MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling.

Tumor cells metastasize to distant organs through genetic and epigenetic alterations, including changes in microRNA (miR) expression. Here we find miR-22 triggers epithelial-mesenchymal transition (EMT), enhances invasiveness and promotes metastasis in mouse xenografts. In a conditional mammary gland-specific transgenic (TG) mouse model, we show that miR-22 enhances mammary gland side-branching, expands the stem cell compartment, and promotes tumor development. Critically, miR-22 promotes aggressive metastatic disease in MMTV-miR-22 TG mice, as well as compound MMTV-neu or -PyVT-miR-22 TG mice. We demonstrate that miR-22 exerts its metastatic potential by silencing antimetastatic miR-200 through direct targeting of the TET (Ten eleven translocation) family of methylcytosine dioxygenases, thereby inhibiting demethylation of the mir-200 promoter. Finally, we show that miR-22 overexpression correlates with poor clinical outcomes and silencing of the TET-miR-200 axis in patients. Taken together, our findings implicate miR-22 as a crucial epigenetic modifier and promoter of EMT and breast cancer stemness toward metastasis.

Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner.

PTEN is a frequently mutated tumor suppressor gene that opposes the PI3K/AKT pathway through dephosphorylation of phosphoinositide-3,4,5-triphosphate. Recently, nuclear compartmentalization of PTEN was found as a key component of its tumor-suppressive activity; however its nuclear function remains poorly defined. Here we show that nuclear PTEN interacts with APC/C, promotes APC/C association with CDH1, and thereby enhances the tumor-suppressive activity of the APC-CDH1 complex. We find that nuclear exclusion but not phosphatase inactivation of PTEN impairs APC-CDH1. This nuclear function of PTEN provides a straightforward mechanistic explanation for the fail-safe cellular senescence response elicited by acute PTEN loss and the tumor-suppressive activity of catalytically inactive PTEN. Importantly, we demonstrate that PTEN mutant and PTEN null states are not synonymous as they are differentially sensitive to pharmacological inhibition of APC-CDH1 targets such as PLK1 and Aurora kinases. This finding identifies a strategy for cancer patient stratification and, thus, optimization of targeted therapies. PAPERCLIP:

Is Kidney Function Associated with Age-Related Macular Degeneration?: Findings from the Asian Eye Epidemiology Consortium.

PURPOSE: Chronic kidney disease (CKD) may elevate susceptibility to age-related macular degeneration (AMD) because of shared risk factors, pathogenic mechanisms, and genetic polymorphisms. Given the inconclusive findings in prior studies, we investigated this association using extensive datasets in the Asian Eye Epidemiology Consortium. DESIGN: Cross-sectional study. PARTICIPANTS: Fifty-one thousand two hundred fifty-three participants from 10 distinct population-based Asian studies. METHODS: Age-related macular degeneration was defined using the Wisconsin Age-Related Maculopathy Grading System, the International Age-Related Maculopathy Epidemiological Study Group Classification, or the Beckman Clinical Classification. Chronic kidney disease was defined as estimated glomerular filtration rate (eGFR) of less than 60 ml/min per 1.73 m2. A pooled analysis using individual-level participant data was performed to examine the associations between CKD and eGFR with AMD (early and late), adjusting for age, sex, hypertension, diabetes, body mass index, smoking status, total cholesterol, and study groups. MAIN OUTCOME MEASURES: Odds ratio (OR) of early and late AMD. RESULTS: Among 51 253 participants (mean age, 54.1 ± 14.5 years), 5079 had CKD (9.9%). The prevalence of early AMD was 9.0%, and that of late AMD was 0.71%. After adjusting for confounders, individuals with CKD were associated with higher odds of late AMD (OR, 1.46; 95% confidence interval [CI], 1.11-1.93; P = 0.008). Similarly, poorer kidney function (per 10-unit eGFR decrease) was associated with late AMD (OR, 1.12; 95% CI, 1.05-1.19; P = 0.001). Nevertheless, CKD and eGFR were not associated significantly with early AMD (all P ≥ 0.149). CONCLUSIONS: Pooled analysis from 10 distinct Asian population-based studies revealed that CKD and compromised kidney function are associated significantly with late AMD. This finding further underscores the importance of ocular examinations in patients with CKD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Immunogenicity of COVID-19 vaccines in chronic liver disease patients and liver transplant recipients: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Chronic liver disease (CLD) patients and liver transplant (LT) recipients have an increased risk of morbidity and mortality from coronavirus disease 2019 (COVID-19). The immunogenicity of COVID-19 vaccines in CLD patients and LT recipients is poorly understood. The present study aimed to evaluate the immunogenicity of COVID-19 vaccines in CLD patients and LT recipients. METHODS: We searched electronic databases for eligible studies. Two reviewers independently conducted the literature search, extracted the data and assessed the risk of bias of included studies. The rates of detectable immune response were pooled from single-arm studies. For comparative studies, we compared the rates of detectable immune response between patients and healthy controls. The meta-analysis was conducted using the Stata software with a random-effects model. RESULTS: In total, 19 observational studies involving 4191 participants met the inclusion criteria. The pooled rates of detectable humoral immune response after two doses of COVID-19 vaccination in CLD patients and LT recipients were 95% (95% confidence interval [CI] = 88%-99%) and 66% (95% CI = 57%-74%) respectively. After two doses of vaccination, the humoral immune response rate was similar in CLD patients and healthy controls (risk ratio [RR] = 0.96; 95% CI = 0.90-1.02; p = .14). In contrast, LT recipients had a lower humoral immune response rate after two doses of vaccination than healthy controls (RR = 0.68; 95% CI = 0.59-0.77; p < .01). CONCLUSIONS: Our meta-analysis demonstrated that COVID-19 vaccination induced strong humoral immune responses in CLD patients but poor humoral immune responses in LT recipients.

Strepolyketide D, a new SEK15-derived polyketide compound from salt-lake-derived Streptomyces sp. DBC5.

A new SEK15-derived polyketide compound, strepolyketide D (1), was isolated from salt-lake-derived Streptomyces sp. DBC5, together with two known analogues (2-3). Their structures were elucidated based on spectroscopic analysis of IR, MS, 1 D and 2 D NMR. Compound 2 elicited moderate antioxidation with IC50 value of 39.26 µg/ml. The results of the study revealed that salt-lake actinomycetes of Lake Dabancheng appear to have immense potential as a source of polyketide compounds.

Low vitamin D levels in follicular fluid, but not in serum, are associated with adverse outcomes in assisted reproduction.

PURPOSE: To assess the relationship between serum/follicular fluid (FF) vitamin D (VD) status and assisted reproductive technology (ART) treatment outcomes among infertile patients. METHODS: A prospective cohort study, including 132 infertile patients scheduled for their first ART treatment cycle, was carried out in a Reproductive Medical Center. Serum and FF samples were collected to assess 25-hydroxy VD [25(OH)D] levels. Low VD level was defined as 25(OH)D concentration of less than 30 ng/mL. RESULTS: Most infertile patients had low VD levels in serum (88%) and FF (90%). We observed a moderately positive correlation between VD levels in serum and FF (r = 0.34, p < 0.0001). Compared to the group of patients with low VD levels in the FF, those with sufficient VD levels had a significantly higher number of retrieved oocytes (p = 0.03), normal fertilization (p = 0.01), and high-quality embryos (p = 0.001). Moreover, patients with sufficient VD levels in the FF also had significantly higher implantation rates than those with low VD levels (76.92% vs. 46.58%, respectively, p = 0.01) and clinical pregnancy rates (92.31% vs. 61.54%, respectively, p = 0.04). CONCLUSION: These data collectively revealed that low VD levels in serum and FF were common among infertile patients. VD levels in FF, but not in serum, were associated with embryo quality, normal fertilization, implantation rates, and clinical pregnancy rates. Further studies are mandatory to determine the molecular mechanism and VD's potential therapeutic benefits in infertile patients.

Evidence of higher-order topology in multilayer WTe2 from Josephson coupling through anisotropic hinge states.

Td-WTe2 (non-centrosymmetric and orthorhombic), a type-II Weyl semimetal, is expected to have higher-order topological phases with topologically protected, helical one-dimensional hinge states when its Weyl points are annihilated. However, the detection of these hinge states is difficult due to the semimetallic behaviour of the bulk. In this study, we have spatially resolved the hinge states by analysing the magnetic field interference of the supercurrent in Nb-WTe2-Nb proximity Josephson junctions. The Josephson current along the a axis of the WTe2 crystal, but not along the b axis, showed a sharp enhancement at the edges of the junction, and the amount of enhanced Josephson current was comparable to the upper limits of a single one-dimensional helical channel. Our experimental observations suggest a higher-order topological phase in WTe2 and its corresponding anisotropic topological hinge states, in agreement with theoretical calculations. Our work paves the way for the study of hinge states in topological transition-metal dichalcogenides and analogous phases.

Author Correction: Evidence of higher-order topology in multilayer WTe2 from Josephson coupling through anisotropic hinge states.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Damage to Olfactory Organs of Adult Zebrafish Induced by Diesel Particulate Matter.

Particulate matter (PM) is an environmental hazard that is associated with various human health risks. The olfactory system is directly exposed to PM; therefore, the influence of PM exposure on olfactory function must be investigated. In this study, we propose a zebrafish olfactory model to evaluate the effects of exposure to diesel particulate matter (DPM), which was labeled Korean diesel particulate matter (KDP20). KDP20 comprises heavy metals and polycyclic aromatic hydrocarbons (PAHs). KDP20 exposed olfactory organs exhibited reduced cilia and damaged epithelium. Olfactory dysfunction was confirmed using an odor-mediated behavior test. Furthermore, the olfactory damage was analyzed using Alcian blue and anti-calretinin staining. KDP20 exposed olfactory organs exhibited histological damages, such as increased goblet cells, decreased cell density, and calretinin level. Quantitative real-time polymerase chain reaction (qRT-PCR) revealed that PAHs exposure related genes (AHR2 and CYP1A) were upregulated. Reactive oxidation stress (ROS) (CAT) and inflammation (IL-1B) related genes were upregulated. Furthermore, olfactory sensory neuron (OSN) related genes (OMP and S100) were downregulated. In conclusion, KDP20 exposure induced dysfunction of the olfactory system. Additionally, the zebrafish olfactory system exhibited a regenerative capacity with recovery conditions. Thus, this model may be used in future investigating PM-related diseases.

New application for assessment of dry eye syndrome induced by particulate matter exposure.

Dry eye syndrome (DES) is a multifactorial condition characterized by insufficient tear lubrication and eye irritation. Air pollutants, including particulate matter (PM), are an emerging threat to human health causing DES and other diseases. However, the pathogenic mechanisms of DES induced by PM exposure remain to be fully elucidated. Recent studies have attempted to create DES animal model using PM exposure. In this study, we explored a novel in vivo exposure model of DES, utilizing an inhalation device (aerosol exposure system) to reproduce the natural exposure to atmospheric PM. Rats were exposed to urban PM (UPM) using this aerosol system for 5 h per day over 5 days. Tear volume in UPM-exposed rats decreased significantly, whereas corneal irregularity and lissamine green staining significantly increased following UPM exposure. Additional effects observed following UPM exposure included apoptosis in the corneal epithelium and a decrease in the number of goblet cells in the conjunctiva. UPM also affected the stability of the tear film by disrupting its mucin-4 layer. In conclusion, aerosol exposure systems have proven effective as assessment tools for DES caused by PM.

Regulatory Mechanism of MicroRNA Expression in Cancer.

Altered gene expression is the primary molecular mechanism responsible for the pathological processes of human diseases, including cancer. MicroRNAs (miRNAs) are virtually involved at the post-transcriptional level and bind to 3' UTR of their target messenger RNA (mRNA) to suppress expression. Dysfunction of miRNAs disturbs expression of oncogenic or tumor-suppressive target genes, which is implicated in cancer pathogenesis. As such, a large number of miRNAs have been found to be downregulated or upregulated in human cancers and to function as oncomiRs or oncosuppressor miRs. Notably, the molecular mechanism underlying the dysregulation of miRNA expression in cancer has been recently uncovered. The genetic deletion or amplification and epigenetic methylation of miRNA genomic loci and the transcription factor-mediated regulation of primary miRNA often alter the landscape of miRNA expression in cancer. Dysregulation of the multiple processing steps in mature miRNA biogenesis can also cause alterations in miRNA expression in cancer. Detailed knowledge of the regulatory mechanism of miRNAs in cancer is essential for understanding its physiological role and the implications of cancer-associated dysfunction and dysregulation. In this review, we elucidate how miRNA expression is deregulated in cancer, paying particular attention to the cancer-associated transcriptional and post-transcriptional factors that execute miRNA programs.

PCR Screening of Enterococcus faecalis from Mixture of Lactic Acid Bacteria Using Bile Salt Hydrolase Gene as a Selective Marker.

It is very important to rapidly detect the contamination of Enterococcus faecalis in fermented foods such as Korean Kimchi to maintain its freshness since Kimchi is exported to all over the world. However, gene sequence of E. faecalis is very similar among various Lactobacillus. So, there have been difficulties in its screening. We have designed primers based on Bile salt hydrolase gene of E. faecalis and applied them to PCR test. PCR band was identified only from E. faecalis and only from the mixture contaminated with E. faecalis. It means that the primers we designed are highly specific for distinguishing contamination of E. faecalis. It will be possible to precisely screen within 1 h, which will greatly contribute to the prevention of food poisoning and quick quarantine.

Tripartite Regulation of the glpFKD Operon Involved in Glycerol Catabolism by GylR, Crp, and SigF in Mycobacterium smegmatis.

The glpD (MSMEG_6761) gene encoding glycerol-3-phosphate dehydrogenase was shown to be crucial for M. smegmatis to utilize glycerol as the sole carbon source. The glpD gene likely forms the glpFKD operon together with glpF and glpK, encoding a glycerol facilitator and glycerol kinase, respectively. The gylR (MSMEG_6757) gene, whose product belongs to the IclR family of transcriptional regulators, was identified 182 bp upstream of glpF It was demonstrated that GylR serves as a transcriptional activator and is involved in the induction of glpFKD expression in the presence of glycerol. Three GylR-binding sites with the consensus sequence (GKTCGRC-N3-GYCGAMC) were identified in the upstream region of glpF by DNase I footprinting analysis. The presence of glycerol-3-phosphate was shown to decrease the binding affinity of GylR to the glpF upstream region with changes in the quaternary structure of GylR from tetramer to dimer. Besides GylR, cAMP receptor protein (Crp) and an alternative sigma factor, SigF, are also implicated in the regulation of glpFKD expression. Crp functions as a repressor, while SigF induces expression of glpFKD under energy-limiting conditions. In conclusion, we suggest here that the glpFKD operon is under the tripartite control of GylR, SigF, and Crp, which enables M. smegmatis to integrate the availability of glycerol, cellular energy state, and cellular levels of cAMP to exquisitely control expression of the glpFKD operon involved in glycerol metabolism.IMPORTANCE Using genetic approaches, we first revealed that glycerol is catabolized through the glycolytic pathway after conversion to dihydroxyacetone phosphate in two sequential reactions catalyzed by glycerol kinase (GlpK) and flavin adenine dinucleotide (FAD)-containing glycerol-3-phosphate dehydrogenase (GlpD) in M. smegmatis Our study also revealed that in addition to the GylR transcriptional activator that mediates the induction of the glpFKD operon by glycerol, the operon is regulated by SigF and Crp, which reflect the cellular energy state and cAMP level, respectively.

Targeting of SPP1 by microRNA-340 inhibits gastric cancer cell epithelial-mesenchymal transition through inhibition of the PI3K/AKT signaling pathway.

Gastric cancer (GC) is a common heterogeneous disease. The critical roles of microRNA-340 (miR-340) in the development and progression of GC were emphasized in accumulating studies. This study aims to examine the regulatory mechanism of miR-340 in GC cellular processes. Initially, microarray technology was used to identify differentially expressed genes and regulatory miRs in GC. After that, the potential role of miR-340 in GC was determined via ectopic expression, depletion, and reporter assay experiments. Expression of secreted phosphoprotein 1 (SPP1), miR-340, phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, and epithelial-mesenchymal transition (EMT)-related genes was measured. Moreover, to further explore the function of miR-340 in vivo and in vitro, proliferation, apoptosis, migration, invasion, and tumorigenic capacity were evaluated. SPP1 was a target gene of miR-340 which could then mediate the PI3K/AKT signaling pathway by targeting SPP1 in GC. Furthermore, miR-340 levels were reduced and SPP1 was enriched in GC tissues and cells, with the PI3K/AKT signaling pathway being activated. Inhibitory effects of upregulated miR-340 on SPP1 and the PI3K/AKT signaling pathway were confirmed in vivo and in vitro. Overexpression of miR-340 or the silencing of SPP1 inhibited GC cell proliferation, invasion, migration, and EMT process, but promoted apoptosis of GC cells. Typically, targeting of SPP1 by miR-340 may contribute to the inhibition of proliferation, migration, invasion, and EMT of GC cells via suppression of PI3K/AKT signaling pathway.

Antibacterial Film Formation through Iron(III) Complexation and Oxidation-Induced Cross-Linking of OEG-DOPA.

Catechols are prone to oxidative polymerization as well as complex formation with metal ions. These two features of catechols have played an important role in the construction of functional films on various surfaces. For example, marine antifouling films and antibacterial films were successfully prepared by oxidative polymerization and metal complexation of catechol-containing molecules, respectively. However, the effect of simultaneous metal complexation and oxidative polymerization on functional film formation has not yet been fully investigated. Herein, as a derivative of 3-(3,4-dihydroxyphenyl)-l-alanine (DOPA), we synthesized an ethylene glycol-derivatized DOPA (OEG-DOPA) and formed OEG-DOPA thin films based on (1) oxidative polymerization and (2) the complexation between catechol groups of OEG-DOPA and iron(III) (FeIII) ions. Either or both approaches were used for the film formation. OEG-DOPA film formation was characterized by ellipsometry, contact angle goniometry, field emission scanning electron microscopy, and X-ray photoelectron spectroscopy. Among the conditions used, the formation of a uniform film was only achieved with the dual cross-linking system of FeIII complexation and oxidation-induced covalent bond formation. Compared to the uncoated substrate and other OEG-DOPA films prepared under different conditions, the uniform OEG-DOPA film strongly inhibited bacterial adhesion, showing excellent antibacterial capability. We think that our surface-coating strategy can be applied to medical devices, tools, and implants where bacterial adhesion and biofilm formation should be prevented. This work can also serve as a basis for the construction of functional thin films for other catechol-functionalized materials.

Low MFN2 expression related to ageing in granulosa cells is associated with assisted reproductive technology outcome.

RESEARCH QUESTION: Is low MFN2 expression associated with ageing in granulosa cells as well as assisted reproductive technology (ART) outcome, and what is the underlying mechanism of action of MFN2? DESIGN: In a prospective study, fresh granulosa cells were obtained from 161 women aged 20-40 years who underwent IVF with embryo transfer and who were divided into two groups: the diminished ovarian reserve (DOR) group (n = 51) and the control group (n = 110). Patient characteristics including age, infertility duration, body mass index, FSH, anti-Müllerian hormone (AMH), antral follicle count (AFC) and husband's semen parameters and granulosa cell MFN2 expression levels, cell apoptosis, mitochondrial membrane potential (ΔΨm) and ATP levels were analysed. RESULTS: There were no significant differences between the DOR and control groups in terms of age, infertility duration and husband'' semen parameters; however, significant (P< 0.05) changes were found between the two groups in FSH, AMH and AFC levels. MFN2 expression was remarkably lower in granulosa cells from the DOR group and decreased in both groups as age increased. Furthermore, among young patients, MFN2 levels significantly increased in patients with pregnancy. MFN2 protein levels and cell apoptosis were lower in the MFN2 knockdown (MFN2-siRNA) group than in the control (Cy3-siRNA) group. ΔΨm and ATP levels were reduced in the MFN2-siRNA group compared with the Cy3-siRNA group. CONCLUSIONS: Low MFN2 expression levels in granulosa cells were related to ageing, which may be involved in the clinical outcome of ART by promoting cell apoptosis and affecting mitochondrial function.

FIVE-YEAR INCIDENCE AND RISK FACTORS FOR IDIOPATHIC EPIRETINAL MEMBRANES.

PURPOSE: The aim of this was to determine the 5-year incidence of idiopathic epiretinal membrane (ERM) and its risk factors in Korean adults. METHODS: A total of 2,152 participants aged 50 years or older enrolled in a health screening program. All participants underwent baseline ophthalmic and systemic examinations in 2006, and were reexamined after 5 years. Epiretinal membranes were diagnosed using fundus photographs taken at baseline and at the 5-year follow-up. The incidence of idiopathic ERM was calculated in this study cohort, and then age-standardized to the 2010 Korean Census. Epiretinal membranes were classified as preretinal macular fibrosis with prominent retinal folds or cellophane macular reflex without retinal folds. Associated risk factors for idiopathic ERM were also analyzed. RESULTS: Idiopathic ERM developed in 82 of 2,152 participants who had no previous ERM in either eye at baseline. The overall age-standardized incidence was 3.8% (95% confidence interval, 2.8-4.8), including 2.3% with cellophane macular reflex and 1.5% with preretinal macular fibrosis. Multivariate logistic regression analyses revealed that the factors related to the development of idiopathic ERM were age (adjusted odds ratio, 1.04; 95% confidence interval, 1.00-1.08) and hypertriglyceridemia (250 mg/dL or more; adjusted odds ratio, 3.16; 95% confidence interval, 1.54-6.49) after adjusting for confounding factors. CONCLUSION: Our results suggest that the 5-year incidence of idiopathic ERM in Korean adults is relatively similar to that in similar-aged white persons. Age and hypertriglyceridemia may increase the risk of developing idiopathic ERM.

Ten Cases of Taenia saginata Infection Confirmed by Analysis of the Internal Transcribed Spacer 1 rDNA Region in the Republic of Korea.

From October 2015 to August 2018, tapeworm proglottids were obtained from 10 patients who were residents of Daegu and Gyeongbuk provinces and had a history of raw beef consumption. Most of them had no overseas travel experience. The gravid proglottids obtained from the 10 cases had 15-20 lateral uterine branches. A part of internal transcribed spacer 1 (ITS1) DNA of the 10 cases, amplified by polymerase chain reaction (PCR) and digested with AleI restriction enzyme, produced the same band pattern of Taenia saginata, which differentiated from T. asiatica and T. solium. Sequences of ITS1 and cytochrome c oxidase subunit 1 (cox1) showed higher homology to T. saginata than to T. asiatica and T. solium. Collectively, these 10 cases were identified as T. saginata human infections. As taeniasis is one of the important parasitic diseases in humans, it is necessary to maintain hygienic conditions during livestock farming to avoid public health concerns.

miR-218 and miR-129 regulate breast cancer progression by targeting Lamins.

Breast cancer is the most frequently diagnosed life-threatening cancer in women. Triple-negative breast cancer (TNBC) has an aggressive clinical behavior, but the treatment of TNBC remains challenging. MicroRNAs (miRNAs) have emerged as a potential target for the diagnosis, therapy and prognosis of breast cancer. However, the precise role of miRNAs and their targets in breast cancer remain to be elucidated. Here we show that miR-218 is downregulated and miR-129 is upregulated in TNBC samples and their expressions confer prognosis to patients. Gain-of-function and loss-of-function analysis reveals that miR-218 has a tumor suppressive activity, while miR-129 acts as an oncomir in breast cancer. Notably, miR-218 and miR-129 directly target Lamin B1 and Lamin A, respectively, which are also found to be deregulated in human breast tumors. Finally, we demonstrate Lamins as the major factors in reliable miR-218 and miR-129 functions for breast cancer progression. Our findings uncover a new miRNA-mediated regulatory network for different Lamins and provide a potential therapeutic target for breast cancer.

Necrostatin-1 ameliorates adjuvant arthritis rat articular chondrocyte injury via inhibiting ASIC1a-mediated necroptosis.

Necroptosis, a necrotic cell death pathway regulated by receptor interacting protein (RIP) 1 and 3, plays a key role in pathophysiological processes, including rheumatoid arthritis (RA). However, whether necroptosis is involved in RA articular cartilage damage processes remain unclear. The aim of present study was to investigate the dynamic changes in arthritic chondrocyte necroptosis and the effect of RIP1 inhibitor necrostatin-1 (Nec-1) and acid-sensing ion channels (ASICs) inhibitor amiloride on arthritic cartilage injury and acid-induced chondrocyte necroptosis. Our results demonstrated that the expression of RIP1, RIP3 and mixed lineage kinase domain-like protein phosphorylation (p-MLKL) were increased in adjuvant arthritis (AA) rat articular cartilage in vivo and acid-induced chondrocytes in vitro. High co-expression of ASIC1a and RIP1 showed in AA rat articular cartilage. Moreover, Nec-1 and amiloride could reduce articular cartilage damage and necroinflammation in AA rats. In addition, acid-induced increase in necroptosis markers RIP1/RIP3 were inhibited by Nec-1, ASIC1a-specific blocker psalmotoxin-1 (PcTx-1) or ASIC1a-short hairpin RNA respectively, which revealed that necroptosis is triggered in acid-induced chondrocytes and mediated by ASIC1a. These findings indicated that blocking ASIC1a-mediated chondrocyte necroptosis may provide potential therapeutic strategies for RA treatment.