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Tanshinone IIA alleviates IL-1β-induced chondrocyte apoptosis and inflammation by regulating FBXO11 expression
Jin Xu, XiaoCheng Zhi, YunHui Zhang, Ren Ding
Corresponding author
dr.dingren1390@outlook.com

Corresponding author.
Department of Orthopaedics, Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai City, China
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0008">Introduction</span><p id="para0009" class="elsevierStylePara elsevierViewall">As an aging process&#44; Osteoarthritis &#40;OA&#41; is characterized by the breakdown of articular cartilage&#44; and the formation of subchondral osteosclerosis and osteophyte&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> With high incidences in patients&#44;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> OA causes poor quality of life&#44; severe symptoms&#44; and unsatisfactory outcomes&#46; OA involves continuous chondrocyte inflammation and apoptosis&#44;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a> however&#44; its pathogenesis has not been fully elucidated&#46;</p><p id="para0010" class="elsevierStylePara elsevierViewall">Tanshinone IIA &#40;Tan IIA&#59; C19H18O3&#44; 14&#44; 16-epoxy-20-NOR-5&#40;10&#41;&#44;6&#44;8&#44;13&#44; 15-Abietapentaene-11&#44; 12&#8209;dione&#41; is a fat-soluble diterpenoid quinone isolated from Salvia miltiorrhiza&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> Salvia miltiorrhiza is widely distributed in China&#46; Aside from promoting blood circulation and removing blood stasis&#44; it alleviates menstrual pain&#44; clears the heart and reduces irritability&#44; and cools blood to alleviate pain&#46; In 1934&#44; Nakao isolated TAN IIA from Salvia miltiorrhiza and identified it as a representative monomer compound&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> Because Tan IIA is a quinone-type compound&#44; it has more active electronic properties&#44; is susceptible to REDOX reactions&#44; and can participate in a variety of biochemical reactions&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> Several recent studies have shown that TAN IIA can play an anti-apoptotic and anti-inflammatory role&#46; For example&#44; TAN IIA protects acute ethanol-induced myocardial injury <span class="elsevierStyleItalic">in vivo</span> and cardiomyocyte apoptosis <span class="elsevierStyleItalic">in vitro</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> and Tan IIA regulates the expression of the miR-133a-3p&#47;EGFR axis&#44; thereby inhibiting the apoptosis of H9c2 cells <span class="elsevierStyleItalic">in vivo</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> In addition&#44; Tan IIA plays an anti-inflammatory role by inhibiting iNOS and inflammatory cytokines in RAW 264&#46;7 cells&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> Tan IIA can attenuate arthritis&#44; confirming that TAN IIA can also play an anti-inflammatory role <span class="elsevierStyleItalic">in vivo</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a> Although TAN IIA has been reported to inhibit articular cartilage degradation<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> and alleviate IL-1&#946;-induced chondrocyte inflammatory damage&#44; and is a promising new candidate target for the treatment of arthritis&#44; its anti-apoptotic and anti-inflammatory effects in OA remain unclear and need to be further clarified&#46; At the same time&#44; in clinical application&#44; TAN IIA is mainly used for the treatment of cardiovascular and cerebrovascular diseases&#44;<a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> which has been proven to improve cardiac function&#46; Therefore&#44; TAN IIA has a broad prospect as a clinical drug for the treatment of OA&#46;</p><p id="para0011" class="elsevierStylePara elsevierViewall">FBXO11&#44; a constituent of the F-box protein family&#44; assumes the role of facilitating substrate ubiquitination and degradation&#44; as well as maintaining genome stability&#46; Moreover&#44; FBXO11 functions as a regulator of the TGF-&#946; pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> The Jeff mutation is localized within the FBXO11 gene and impairs FBXO11&#8242;s capacity to stabilize p53&#44; consequently resulting in the downregulation of the TGF-&#946;&#47;Smad2 pathway&#46; This pathway holds significant importance in the context of immunity and inflammation&#44; as evidenced by similar observations in Fbxo11 knockout mice&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> In addition&#44; downregulating FBXO11 in 16HBE cells can reduce apoptosis and inflammation regulated by cigarette smoke extract <span class="elsevierStyleItalic">in vivo</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a> However&#44; the effect of FBXO11 on OA cell apoptosis and inflammation therapy is still weak&#46;</p><p id="para0012" class="elsevierStylePara elsevierViewall">The PI3K&#47;Akt and NF-&#954;B pathways mediate many cell biological activities&#44; such as cell proliferation&#44; apoptosis&#44; and inflammation&#46; Based on previous <span class="elsevierStyleItalic">in vivo</span> and <span class="elsevierStyleItalic">in vitro</span> experiments&#44; it has been reported that curcumin attenuates high-glucose-induced cardiomyocyte apoptosis by inhibiting NADPH&#44; and this protective effect is mediated by the PI3K&#47;Akt pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> Blocking the phosphorylation of the PI3K&#47;AKT signaling pathway mainly mediates anti-inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a> NF-&#954;B has an anti-apoptotic effect&#46; For example&#44; vitamin D promotes the anti-apoptotic effect of TNF-&#945;-induced human myeloid nucleus cells by inhibiting the NF-&#954;B pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a> Meng et al&#46; also demonstrated the anti-apoptotic effect of NF-&#954;B in IVDD rat models&#46;<a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a> The NF-kB signaling pathway is considered a typical pro-inflammatory pathway&#44; and studies have shown that OrA activates the NF-&#954;B signaling pathway to reduce LPS-induced inflammatory response and inhibit the expression of iNOS and COX-2 genes through <span class="elsevierStyleItalic">in vivo</span> and <span class="elsevierStyleItalic">in vitro</span> experiments&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a> Most importantly&#44; the importance of NF-&#954;B in OA has been demonstrated through <span class="elsevierStyleItalic">in vivo</span> and <span class="elsevierStyleItalic">in vitro</span> experiments&#46;<a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> NF-&#954;B is activated during aging and inflammation of OA chondrocytes and is widely involved in the pathophysiological processes of OA&#46;</p><p id="para0013" class="elsevierStylePara elsevierViewall">Under normal circumstances&#44; articular cartilage is maintained by a balance between ECM synthesis and degradation&#44; but inflammatory cytokines&#44; especially IL-1&#946;&#44; disrupt this balance and lead to cartilage degradation&#46;<a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a> It has previously been reported that OA progression is reduced by inhibiting IL-1&#946;-regulated ERK activation&#44;<a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a> and IL-1&#946; down-regulates type II collagen&#44; thus leading to the degradation of articular cartilage&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a> PI3K&#47;Akt or NF-&#954;B pathway suppression can alleviate apoptosis and inflammation in OA chondrocytes&#46;</p><p id="para0014" class="elsevierStylePara elsevierViewall">Whether Tan IIA inhibits IL-1&#946;-regulated OA chondrocyte apoptosis by activating FBXO11 protein levels remains unclear&#46; This study aimed to explore whether Tan IIA has a definite protective effect on apoptosis and inflammation of OA chondrocytes by regulating FBXO11 and to explore relevant mechanisms involved in the PI3K&#47;Akt and NF-&#954;B pathways on OA progression&#46;</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Materials and methods</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Cell culture and induction</span><p id="para0015" class="elsevierStylePara elsevierViewall">CHON-001 cells &#40;ATCC&#44; USA&#41; were routinely cultured in DMEM plus 10 &#37; FBS &#40;10&#44;099&#44;141&#44; Thermo Fisher Scientific&#44; USA&#41; and 1 U&#47;mL penicillin&#47;streptomycin &#40;10&#44;378&#44;016&#44; Thermo Fisher Scientific&#41;&#46; Cells in passages 5&#8210;10 were selected&#46;</p><p id="para0016" class="elsevierStylePara elsevierViewall">For IL-1&#946; treatment&#44; IL-1&#946; &#40;0&#44; 1&#44; 5&#44; and 10 &#956;g&#47;mL&#41; was added to the medium&#44; and finally 10 &#956;g&#47;mL was selected for subsequent experiments&#46; The medium was changed at 70 &#37;&#8210;80 &#37; cell confluence&#44; and cells were divided into different treatment groups&#46; TAN IIA &#40;1&#44;643&#44;339&#44; Sigma&#44; USA&#41; was dissolved in DMSO &#40;Beyotime&#41; to 250 mM and then diluted to 5&#44; 10&#44; 50&#44; and 100 &#956;M&#46; Celecoxib &#40;10 &#956;m&#44; Sigma Aldrich&#41;&#44; as a positive agent&#44; was used to treat IL-1&#946;-induced CHON-001 cells&#46;</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Cell transfection and treatment</span><p id="para0017" class="elsevierStylePara elsevierViewall">Transfection was achieved in CHON-001 cells by Lipofectamine 3000 &#40;Thermo Fisher Scientific&#41;&#46; pcDNA3&#46;1-FBXO11 was transfected into CHON-001 cells&#44; with pcDNA3&#46;1 &#40;GenePharma&#44; Shanghai&#44; China&#41; as a negative control&#46; Transfection efficiency was evaluated by RT-qPCR&#46;</p><p id="para0018" class="elsevierStylePara elsevierViewall">To explore the effects of inhibition of PI3K&#47;AKT and NF-&#954;B pathways on apoptosis and inflammation of OA chondrocytes&#44; 5 &#956;M PI3K&#47;AKT inhibitor LY294002 &#40;MedChemExpress&#41; or NF-&#954;B inhibitor &#40;PDTC&#44; Sigma&#41; was added to TAN IIA-treated IL-1&#946;-regulated CHON-001 cells&#46;</p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">Cell viability assay</span><p id="para0019" class="elsevierStylePara elsevierViewall">CHON-001 cells &#40;5 &#215; 10<span class="elsevierStyleSup">4</span> cells&#47;well&#41; were maintained in 96-well plates of 100 &#956;L medium and attached to the wall after overnight culture&#46; Cells were incubated with 10 &#956;L CCK-8 &#40;Beyotime&#41; for 2 h at 37 &#176;C and analyzed on a Thermomax &#40;Bio-Tek&#44; USA&#41; to read optical density values at 450 nm&#46;</p></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Flow cytometry</span><p id="para0020" class="elsevierStylePara elsevierViewall">Apoptotic cells were detected by Annexin V-FITC apoptosis detection kit &#40;Thermo Fisher Scientific&#41;&#46; CHON-001 cells were put in 6-well plates with 5 &#215; 10<span class="elsevierStyleSup">4</span> cells&#47;well overnight&#44; digested with EDTA-free trypsin &#40;0&#46;25 &#37;&#44; Beyotime&#41;&#44; and centrifuged at 1200 rpm for 5 min&#46; The cell precipitations were suspended in 500 &#956;L 1 &#215; Annexin V binding buffer and stained with 10 &#956;L Annexin V-FITC and 5 &#956;L PI for 30 min away from light&#46; Apoptotic cells &#40;Annexin <span class="elsevierStyleItalic">V</span><span class="elsevierStyleSup">&#43;</span> and PI<span class="elsevierStyleSup">&#8722;</span>&#41; were distinguished from necrotic cells &#40;Annexin <span class="elsevierStyleItalic">V</span><span class="elsevierStyleSup">&#43;</span> and PI<span class="elsevierStyleSup">&#43;</span>&#41; on the FACS Calibur flow cytometry &#40;BD Biosciences&#44; USA&#41;&#46;</p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0014">TUNEL assay</span><p id="para0021" class="elsevierStylePara elsevierViewall">Cartilage tissues were fixed with 4 &#37; paraformaldehyde &#40;Beyotime&#41; for 30 min&#44; permeated with 0&#46;1 &#37; Triton-X 100 for 3 min&#44; stained with <span class="elsevierStyleItalic">in situ</span> apoptosis detection kit &#40;Sigma-Aldrich&#41;&#44; and then re-stained with DAPI for 10 min&#46; Images were taken under a confocal microscope &#40;Nikon Eclipse 80i&#44; Japan&#41;&#46;</p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0015">RT-qPCR assay</span><p id="para0022" class="elsevierStylePara elsevierViewall">Total RNA was isolated from CHON-001 cells and tissues using TRIzol reagent &#40;Invitrogen&#44; USA&#41; and processed with Prime Script RT Reagent Kit &#40;Takara&#41;&#46; The obtained cDNA was considered a template for SYBR Green qRT-PCR &#40;Takara&#41; analysis&#46; PCR was implemented with a 7500 real-time fluorescent quantitative PCR system &#40;Applied Biosystems&#44; USA&#41; and SYBR Premix Ex Taq Kit &#40;Takara&#41;&#44; and mRNA expression was standardized at GAPDH levels&#46; Specific primers designed for target mRNA are shown in <a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#46; The results are shown as relative expressions&#44; and the formula is the 2<span class="elsevierStyleSup">&#8722;&#916;&#916;CT</span> method&#46;</p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0016">Immunoblot assay</span><p id="para0023" class="elsevierStylePara elsevierViewall">The collected cells and tissues were lysed in a RIPA lysis buffer mixed with protease inhibitor and phosphatase inhibitor &#40;Roche&#44; Switzerland&#41; for 30 min&#46; After detection with the BCA Protein Assay Kit &#40;Beyotime&#41;&#44; proteins were isolated on 10 &#37; SDS-PAGE&#44; loaded to a PVDF membrane &#40;Millipore&#44; USA&#41;&#44; and sealed with 5 &#37; skim milk for 2 h&#46; Specific primary antibodies &#946;-actin &#40;15&#44;204&#8211;1-p&#44; Proteintech&#41;&#44; Cleaved caspase-3 &#40;Asp175&#44; Cell Signaling Technology&#44; USA&#41;&#44; FBXO11 &#40;ab181801&#44; Abcam&#41;&#44; iNOS &#40;ab178945&#44; Abcam&#41;&#44; PI3K &#40;ab302958&#44; Abcam&#41;&#44; p-PI3K&#44; AKT &#40;ab8805&#44; Abcam&#41;&#44; p-AKT&#44; p65 &#40;ab111577&#44; Abcam&#41;&#44; and p-p65 were incubated overnight and washed in three-buffered saline containing 0&#46;1 &#37; Tween-20&#46; The secondary antibody coupled with horseradish peroxidase was reacted for 6 h&#46; Protein bands were developed by the Chemo Dox XRS system &#40;Bio-Rad&#44; USA&#41;&#44; of which the optical density was calculated by ImageJ version 6&#46;0&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0017">ELISA test</span><p id="para0024" class="elsevierStylePara elsevierViewall">As requested by the manufacturer&#44; TNF-&#945;&#44; IL-6&#44; and iNOS in tissues and cells were determined using ELISA Kits &#40;R&#38;D Systems&#44; USA&#41;&#46;</p></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0018">Rat oa model</span><p id="para0025" class="elsevierStylePara elsevierViewall">All procedures were conducted in accordance with the ARRIVE Guidelines&#44; and the Animal Research Ethics Committee of Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine &#40;n&#176; 2020B0633&#41; approved all rat experiments&#46; The Experimental Animal Center of Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine provided 50 male Sprague Dawley rats &#40;10&#8210;12 weeks&#44; 250&#8210;300 g&#41;&#46; An Anterior Cruciate Ligament Transaction &#40;ACLT&#41; at the right knee induced OA&#46; Under anesthesia with an intraperitoneal injection of 50 mg&#47;L chloral hydrate &#40;Beyotime&#41;&#44; the rats were placed with the left posterior region fixed in a supine position&#46; The medial joint capsule was incised&#44; the extensor muscles were gently displaced laterally without severing the patellar ligament&#44; the anterior cruciate ligament was severed&#44; and the joint was rinsed with sterile saline&#46; The joint was then closed with 7&#8210;0 surgical sutures and the skin wound was closed&#46; To prevent wound infection&#44; amoxicillin was applied topically&#44; and rat status was monitored&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a> Another 10 rats that did not undergo ACLT surgery served as a control group&#46; The rats were randomly divided into 5 groups&#58; sham group&#44; ACLT group&#44; ACLT &#43; celecoxib &#40;10 mg&#47;kg&#41; group&#44; ACLT &#43; low-dose TAN IIA group&#44; and ACLT &#43; high-dose TAN IIA group&#46; After one week of adaptive feeding&#44; celecoxib was dissolved in normal saline containing 0&#46;1 &#37; DMSO and administered orally at a dose of 10 mg&#47;kg&#47;day&#46; TAN IIA was injected once a day into the peritoneum of the rats at either a low dose &#40;50 mg&#47;kg&#41; or a high dose &#40;150 mg&#47;kg&#41; for 7-weeks&#46; After euthanized rats&#44; knee joint samples were collected for follow-up analysis&#46;</p></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0019">HE-staining</span><p id="para0026" class="elsevierStylePara elsevierViewall">Cartilages were fixed in 4 &#37; paraformaldehyde for 24 h and immersed in 10 &#37; EDTA for 2&#8210;3 weeks&#46; After dehydration&#44; the cartilages were embedded in paraffin and sectioned to 5 &#956;m&#46; HE-staining was conducted &#40;Beyotime&#41; and samples were observed under a microscope &#40;Leica&#41;&#46;</p></span><span id="sec0013" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0020">Immunohistochemistry &#40;IHC&#41;</span><p id="para0027" class="elsevierStylePara elsevierViewall">Cartilages were fixed in 4 &#37; paraformaldehyde and prepared into paraffin slices with 5 mm thickness&#46; The slices were dewaxed and treated with 3 &#37; H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span> for 15 min and sealed with 5 &#37; normal serum for 30 min&#46; After Cleaved caspase-3 and FBXO11 antibody treatment at 4 &#176;C&#44; the slices were incubated with the secondary antibody and imaged under an optical microscope&#46; Images were analyzed by ImageJ 6&#46;0&#46;</p></span><span id="sec0014" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0021">Data analysis</span><p id="para0028" class="elsevierStylePara elsevierViewall">SPSS20 statistical software analyzed the experimental data&#46; Measurement data were expressed as mean &#177; SD and conditioned to a comparative analysis by <span class="elsevierStyleItalic">t</span>-test or one-way ANOVA&#44; with &#42; <span class="elsevierStyleItalic">p</span> &#60; 0&#46;05 emphasizing statistical significance&#46; All analyses were performed using GraphPad Prism 8&#46;0&#46;</p></span></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0022">Results</span><span id="sec0016" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0023">TAN iia inhibits IL-1&#946; from inducing apoptosis and inflammation in CHON-001 cells</span><p id="para0029" class="elsevierStylePara elsevierViewall">Based on CCK-8&#44; the cell viability of CHON-001 showed a significant decrease at an IL-1&#946; concentration of 10 &#956;g&#47;mL &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>A&#41;&#46; Therefore&#44; CHON-001 cells were treated with 10 &#956;g&#47;mL IL-1&#946; to establish a cell model&#46;</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia><p id="para0030" class="elsevierStylePara elsevierViewall">The effect of different concentrations of TAN IIA on IL-1&#946;-regulated CHON-001 cell viability was determined by CCK-8 assay&#44; and it was found that under IL-1&#946; treatment&#44; there was no cytotoxicity when TAN IIA concentration was less than 100 &#956;M&#44; and 10&#8210;100 &#956;M was the most suitable dose range for studying the effect of TAN IIA &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>B&#41;&#46; IL-1&#946;-induced CHON-001 cells were treated with 0&#8210;100 &#956;M TAN IIA for 48 h&#44; and celecoxib significantly rescued IL-1&#946;-induced cytotoxicity of CHON-001 cells&#44; while 10&#8210;100 &#956;M TAN IIA significantly reduced IL-1&#946;-induced cytotoxicity in a dose-dependent manner &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>C&#41;&#46; Therefore&#44; to mimic the OA treatment model&#44; CHON-001 cells were exposed to IL-1&#946; at 10 &#956;g&#47;mL for 48 h&#44; followed by treatment with TAN IIA at 10 &#956;M for the same duration&#46;</p><p id="para0031" class="elsevierStylePara elsevierViewall">The anti-apoptotic and anti-inflammatory effects of TAN IIA in CHON-001 chondrocytes were analyzed <span class="elsevierStyleItalic">in vitro</span>&#46; Flow cytometry evaluated that apoptosis was significantly increased after IL-1&#946; treatment&#44; while TAN IIA or celecoxib significantly inhibited the induction of apoptosis by IL-1&#946; and reversed the promoting effect of IL-1&#946; on apoptosis of CHON-001 cells &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>D&#41;&#46; The results were further confirmed by Western Blot and RT-qPCR detection of apoptosis-related proteins&#46; TAN IIA or celecoxib inhibited expression of the pro-apoptotic protein Cleaved caspase-3 &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>E&#44; <a class="elsevierStyleCrossRef" href="#fig0001">1</a>F&#41;&#46;</p><p id="para0032" class="elsevierStylePara elsevierViewall">TNF-&#945;&#44; IL-6&#44; and iNOS in CHON-001 cells were measured by RT-qPCR&#44; and the three indices were upregulated by IL-1&#946;&#44; but TAN IIA or celecoxib TAN IIA or celecoxib significantly reversed this effect&#44; inhibiting the production of pro-inflammatory factors &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>G&#41;&#46; ELISA results were consistent with RT-qPCR results &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>H&#41;&#46;</p></span><span id="sec0017" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0024">TAN iia regulates FBXO11 expression</span><p id="para0033" class="elsevierStylePara elsevierViewall">To determine the regulation of FBXO11 by TAN IIA and its role in CHON-001 cells&#44; FBXO11 in CHON-001 cells was measured by RT-qPCR&#46; IL-1&#946; promoted FBXO11 expression&#44; while TAN IIA could eliminate the pro-inflammatory effects of IL-1&#946; on FBXO11 expression &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>A&#41;&#46; Immunoblot results showed the same trend &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>B&#41;&#46;</p><elsevierMultimedia ident="fig0002"></elsevierMultimedia></span><span id="sec0018" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0025">FBXO11 overexpression inhibits the protective effect of tan iia on apoptosis and inflammation of CHON-001 cells</span><p id="para0034" class="elsevierStylePara elsevierViewall">To verify whether FBXO11 is involved in TAN IIA&#39;s inhibition of apoptosis and inflammation of CHON-001 cells and the relationship between them&#44; pcDNA3&#46;1-FBXO11 was transfected into CHON-001 cells treated with TAN IIA&#46; RT-qPCR determined that after transfection for 24 h&#44; FBXO11 mRNA in the pcDNA3&#46;1 group and the control group had no significant change&#44; while increased in the PCDNA3&#46;1-FBXO11 group &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>A&#41;&#44; indicating successful transfection&#46;</p><elsevierMultimedia ident="fig0003"></elsevierMultimedia><p id="para0035" class="elsevierStylePara elsevierViewall">CCK-8 evaluated the effect of TAN IIA on CHON-001 cell viability after transfection with pcDNA3&#46;1-FBXO11&#44; and upregulation of FBXO11 significantly inhibited the promotion of TAN IIA on CHON-001 cell viability &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>B&#41;&#46; Flow cytometry results showed that overexpressing FBXO11 weakened the anti-apoptotic effect of TAN IIA on CHON-001 cells &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>C&#41;&#46; Immunoblot and RT-qPCR assay showed that pcDNA3&#46;1-FBXO11 increased Cleaved caspase-3 levels &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>D&#44; <a class="elsevierStyleCrossRef" href="#fig0003">3</a>E&#41;&#44; promoting apoptosis of CHON-001 cells&#46;</p><p id="para0036" class="elsevierStylePara elsevierViewall">RT-qPCR detected that overexpression of FBXO11 significantly increased TNF-&#945;&#44; IL-6&#44; and iNOS mRNA&#44; and inhibited the anti-inflammatory effect of TAN IIA on CHON-001 cells &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>F&#41;&#46; In addition&#44; ELISA also found consistent results&#44; indicating that upregulation of FBXO11 promoted TNF-&#945;&#44; IL-6&#44; and iNOS contents &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>G&#41;&#46;</p></span><span id="sec0019" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0026">FBXO11 activates PI3K&#47;AKT and nf-&#954;b pathways</span><p id="para0037" class="elsevierStylePara elsevierViewall">According to the present results&#44; TAN IIA inhibits IL-1&#946;-induced apoptosis of CHON-001 chondrocytes by down-regulating FBXO11 expression&#46; To further investigate the relationship between FBXO11 and PI3K&#47;AKT and NF-&#954;B pathways&#44; immunoblot analysis was performed to detect the effect of transfection of pcDNA3&#46;1-FBXO11 on the expression level of related proteins in PI3K&#47;AKT and NF-&#954;B pathways&#46; FBXO11 overexpression upregulated p-PI3K&#44; p-AKT&#44; and p-p65 in CHON-001 cells &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0004"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0027">Suppressing PI3K&#47;AKT and nf-&#954;b pathways protects against apoptosis and inflammation of CHON-001 cells</span><p id="para0038" class="elsevierStylePara elsevierViewall">To investigate the potential involvement of the PI3K&#47;AKT and NF-&#954;B pathways in the effects of TAN IIA on apoptosis and inflammation in CHON-001 cells&#44; subsequent to TAN IIA pretreatment&#44; the PI3K&#47;AKT pathway inhibitor LY294002 or the NF-&#954;B pathway inhibitor PDTC was introduced to the CHON-001 cells&#46;</p><p id="para0039" class="elsevierStylePara elsevierViewall">The effect of PI3K&#47;AKT and NF-&#954;B signaling pathway inhibitors on TAN IIA&#39;s promotion of CHON-001 cell viability was investigated by CCK-8 assay&#44; and the results showed that LY294002 and PDTC promoted the protective effect of TAN IIA on CHON-001 cell apoptosis &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>A&#41;&#46; Flow cytometry found that LY294002 and PDTC inhibited CHON-001 cell apoptosis and promoted the anti-apoptotic effect of TAN IIA &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>B&#41;&#46; In addition&#44; RT-qPCR and immunoblot analysis showed that LY294002 and PDTC reduced Cleaved caspase-3 expressions &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>C&#44; <a class="elsevierStyleCrossRef" href="#fig0005">5</a>D&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="para0040" class="elsevierStylePara elsevierViewall">RT-qPCR showed that after treatment with LY294002 or PDTC&#44; TNF-&#945;&#44; IL-6 and iNOS mRNA was decreased&#44; which promoted the anti-inflammatory effect of TAN IIA on IL-1&#946;-induced CHON-001 cells &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>E&#41;&#46; In addition&#44; ELISA assay showed that TNF-&#945;&#44; IL-6 and iNOS contents were inhibited by LY294002 or PDTC treatment &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>F&#41;&#46;</p></span><span id="sec0021" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0028">TAN iia treatment improves apoptosis and inflammation of chondrocytes in oa rats</span><p id="para0041" class="elsevierStylePara elsevierViewall">TAN IIA in OA was further studied by establishing a rat model of OA <span class="elsevierStyleItalic">in vivo</span>&#46; The OA model was established by surgical transection of the anterior cruciate ligament of the right knee&#44; and the rats were injected intraperitoneally once a day with either 50 mg&#47;kg or 150 mg&#47;kg TAN IIA&#46; The rats were euthanized after 7-weeks&#44; and tissue samples were collected&#46;</p><p id="para0042" class="elsevierStylePara elsevierViewall">To evaluate the effect of TAN IIA on cartilage degeneration and osteophyte formation in ACLT rats&#44; HE-staining was used for histological analysis&#46; HE-staining showed that articular cartilage was damaged and destroyed&#44; and chondrocytes were reduced in OA rats&#46; TAN IIA or celecoxib improved cartilage injury and delayed OA progression in OA rats &#40;<a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 6</a>A&#41;&#46; TUNEL staining measured apoptosis in rat cartilage tissue samples&#44; and the percentage of apoptosis was significantly higher in OA rats&#44; while TAN IIA reduced apoptosis levels in a dose-dependent manner &#40;<a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 6</a>B&#41;&#46; To verify the mechanism by which TAN IIA inhibited chondrocyte apoptosis in the treatment of OA by regulating FBXO11&#44; expression levels of Cleaved caspase-3&#44; were measured&#46; IHC staining determined that TAN IIA reduced Cleaved caspase-3 and FBXO11 intensity in the OA cartilage &#40;Supplementary Fig&#46; 1A&#41;&#46; RT-qPCR and immunoblot assay were consistent with IHC results&#44; and these markers were significantly increased after ACLT surgery&#44; and TAN IIA significantly decreased Cleaved caspase-3 and FBXO11 expression &#40;Supplementary Fig&#46; 1B&#44; 1C&#41;&#46;</p><elsevierMultimedia ident="fig0006"></elsevierMultimedia><p id="para0043" class="elsevierStylePara elsevierViewall">To verify the effect of TAN IIA treatment on OA synovial inflammation&#44; the effect of TAN IIA on OA rat chondrocyte inflammation was evaluated by ELISA experiment&#44; and the levels of TNF-&#945;&#44; IL-6&#44; and iNOS in OA rat tissues were detected&#46; After TAN IIA treatment&#44; TNF-&#945;&#44; IL-6&#44; and iNOS in OA rat chondrocytes were significantly decreased&#44; indicating that TAN IIA had an anti-inflammatory effect on OA rat chondrocytes &#40;<a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 6</a>C&#41;&#46;</p></span></span><span id="sec0022" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0029">Discussion</span><p id="para0044" class="elsevierStylePara elsevierViewall">OA progression is attributed to apoptosis and inflammation of a large number of chondrocytes&#44; which leads to the degeneration of cartilage and thickening of subchondral bone&#46;<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> Current OA treatment strategies to relieve pain symptoms are limited&#44; and although medications can be used to relieve pain&#44; serious side effects often occur&#46; TAN IIA is a phytochemical that has anti-apoptotic&#44; anti-inflammatory bioactivity&#44; and research on its role in OA therapy remains limited&#46; This study demonstrated that TAN IIA inhibits PI3K&#47;Akt and NF-&#954;B pathways by regulating FBXO11 expression&#44; thereby alleviating apoptosis and inflammation of OA chondrocytes&#46;</p><p id="para0045" class="elsevierStylePara elsevierViewall">The induction of OA is attributed to the release of inflammatory cytokines&#44; with IL-1&#946; playing a significant role in disrupting the typical structure and function of chondrocytes&#46; This disruption leads to chondrocyte apoptosis&#44; degradation of chondrocyte Extracellular Matrix &#40;ECM&#41;&#44; involvement in synovial inflammatory lesions&#44; and impact on bone metabolism&#46; Moreover&#44; the ACLT rat model is widely recognized as the standard OA model and has been extensively employed in numerous research studies&#46;<a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a> Therefore&#44; in this study&#44; IL-1&#946; was used to induce CHON-001 cells to establish an inflammatory environment <span class="elsevierStyleItalic">in vitro</span>&#46; ACLT rat models were used to simulate OA progression <span class="elsevierStyleItalic">in vivo</span>&#46;</p><p id="para0046" class="elsevierStylePara elsevierViewall">There are several therapeutic effects of Tan IIA&#44; a compound isolated from Salvia miltiorrhiza&#44; including pro-apoptotic and anti-inflammatory actions&#46; TAN IIA alleviates inflammation&#44; oxidative stress&#44; and apoptosis induced by mouse protocells by inhibiting the PI3K&#47;Akt&#47;FoxO1 pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0028"><span class="elsevierStyleSup">28</span></a> and TAN IIA inhibits apoptosis in cirrhotic rat models by activating Akt and inhibiting p38 MAPK&#46;<a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a> Therefore&#44; Tan IIA is feasible in OA therapeutic applications&#46; To test this hypothesis&#44; IL-1&#946;-stimulated chondrocytes were treated with TAN IIA&#46; TAN IIA promoted chondrocyte proliferation and viability in a concentration-dependent manner at 0&#8210;50 &#956;M but was inhibited by TAN IIA at 100&#8210;150 &#956;M&#46; This was demonstrated by histomorphologic analysis of the TAN IIA group compared with the control group and by immunohistochemical analysis of Cleaved Caspase-3 expression&#46; In a previous study&#44;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> after treating chondrocytes with 0&#8210;50 &#956;M TAN IIA for 72 h&#44; 0&#8210;20 &#956;M TAM IIA showed no toxicity&#44; and when the concentration of Tan IIA exceeded 40 &#956;M&#44; it produced cytotoxicity to chondrocytes&#46; In this study&#44; 0&#8210;150 &#956;M TAN IIA was treated for 48 h&#44; and the results showed that there was no cytotoxicity when TAN IIA concentration was less than 100 &#956;M&#44; and 100&#8210;150 &#956;M TAN IIA significantly reduced the viability of chondrocytes&#46; Therefore&#44; it is speculated that the effect of TAN IIA on chondrocytes is closely related to the concentration level&#44; and further studies are still needed to clarify&#46; Importantly&#44; 10 or 20 &#956;M TAN IIA inhibited 20 ng&#47;mL TNF-&#945;-induced apoptosis and inflammatory cytokine production&#46; In addition&#44; 1 &#956;M TAN IIA derivative &#40;sodium TAN IIA sulfonate&#44; STS&#41; can reduce apoptosis and inflammation of chondrocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a> These studies show that TAN IIA has proven anti-apoptotic and anti-inflammatory effects despite the different concentrations of action of TAN IIA and its derivatives&#46;</p><p id="para0047" class="elsevierStylePara elsevierViewall">To further emphasize the potential of Tan IIA as a treatment for OA&#44; the therapeutic effect of this compound was verified using ACLT rat models&#46; The ACLT model has been extensively employed to elucidate OA pathogenesis and investigate potential therapeutic targets&#44; including the validation of the therapeutic efficacy of novel medications&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> Due to the poor solubility of Tan IIA&#44; studies have shown that they exhibit a strong first-pass effect after oral administration and are excreted through the liver&#46;<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a> In addition&#44; Tan IIA is easily eliminated from the bloodstream after intravenous injection&#44; so it has a short shelf life&#46; STS is the most commonly used of the drugs currently available&#46; In experimental studies&#44; STS and TAN IIA were utilized interchangeably&#59; however&#44; their distinct chemical structures resulted in dissimilar biological effects and pharmacological activities&#46; Consequently&#44; the reliability of interchangeably applying STS and TAN IIA is compromised&#46; The alteration of TAN IIA to STS not only modifies its molecular structure&#44; chemical properties&#44; and pharmacokinetics&#44; but also impacts its pharmacological activity&#46;<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a> In a previous study&#44; peritoneal injection was also used for dosing&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> Therefore&#44; TAN IIA was administered to rats by intraperitoneal injection&#46; In addition&#44; celecoxib was used as a positive control drug in this study&#46; Celecoxib was the first approved COX-2-specific inhibitor to significantly improve pain and inflammation in OA and rheumatoid arthritis&#46; Compared with non-steroidal anti-inflammatory drugs&#44; it is more safe to protect the gastrointestinal tract and can continuously relieve OA symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0032"><span class="elsevierStyleSup">32</span></a> The present results showed that celecoxib had a significant effect on the improvement of OA and reduced the inflammatory environment&#46; The symptoms of ACLT rats treated with Tan IIA were significantly reduced&#44; the level of inflammatory factors was significantly reduced&#44; and the pathological manifestations were improved&#46; More importantly&#44; low-dose TAN IIA had less anti-apoptotic and anti-inflammatory capacity than celecoxib&#44; while high-dose TAN IIA showed a greater OA improvement advantage than celecoxib&#46; At the same time&#44; the anti-inflammatory effect of TAN IIA on IL-1&#946;-stimulated chondrocytes was verified by <span class="elsevierStyleItalic">in vitro</span> experiments&#46; These data all confirm the present study&#39;s hypothesis that TAN IIA has the potential to treat OA&#46;</p><p id="para0048" class="elsevierStylePara elsevierViewall">At present&#44; studies on the FBXO11 gene mainly focus on various tumors&#44; such as renal cell carcinoma&#44; gastric cancer&#44; human B-cell lymphoma&#44; etc&#46;<a class="elsevierStyleCrossRefs" href="#bib0033"><span class="elsevierStyleSup">33-35</span></a> Other diseases related to FBXO11 gene variation include chronic otitis media&#44; vitiligo&#44; etc&#46; For the mechanism of OA&#44; FBXO11 has not been deeply studied in this respect&#46; In the present study&#44; TAN IIA protected against apoptosis and inflammation in OA by down-regulating FBXO11 expression&#46; FBXO11 was involved in apoptosis and inflammation of NT-AS1&#47;miR-582&#8211;5p&#47;FBXO11 pathway induced by CSE&#44;<a class="elsevierStyleCrossRef" href="#bib0036"><span class="elsevierStyleSup">36</span></a> and FBXO11 could regulate miR-26a to inhibit the proliferation&#44; migration&#44; and invasion of liver cancer cells&#46;<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a> In these experiments&#44; TAN IIA regulated FBXO11 and inhibited its expression in OA chondrocytes&#44; and its knockdown promoted the anti-apoptotic and anti-inflammatory effects of TAN IIA&#44; which was also verified <span class="elsevierStyleItalic">in vivo</span>&#46; FBXO11 serves as a substrate recognition component that encodes the SKP1-cullin-F-box complex&#44; responsible for the ubiquitination and subsequent degradation of substrates&#44; thereby contributing to the maintenance of genomic stability&#46; Furthermore&#44; FBXO11 assumes a regulatory role in the cell cycle by facilitating substrate degradation&#44; consequently influencing the apoptosis process&#46;<a class="elsevierStyleCrossRef" href="#bib0038"><span class="elsevierStyleSup">38</span></a> Simultaneously&#44; FBXO11 serves as a regulator of the TGF-&#946; pathway&#44; and the Jeff mutation is localized within the FBXO11 gene&#44; thereby impacting the capacity of FBXO11 to maintain the stability of p53&#46; Consequently&#44; this disruption leads to an alteration in the TGF-&#946;&#47;Smad2 signaling pathway&#44; thereby signifying the significant involvement of FBXO11 in the inflammatory process&#46;</p><p id="para0049" class="elsevierStylePara elsevierViewall">The impact of Tan IIA on the proliferation&#44; invasion&#44; and migration of tumor cells has been documented through various signaling pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0039"><span class="elsevierStyleSup">39</span></a> Nevertheless&#44; the precise molecular mechanism by which Tan IIA affects OA remains undisclosed&#46; The PI3K&#47;AKT and NF-&#954;B pathways play a crucial role in chondrocyte apoptosis and inflammation&#44;<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> and comprehending their regulation would greatly contribute to the management of OA&#46; Activation of the PI3K&#47;AKT pathway seems to be a pivotal factor in promoting proliferation and anti-apoptotic responses&#44; which are characteristic of inflammatory processes in OA tissue&#46; In the present data&#44; Tan IIA was found to block IL-1&#946;-stimulated protein phosphorylation associated with the PI3K&#47;AKT and NF-&#954;B pathways&#46; These results suggest that Tan IIA exerts anti-apoptotic and anti-inflammatory activities through PI3K&#47;AKT and NF-&#954;B pathways&#46;</p><p id="para0050" class="elsevierStylePara elsevierViewall">Combined with previous studies&#44; it is possible to improve clinical symptoms of OA with Tan IIA alone or in combination with other drugs&#46; However&#44; when applied to actual clinical treatment&#44; the oral dose and specific protective effect of TAN IIA still need to be further studied on TAN IIA in clinical practice and the detailed physiological mechanism&#46; Secondly&#44; this study focused on the effects of TAN IIA on chondrocytes and cartilage tissue&#44; excluding the effects on other related cells and tissues&#46;</p><p id="para0051" class="elsevierStylePara elsevierViewall">In brief&#44; this study investigated the effect of TAN IIA on IL-1&#946;-regulated chondrocyte apoptosis and inflammation and its potential pathways and again confirmed that IL-1&#946; stimulated chondrocyte apoptosis and inflammatory response&#44; and demonstrated that TAN IIA regulated FBXO11 expression&#44; inhibited PI3K&#47;Akt and NF-&#954;B pathway&#44; alleviated IL-1&#946;-regulated chondrocyte apoptosis and inflammation&#46; This study helps us further understand the protective effect of TAN IIA and suggests that TAN IIA may be an effective new therapeutic agent to delay OA progression&#46;</p></span><span id="sec0023" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0030">Availability of data and materials</span><p id="para0052" class="elsevierStylePara elsevierViewall">The datasets used and&#47;or analyzed during the present study are available from the corresponding author upon reasonable request&#46;</p></span><span id="sec0024" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0031">Ethics statement</span><p id="para0053" class="elsevierStylePara elsevierViewall">The present study was approved by the Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine &#40;n&#176; 2020B0633&#41; Animal Experimental Ethics Committee&#46; All procedures complied with the National Institutes of Health Guide for the Use of Laboratory Animals&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0032">Authors&#39; contributions</span><p id="para0054" class="elsevierStylePara elsevierViewall">Jin Xu designed the research study&#46; Jin Xu and Ren Ding performed the research&#46; Xiao Cheng Zhi and Yun Hui Zhang provided help and advice&#46; Xiao Cheng Zhi and Yun Hui Zhang analyzed the data&#46; Jin Xu wrote the manuscript&#46; Jin Xu and Ren Ding reviewed and edited the manuscript&#46; All authors contributed to editorial changes in the manuscript&#46; All authors read and approved the final manuscript&#46;</p></span><span id="sec0026" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0033">Funding</span><p id="para0055" class="elsevierStylePara elsevierViewall">Excellent Young Medical Talents Training Program of Shanghai Baoshan Hospital of Integrated Chinese and Western Medicine &#40;n&#176; 2021BY001&#41;</p></span></span>"
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          "titulo" => "Materials and methods"
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              "titulo" => "TAN iia inhibits IL-1&#946; from inducing apoptosis and inflammation in CHON-001 cells"
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              "titulo" => "TAN iia regulates FBXO11 expression"
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              "titulo" => "FBXO11 overexpression inhibits the protective effect of tan iia on apoptosis and inflammation of CHON-001 cells"
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              "titulo" => "FBXO11 activates PI3K&#47;AKT and nf-&#954;b pathways"
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              "titulo" => "Suppressing PI3K&#47;AKT and nf-&#954;b pathways protects against apoptosis and inflammation of CHON-001 cells"
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              "titulo" => "TAN iia treatment improves apoptosis and inflammation of chondrocytes in oa rats"
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            2 => "Tanshinone iia"
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    "highlights" => array:2 [
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      "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara008" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001"><span class="elsevierStyleLabel">&#8226;</span><p id="para0001" class="elsevierStylePara elsevierViewall">TAN IIA inhibits IL-1&#946; from inducing apoptosis and inflammation in CHON-001 cells&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0002"><span class="elsevierStyleLabel">&#8226;</span><p id="para0002" class="elsevierStylePara elsevierViewall">FBXO11 overexpression inhibits the protective effect of TAN IIA on apoptosis and inflammation of CHON-001 cells&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0003"><span class="elsevierStyleLabel">&#8226;</span><p id="para0003" class="elsevierStylePara elsevierViewall">Suppressing PI3K&#47;AKT and NF-&#954;B pathways protects against apoptosis and inflammation of CHON-001 cells&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0004"><span class="elsevierStyleLabel">&#8226;</span><p id="para0004" class="elsevierStylePara elsevierViewall">TAN IIA treatment improves apoptosis and inflammation of chondrocytes in OA rats&#46;</p></li></ul></p></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abss0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Objective</span><p id="spara009" class="elsevierStyleSimplePara elsevierViewall">This study explored the pharmacological mechanism of Tanshinone IIA &#40;TAN IIA&#41; in the treatment of Osteoarthritis &#40;OA&#41;&#44; which provided a certain reference for further research and clinical application of Tan IIA in OA&#46;</p></span> <span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Methods</span><p id="spara010" class="elsevierStyleSimplePara elsevierViewall">CHON-001 cells were stimulated with 10 &#956;g&#47;mL IL-1&#946; for 48 h and treated with 10 &#956;M TAN IIA for 48 h&#46; Cellular viability and apoptosis were evaluated by CCK-8 assay and flow cytometry&#44; and Cleaved caspase-3 was measured by Immunoblot assay and RT-qPCR&#46; TNF-&#945;&#44; IL-6&#44; and iNOS in CHON-001 cells were determined by RT-qPCR and ELISA&#46; To further verify the effect of TAN IIA on OA&#44; a rat model of OA <span class="elsevierStyleItalic">in vivo</span> was established by right anterior cruciate ligament transection&#46; TAN IIA was administered at 50 mg&#47;kg or 150 mg&#47;kg for 7 weeks&#46; The degree of cartilage destruction in OA rats was observed by TUNEL and HE staining&#46; Cleaved caspase-3 and FBXO11 were measured by immunohistochemical staining&#44; RT-qPCR&#44; and Immunoblot&#46; TNF-&#945;&#44; IL-6&#44; and iNOS in chondrocytes of OA rats were detected by ELISA&#46;</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Results</span><p id="spara011" class="elsevierStyleSimplePara elsevierViewall">IL-1&#946; stimulated CHON-001 cell apoptosis and inflammation&#44; and TAN IIA had anti-apoptosis and anti-inflammatory effects on IL-1&#946;-regulated CHON-001 cells&#46; TAN IIA down-regulated FBXO11 and inhibited PI3K&#47;AKT and NF-&#954;B pathways&#44; thereby alleviating apoptotic and inflammatory reactions in CHON-001 cells under IL-1&#946; treatment&#46; Moreover&#44; TAN IIA treatment improved chondrocyte apoptosis and inflammations in OA rats&#46;</p></span> <span id="abss0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Conclusion</span><p id="spara012" class="elsevierStyleSimplePara elsevierViewall">TAN IIA inhibits PI3K&#47;Akt and NF-&#954;B pathways by down-regulating FBXO11 expression&#44; alleviates chondrocyte apoptosis and inflammation&#44; and delays the progression of OA&#46;</p></span>"
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