for urban planning and transportation development. However, due to the confusion of spectral characteristic, it is difficult to distinguish roads from other objects by merely using traditional classification methods that mainly depend on spectral information. Edge is an important feature for the identification of linear objects (e. g. , roads). The distribution patterns of edges vary greatly among different objects. It is crucial to merge edge statistical information into spectral ones. In this study, a new method that combines spectral information and edge statistical features has been proposed. First, edge detection is conducted by using self-adaptive mean-shift algorithm on the panchromatic band, which can greatly reduce pseudo-edges and noise effects. Then, edge statistical features are obtained from the edge statistical model, which measures the length and angle distribution of edges. Finally, by integrating the spectral and edge statistical features, SVM algorithm is used to classify the image and roads are ultimately extracted. A series of experiments are conducted and the results show that the overall accuracy of proposed method is 93% comparing with only 78% overall accuracy of the traditional. The results demonstrate that the proposed method is efficient and valuable for road extraction, especially on high-resolution images.

SEPT3 as a Potential Molecular Target of Triple-Negative Breast Cancer.

Background: The survival rate for triple-negative breast cancer (TNBC) is very low due to its advanced metastatic and aggressive nature, and there is no specific target to improve the survival rate. The expression and clinical signature of neuronal-specific septin-3 (Septin3, SEPT3) in TNBC remain undetermined. Methods: SEPT3 differential expression in TNBC was detected with the use of bioinformatic approaches based on TCGA and GEO database, which was verified with immunohistochemistry in TNBC tissues. Next, the effect of SEPT3 on survival and the association between SEPT3 expression and clinical characteristics were assessed for TNBC patients. We performed Cox analysis to evaluate whether SEPT3 is an independent predictor for TNBC patients. Results: SEPT3 was identified as a key differentially expressed gene. SEPT3 was observed to be elevated in 112 TNBC significantly. Increased expression of SEPT3 contributed to an unfavorable prognosis in patients with TNBC. Additionally, SEPT3 was associated with several factors including TNM stage, lymph node metastasis, Ki67 level and histological grade. SEPT3 was determined to be an independent risk factor for TNBC patients through Cox regression analysis. Conclusion: This study demonstrated that SEPT3 could be a potential disease marker for TNBC patients by bioinformatics analysis and validation in clinical samples.

Deferoxamine alleviates chondrocyte senescence and osteoarthritis progression by maintaining iron homeostasis.

BACKGROUND: Osteoarthritis (OA) is a prevalent age-related disease characterized by the gradual deterioration of cartilage. The involvement of chondrocyte senescence is crucial in the pathogenesis of OA. Desferoxamine (DFO) is an iron chelator with therapeutic potential in various diseases. However, the relationship of chondrocyte senescence and iron homeostasis is largely unknown. METHODS: Chondrocyte senescence was induced using tert-butyl hydroperoxide (TBHP), and the impact of DFO on chondrocyte senescence and iron metabolism was assessed through techniques such as western blotting, qRT-PCR, and ß-Galactosidase staining. To assess the impact of DFO on chondrocyte senescence and the progression of osteoarthritis (OA), the surgical destabilization of the medial meniscus model was established. RESULTS: In chondrocytes, TBHP administration resulted in elevated expression of P16, P21, and P53, as well as alterations in SA-ß-gal staining. Nevertheless, DFO effectively mitigated chondrocyte senescence induced by TBHP, and reversed the decrease in collagen II expression and increase in MMP13 expression caused by TBHP. Mechanismly, TBHP induced NCOA4 expression and iron release in chondrocytes. Excessive iron could induce chondrocyte senescence, whereas, DFO could inhibit NCOA4 expression and restore ferritin level, and chelate excessive iron. Importantly, intra-articular injection of DFO enhanced collagen II expression and reduced expression of P16, P21, and MMP13 of cartilage in OA mice, and delayed cartilage degeneration. CONCLUSIONS: Overall, this study provides evidence that DFO has the potential to alleviate chondrocyte senescence induced by TBHP and slow down the progression of osteoarthritis (OA) by effectively chelating excessive iron. These findings suggest that iron chelation could be a promising therapeutic strategy for treating OA.

Erratum: Mitoquinone alleviates osteoarthritis progress by activating the NRF2-Parkin axis.

[This corrects the article DOI: 10.1016/j.isci.2023.107647.].

Genomic Insights into the Role of TOP Gene Family in Soft-Tissue Sarcomas: Implications for Prognosis and Therapy.

This study focuses on the role of topoisomerases (TOPs) in sarcomas (SARCs), highlighting TOPs' influence on sarcoma prognosis through mRNA expression, genetic mutations, immune infiltration, and DNA methylation analysis using transcriptase sequencing and other techniques. The findings indicate that TOP gene mutations correlate with increased inflammation, immune cell infiltration, DNA repair abnormalities, and mitochondrial fusion genes alterations, all of which negatively affect sarcoma prognosis. Abnormal TOP expression may independently affect sarcoma patients' survival. Cutting-edge genomic tools such as Oncomine, gene expression profiling interactive analysis (GEPIA), and cBio Cancer Genomics Portal (cBioPortal) are utilized to explore the TOP gene family (TOP1/1MT/2A/2B/3A/3B) in soft-tissue sarcomas (STSs). This in-depth analysis reveals a notable upregulation of TOP mRNA in STS patients arcoss various SARC subtypes, French Federation Nationale des Centres de Lutte Contre le Cancer classification (FNCLCC) grades, and specific molecular profiles correlating with poorer clinical outcomes. Furthermore, this investigation identifies distinct patterns of immune cell infiltration, genetic mutations, and somatic copy number variations linked to TOP genes that inversely affect patient survival rates. These findings underscore the diagnostic and therapeutic relevance of the TOP gene suite in STSs.

Inhibition of SAT1 alleviates chondrocyte inflammation and ferroptosis by repressing ALOX15 expression and activating the Nrf2 pathway.

Aims: Osteoarthritis (OA) is the most common chronic pathema of human joints. The pathogenesis is complex, involving physiological and mechanical factors. In previous studies, we found that ferroptosis is intimately related to OA, while the role of Sat1 in chondrocyte ferroptosis and OA, as well as the underlying mechanism, remains unclear. Methods: In this study, interleukin-1ß (IL-1ß) was used to simulate inflammation and Erastin was used to simulate ferroptosis in vitro. We used small interfering RNA (siRNA) to knock down the spermidine/spermine N1-acetyltransferase 1 (Sat1) and arachidonate 15-lipoxygenase (Alox15), and examined damage-associated events including inflammation, ferroptosis, and oxidative stress of chondrocytes. In addition, a destabilization of the medial meniscus (DMM) mouse model of OA induced by surgery was established to investigate the role of Sat1 inhibition in OA progression. Results: The results showed that inhibition of Sat1 expression can reduce inflammation, ferroptosis changes, reactive oxygen species (ROS) level, and lipid-ROS accumulation induced by IL-1ß and Erastin. Knockdown of Sat1 promotes nuclear factor-E2-related factor 2 (Nrf2) signalling. Additionally, knockdown Alox15 can alleviate the inflammation-related protein expression induced by IL-1ß and ferroptosis-related protein expression induced by Erastin. Furthermore, knockdown Nrf2 can reverse these protein expression alterations. Finally, intra-articular injection of diminazene aceturate (DA), an inhibitor of Sat1, enhanced type II collagen (collagen II) and increased Sat1 and Alox15 expression. Conclusion: Our results demonstrate that inhibition of Sat1 could alleviate chondrocyte ferroptosis and inflammation by downregulating Alox15 activating the Nrf2 system, and delaying the progression of OA. These findings suggest that Sat1 provides a new approach for studying and treating OA.

DMT1-mediated iron overload accelerates cartilage degeneration in Hemophilic Arthropathy through the mtDNA-cGAS-STING axis.

INTRODUCTION: Excess iron contributes to Hemophilic Arthropathy (HA) development. Divalent metal transporter 1 (DMT1) delivers iron into the cytoplasm, thus regulating iron homeostasis. OBJECTIVES: We aimed to investigate whether DMT1-mediated iron homeostasis is involved in bleeding-induced cartilage degeneration and the molecular mechanisms underlying iron overload-induced chondrocyte damage. METHODS: This study established an in vivo HA model by puncturing knee joints of coagulation factor VIII gene knockout mice with a needle, and mimicked iron overload conditions in vitro by treatment of Ferric ammonium citrate (FAC). RESULTS: We demonstrated that blood exposure caused iron overload and cartilage degeneration, as well as elevated expression of DMT1. Furthermore, DMT1 silencing alleviated blood-induced iron overload and cartilage degeneration. In hemophilic mice, articular cartilage degeneration was also suppressed by intro-articularly injection of DMT1 adeno-associated virus 9 (AAV9). Mechanistically, RNA-sequencing analysis indicated the association between iron overload and cGAS-STING pathway. Further, iron overload triggered mtDNA-cGAS-STING pathway activation, which could be effectively mitigated by DMT1 silencing. Additionally, we discovered that RU.521, a potent Cyclic GMP-AMP Synthase (cGAS) inhibitor, successfully suppressed the downward cascades of cGAS-STING, thereby protecting against chondrocyte damage. CONCLUSION: Taken together, DMT1-mediated iron overload promotes chondrocyte damage and murine HA development, and targeted DMT1 may provide therapeutic and preventive approaches in HA.

P21 resists ferroptosis in osteoarthritic chondrocytes by regulating GPX4 protein stability.

Ferroptosis is involved in the pathogenesis of osteoarthritis (OA) while suppression of chondrocyte ferroptosis has a beneficial effect on OA. However, the molecular mechanism of ferroptosis in OA remains to be elucidated. P21, an indicator of aging, has been reported to inhibit ferroptosis, but the relationship between P21 and ferroptosis in OA remains unclear. Here, we aimed to investigate the expression and function of P21 in OA chondrocytes, and the involvement of P21 in the regulation of ferroptosis in chondrocytes. First, we demonstrated that high P21 expression was observed in the cartilage from OA patients and destabilized medial meniscus (DMM) mice, and in osteoarthritic chondrocytes induced by IL-1ß, FAC and erastin. P21 knockdown exacerbated the reduction of Col2a1 and promoted the upregulation of MMP13 in osteoarthritic chondrocytes. Meanwhile, P21 knockdown exacerbated cartilage degradation in DMM-induced OA mouse models and decreased GPX4 expression in vivo. Furthermore, P21 knockdown sensitized chondrocytes to ferroptosis induced by erastin, which was closely associated with the accumulation of lipid peroxides. In mechanism, we demonstrated that P21 regulated the stability of GPX4 protein, and the regulation was independent of NRF2. Meanwhile, we found that P21 significantly affected the recruitment of GPX4 to linear ubiquitin chain assembly complex (LUBAC) and regulated the level of M1-linked ubiquitination of GPX4. Overall, our results suggest that P21 plays an essential anti-ferroptosis role in OA by regulating the stability of GPX4.

[Comparison of hand-assisted laparoscopic surgery and open surgery for portal hypertension: a meta-analysis].

OBJECTIVE: To evaluate the clinical efficacy and safety of hand-assisted laparoscopic surgery (HALS) vs. open surgery (OS) for portal hypertension. METHODS: Relevant literature was retrieved from databases including PubMed, EMBASE, Cochrane Library, Chinese Biomedical Literature Database, Chinese Journal Full Text Database, Chinese Vip Datebase, and Chinese Wanfang. All the relevant trials were collected and then we performed the literature screening. The quality of the included trials was assessed by Cochrane Systematic Review Handbook 5.1. Meta-analyses were conducted by RevMan 5.1 software. RESULTS: Eight studies were involved and 435 patients were included. Meta-analysis showed that there was significant difference in intraoperative blood loss [MD = -140.95, 95% CI = (-233.58--48.32), P=0.003], total abdominal drainage volume [MD = -544.32, 95% CI= (-789.97--298.67), P<0.0001], postoperative exhaust time [MD = -28.30, 95% CI= (-41.90--14.69), P<0.0001], length of postoperative hospital stay [MD =-3.61, 95% CI= (-4.16--3.07), P<0.00001], postoperative complication [OR=0.35, 95% CI= (0.15-0.82), P=0.02] between HALS group and OS group. However, the operative time was not significantly different between these two groups [MD = -7.44, 95% CI = (-36.00 -21.12), P=0.61]. CONCLUSIONS: Compared with the traditional OS, HALS can reduce intraoperative bleeding, postoperative exhaust time, hospitalization time, surgical trauma, and postoperative complications.The patients often recover more quickly from the HALS. However, its long-term effictiveness and safety still needs to be further verified by randomized controlled trials.

[Effects of rhubarb powder on serum complement 3, complement 4, and hs-CRP in patients with intracerebral hemorrhage].

OBJECTIVE: To investigate the effects of rhubarb powder on serum complement 3 (C3), complement 4 (C4), and hypersensitive C-reactive protein (hs-CRP) levels in patients with hypertensive intracerebral hemorrhage (HICH) after operation. METHODS: Forty inpatients with HICH after operation were recruited from Department of Cerebral Surgery, Affiliated Hospital of Shaanxi College of Traditional Chinese Medicine from July 2009 to March 2010. They were randomly assigned to the treatment group (20 cases) and the control group (20 cases). From the 4th day after surgery, all patients received routine Western medical treatment. The rhubarb powder, 5-10 g dissolving in 40 mL warm water, was administered or nasally fed to those in the treatment group, 2 -3 times daily for 10 successive days. The contents of serum C3, C4, and hs-CRP were detected in the two groups on the 7th day and the 14th day after operation. The serum hs-CRP content was detected using latex particle enhanced immunoturbidimetric assay. The Scandinavia Stroke Scale (SSS) scores were recorded in the two groups. RESULTS: Compared with the same group on the 4th day after operation, the levels of serum C3 and C4 increased on the 7th day after operation, and SSS score increased on the 14th day after operation in the control group (P < 0.05). The contents of C4 and hs-CRP decreased, and the SSS score increased on the 14th day after operation in the treatment group (P < 0.05). Compared with the same group on the 7th day after operation, the contents of C4 and hs-CRP decreased and the SSS score increased on the 14th day after operation in the treatment group (P < 0.05). Compared with the control group at the same time points, the contents of C4 and C3 decreased on the 7th day after operation; the contents of C3, C4, and hs-CRP decreased, and SSS score increased in the treatment group on the 14th day after operation (P < 0.05). CONCLUSION: The rhubarb powder could significantly decrease the serum levels of C3, C4, and hs-CRP, and improve the curative effect in patients with HICH after operation.

[Extracting municipal solid waste dumps based on high resolution images].

The dramatically increasing informal MSW dumps are endangering the urban environment. Remote sensing (RS) technologies are more efficient to monitor and manage municipal solid wastes (MSW) than traditional survey-based methods. In high spatial resolution remotely sensed images, these irregularly distributed dumps have complex compositions and strong heterogeneities, thus it is still hard to extract them automatically no matter the pixel-or object-based image analysis method is used. Therefore, based on the analysis of MSW characteristics, the present study develops a multiresolution strategy to extract MSW dumps by combining image features at both high resolution and resampled low heterogeneity images, while the high resolution images can provide detailed information and the low resolution images can suppress the strong heterogeneities of informal MSW dumps. Taking the QuickBird image covering part of Beijing as an example, this multi-resolution strategy produced a high accuracy (75%), indicating that this multi-resolution strategy is quite effective for extracting the open-air informal MSW dumps.

[Green synthesis of silver nanoparticles and their application in SERS].

In the present paper, we have successfully synthesized silver nancomparticles by reducing of silver nitrate in alkaline solution via 60 degrees C water bath for 20 minutes with the use of tyrosine, a nontoxic and green macromolecule, as a reducing and stabilizing agent. The formation of silver nanoparticles was observed visually by color change of the solutions (from faint yellow to brown yellow). The morphologies of the Ag NPs were characterized by UV-Vis absorption spectroscopy and transmission electron microscopy (TEM). The UV-Vis absorption peak of silver nanoparticles located at 412 nm. The TEM image of silver nanoparticles indicated that the diameters of nanospheres are mainly in the range 15-25 nm. In order to evaluate the SERS activity of the silver nancomparticles, crystal violet and folic acid were used as the Raman probe molecule. The experimental results indicated that there are two ascendancies, firstly, the approach is convenient and the reaction condition is facile, secondly, tyrosine is a water-soluble, nontoxic and biodegradable macromolecule, which makes this approach provide a green strategy to prepare Ag NPs. Significantly, the synthesized Ag NPs exhibits good surface enhanced Raman scattering (SERS) activity as SERS substrates to detect crystal violet and folic acid in aqueous solution.

Design and experiment of a combined peeling machine for water chestnut.

Water chestnut is a characteristic aquatic vegetable in China, and its demand for peeling fresh fruit is increasing rapidly. Aiming at the existing problems of high labor intensity and low efficiency of manual peeling, a combined water chestnut peeling machine was designed, which used a rotary knife to remove bud and root, and a differential friction belts to remove side peel. The performance of the peeling machine was tested with water chestnut from Xiaogan, Hubei Provence. Under the conditions of 200 g feeding mass and 10 r/min rotation speed, the single factor test was carried out with cutting speed as the influencing factor and the cutting rate of bud and root as the evaluation index. The results showed that the cutting rate of fresh fruit of water chestnut bud and root were 79.04% and 83.77% respectively when the cutting speed of rotary knife was 1.2 m/s. In the differential friction belts, high and low linear velocities were taken as the influencing factors, and the side peel removal rate was used as the evaluation index. The side peel removal rate was 84.93% at the high-speed linear velocity of 2.1 m/s and the low-speed linear velocity of 1.58 m/s. The performance of the whole machine was evaluated, and the results showed that the working loss of the combined water chestnut peeling machine was 43.03% and the comprehensive peeling rate was 77.43%, which reached the design requirements. This study can provide a reference for the research and development of water chestnut peeling device.

Probucol suppresses osteoclastogenesis via activating Nrf2 signaling and ameliorates ovariectomy-induced bone loss.

Osteoporosis is a systemic and endocrine bone disorder distinguished by declined bone mineral density, compromised bone strength, and destruction of trabecular structure. The abnormally excessive osteoclastogenesis and bone erosion play imperative roles in the progression of osteoporosis. However, treatment of osteoporosis is far from satisfactory due to poor adherence to existing medications and adverse reactions, there is an urgent to develop novel therapies for osteoporosis. Probucol, a synthetic compound with two characteristic phenolic rings, owns anti-inflammatory and antioxidant properties. Accumulating evidence have indicated that intracellular reactive oxygen species (ROS) is closely related to osteoclastogenesis. Hence, we investigated the potential effects of probucol on osteoclastogenesis in vivo and in vitro. In this study, TRAP staining and bone slice resorption assay showed that probucol suppressed RANKL-induced osteoclast formation and function. The mRNA and protein levels of osteoclastogenesis marker genes were reduced by probucol in a concentration-dependent manner. Besides, probucol suppressed osteoclast differentiation by inhibiting ROS production, MAPKs and NF-κB signaling pathways, while Nrf2 silencing reversed the inhibitory effect of probucol on osteoclast formation and function. Consistent with the above findings, in vivo experiments demonstrated that probucol visibly alleviated bone loss caused by estrogen deficiency. In brief, these results showed the potential of anti-oxidant compound probucol in the treatment of osteoporosis, highlighting Nrf2 as a promising target in osteoclast-related disease.

JNK-JUN-NCOA4 axis contributes to chondrocyte ferroptosis and aggravates osteoarthritis via ferritinophagy.

Interruption of iron homeostasis is correlated with cell ferroptosis and degenerative diseases. Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy has been reported as a vital mechanism to control cellular iron levels, but its impact on osteoarthritis (OA) pathology and the underline mechanism are unknown. Herein we aimed to investigate the role and regulatory mechanism of NCOA4 in chondrocyte ferroptosis and OA pathogenesis. We demonstrated that NCOA4 was highly expressed in cartilage of patients with OA, aged mice, post-traumatic OA mice, and inflammatory chondrocytes. Importantly, Ncoa4 knockdown inhibited IL-1ß-induced chondrocyte ferroptosis and extracellular matrix degradation. Contrarily, overexpression of NCOA4 promoted chondrocyte ferroptosis and the delivery of Ncoa4 adeno-associated virus 9 into knee joint of mice aggravated post-traumatic OA. Mechanistic study revealed that NCOA4 was upregulated in a JNK-JUN signaling-dependent manner in which JUN could directly bind to the promoter of Ncoa4 and initial the transcription of Ncoa4. NCOA4 could interact with ferritin and increase autophagic degradation of ferritin and iron levels, which caused chondrocyte ferroptosis and extracellular matrix degradation. In addition, inhibition of JNK-JUN-NCOA4 axis by SP600125, a specific inhibitor of JNK, attenuated development of post-traumatic OA. This work highlights the role of JNK-JUN-NCOA4 axis and ferritinophagy in chondrocyte ferroptosis and OA pathogenesis, suggesting this axis as a potential target for OA treatment.