The Study of PIK3CA Hotspot Mutations and Co-Occurring with EGFR, KRAS, and TP53 Mutations in Non-Small Cell Lung Cancer.

Objective: PIK3CA-mutant non-small-cell lung cancer (NSCLC) is associated with other genetic mutations and may influence treatment strategies and clinical outcomes. We aimed to characterize PIK3CA mutations co-occurring with several major driver mutations using data from published cohorts and our medical center. Materials and Methods: We analyzed NSCLC patients harboring PIK3CA mutations from The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering (MSK) databases and retrospectively identified NSCLC patients with PIK3CA-mutants at a single medical center from our electronic records. The Log rank test was used to determine the association between PIK3CA mutations and overall survival (OS) in NSCLC patients. Results: Common hotspot mutations in PIK3CA were found in exon 9 (c.1633G > A, E545K, and c.1624G > A, E542K) and exon 20 (c.3140A > G, H1047R) in all cohorts. Co-occurring mutations of PIK3CA with EGFR, KRAS, and TP53 have been frequently observed in patients with NSCLC, with different percentages in these datasets generated by different background. PIK3CA mutations were observed to be significantly associated with poor OS in lung adenocarcinomas patients in the MSKCC cohort (hazard ratio [HR] = 0.519, 95% confidence interval [CI] = 0.301-0.896; P <0.05). Conclusion: PIK3CA co-occurring mutations in other genes may represent distinct subsets of NSCLC. Further elucidation of the roles of PIK3CA hotspot mutations combined with other driver mutations, including EGFR and KRAS, is needed to guide effective treatment in patients with advanced NSCLC.

Swertianin Promotes Anti-Tumor activity by facilitating Macrophage M1 polarization via STING signaling.

To investigate the mechanism by which swertiamarin (swertianin, SWE) regulates the polarization of tumor microenvironment-associated macrophages to M1 phenotype, thereby exerting anti-tumor effects.SWE promoted the formation of M1 cells and increased the proportion of CD86 + cells in both RAW264.7 and primary monocyte-derived macrophages, while activating the STING-NF-κB pathway. When STING or P65 was knocked out, the effects of SWE were antagonized, inhibiting the formation of CD86 + M1 cells. At the animal level, SWE inhibited tumor growth, activated STING-NF-κB, and promoted the formation of CD86 + cells. STING-KO inhibited the effects of SWE.SWE can activate the STING-NF-κB signal to promote macrophage M1 polarization, playing an anti-tumor role.

Exploration of novel human neutrophil elastase inhibitors from natural compounds: Virtual screening, in vitro, molecular dynamics simulation and in vivo study.

BACKGROUND: Human neutrophil elastase (HNE) is an important contributor to lung diseases such as acute lung injury (ALI) or acute respiratory distress syndrome. Therefore, this study aimed to identify natural HNE inhibitors with anti-inflammatory activity through machine learning algorithms, in vitro assays, molecular dynamic simulation, and an in vivo ALI assay. METHODS: Based on the optimized Discovery Studio two-dimensional molecular descriptors, combined with different molecular fingerprints, six machine learning models were established using the Naïve Bayesian (NB) method to identify HNE inhibitors. Subsequently, the optimal model was utilized to screen 6925 drug-like compounds obtained from the Traditional Chinese Medicine Systems Pharmacy Database and Analysis Platform (TCMSP), followed by ADMET analysis. Finally, 10 compounds with reported anti-inflammatory activity were selected to determine their inhibitory activities against HNE in vitro, and the compounds with the best activity were selected for a 100 ns molecular dynamics simulation and its anti-inflammatory effect was evaluated using Poly (I:C)-induced ALI model. RESULTS: The evaluation of the in vitro HNE inhibition efficiency of the 10 selected compounds showed that the flavonoid tricetin had the strongest inhibitory effect on HNE. The molecular dynamics simulation indicated that the binding of tricetin to HNE was relatively stable throughout the simulation. Importantly, in vivo experiments indicated that tricetin treatment substantially improved the Poly (I:C)-induced ALI. CONCLUSION: The proposed NB model was proved valuable for exploring novel HNE inhibitors, and natural tricetin was screened out as a novel HNE inhibitor, which was confirmed by in vitro and in vivo assays for its inhibitory activities.

[Retracted] MicroRNA­642a­5p inhibits colon cancer cell migration and invasion by targeting collagen type I α1.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the cell invasion assay data shown in Fig. 6B on p. 940, and western blot data featured in Fig. 7B on p. 942, had already appeared in previously published articles written by different authors at different research institutes. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 45: 933­944, 2021; DOI: 10.3892/or.2020.7905].

Crosstalk between circBMI1 and miR-338-5p/ID4 inhibits AML progression.

BMI1 Polycomb Ring Finger Proto-Oncogene (BMI1) is involved in the pathogenesis of different cancers, including acute myeloid leukemia (AML). However, the role of the circular RNA of BMI1 (circBMI1) has not been studied. Our study aimed to investigate the role and mechanism of circBMI1 in AML. circBMI1 was significantly decreased in bone marrow mononuclear cells aspirated from patients with AML. Receiver operating characteristic curve analysis showed that circBMI1 could distinguish patients with AML from controls. By overexpressing and knocking down circBMI1 in HL-60 cells, we found that circBMI1 inhibited cell proliferation, promoted apoptosis, and increased chemotherapeutic drug sensitivity in AML. Experiments using severe combined immune-deficient mice and circBMI1 transgenic mice showed that mice with circBMI1 overexpression had lower white blood cell counts, which suggested less severe AML invasion. RNA immunoprecipitation and dual-luciferase reporter assay revealed binding sites among circBMI1, miR-338-5p, and inhibitor of DNA binding 4 (ID4). Rescue experiments proved that circBMI1 inhibited AML progression by binding to miR-338-5p, which affected the expression of ID4. By coculturing exosomes extracted from circBMI1-HL-60 and small interfering circBMI1-HL-60 cells with HL-60 cells, we found that exosomes from circBMI1-HL-60 cells showed tumor suppressive effects, namely inhibiting HL-60 proliferation, promoting apoptosis, and increasing chemotherapeutic drug sensitivity. Exosomes from small interfering circBMI1-HL-60 cells showed the opposite effects. circBMI1 may act as an exosome-dependent tumor inhibitor. circBMI1, a potential biomarker for clinical diagnosis, acts as a tumor suppressor in AML by regulating miR-338-5p/ID4 and might affect the pathogenesis of AML by exosome secretion.

High-throughput single-cell mass spectrometry enables metabolic network analysis by resolving phospholipid C[double bond, length as m-dash]C isomers.

Single-cell mass spectrometry (MS) is an essential technology for sensitive and multiplexed analysis of metabolites and lipids for cell phenotyping and pathway studies. However, the structural elucidation of lipids from single cells remains a challenge, especially in the high-throughput scenario. Technically, there is a contradiction between the inadequate sample amount (i.e. a single cell, 0.5-20 pL) for replicate or multiple analysis, on the one hand, and the high metabolite coverage and multidimensional structure analysis that needs to be performed for each single cell, on the other hand. Here, we have developed a high-throughput single-cell MS platform that can perform both lipid profiling and lipid carbon-carbon double bond (C[double bond, length as m-dash]C) location isomer resolution analysis, aided by C[double bond, length as m-dash]C activation in unsaturated lipids by the Paternò-Büchi (PB) reaction and tandem MS, termed single-cell structural lipidomics analysis. The method can achieve a single-cell analysis throughput of 51 cells per minute. A total of 145 lipids were structurally characterized at the subclass level, of which the relative abundance of 17 isomeric lipids differing in the location of C[double bond, length as m-dash]C from 5 lipid precursors was determined. While cell-to-cell variations in MS1-based lipid profiling can be large, an advantage of quantifying lipid C[double bond, length as m-dash]C location isomers is the significantly improved quantitation accuracy. For example, the relative standard deviations (RSDs) of the relative amounts of PC 34:1 C[double bond, length as m-dash]C position isomers in MDA-MB-468 cells are half smaller than those measured for PC 34:1 as a whole by MS1 abundance profiling. Taken together, the developed method can be effectively used for in-depth structural lipid metabolism network analysis by high-throughput analysis of 142 MDA-MB-468 human breast cancer cells.

Structure-based discovery of potent CARM1 inhibitors for colorectal cancer therapy.

Coactivator-associated arginine methyltransferase 1 (CARM1) plays an important role in cell proliferation and gene expression, and is highly expressed in a variety of tumor tissues. Guided by our previous reported structure of DCPR049_12, we focused on designing and evaluating selective CARM1 inhibitors, resulting in the identification of compound 11f as a promising lead candidate. Compound 11f displayed potent inhibition of CARM1 (IC50 = 9 nM). Comprehensive evaluations, including in vitro metabolic stability assessments, molecular modelling, cellular studies, and in vivo anti-tumor studies, confirmed that it induced cancer cell apoptosis and specifically inhibited CARM1's methylation function. Notably, compound 11f displayed significant anti-proliferative effects on colorectal cancer cell lines, showcasing its potential for targeted therapies against CARM1-related diseases. This study provides valuable insights for the future development of specific and effective CARM1 inhibitors.

1-Ethoxycarbonyl-beta-carboline inhibits the M2 polarization of tumor-associated macrophages: A study based on network pharmacology and molecular docking analyses.

AIM: Through network pharmacology, molecular docking, molecular dynamics in combination with experimentation, we explored the mechanism whereby 1-ethoxycarbonyl-beta-carboline (EBC) regulates the M2 polarization of tumor-associated macrophages. METHODS: Network pharmacology was adopted for analyzing the targets and signaling pathways related to the M2 polarization of EBC-macrophages, small molecular-protein docking was employed to analyze the possibility of EBC bonding to related protein, and molecular dynamics was introduced to analyze the binding energy between EBC and HDAC2. The M2 polarization of RAW264.7 macrophages was triggered in vitro by IL-4. After EBC intervention, the expressions of M1/M2 polarization-related cytokines were detected, and the mechanism of EBC action was explored in HDAC2-knockout RAW264.7 macrophages. A tumor-bearing mouse model was established in vitro to find the impact of EBC on tumor-associated M2 macrophages. RESULTS: As revealed by the network pharmacology, molecular docking and molecular dynamics analyses, EBC was associated with 51 proteins, including HDAC2, NF-κB and HDAC4. Molecular docking and dynamics analyses suggested that HDAC2 was the main target of EBC. In vitro experiments discovered that EBC could hinder the M2 polarization of RAW264.7 macrophages, which exerted insignificant effect on the M1-associated cytokines, but could lower the levels of M2-associated cytokines. After knocking out HDAC2, EBC could not further inhibit the M2 polarization of macrophages. At the mouse level, EBC could hinder the tumor growth and the tissue levels of M2 macrophages, whose effect was associated with HDAC2. CONCLUSION: Our study combining multiple methods finds that EBC inhibits the HDAC2-mediated M2 polarization of macrophages, thereby playing an anti-tumor role.

Ganodermanontriol regulates tumor-associated M2 macrophage polarization in gastric cancer.

AIM: We focused on investigating the role and mechanism of ganodermanontriol (GAN) in regulating the M2 polarization of tumor-associated macrophages in the gastric cancer microenvironment. METHODS: M2 polarization of RAW264.7 macrophages was induced by IL-4 or co-culture with MFC, and the expression levels of M1 macrophage markers (TNF-α, IFN-γ, IL-1ß) and M2 macrophage markers (IL-10, TGF-ß, Arg-1) were detected by enzyme-linked immunosorbed assay (ELISA). The protein expression was assayed by Western-Blotting. For in vitro experiments, a tumor-bearing mouse model was established, with which the CD206 level was detected by histochemistry, and the binding mode between GAN and STAT6 was simulated through molecular dynamics. RESULTS: Both IL-4 and MFC could induce the M2 polarization of macrophages. GAN could inhibit such polarization, which produced unobvious effects on M1 markers, but could suppress the levels of M2 markers. GAN could inhibit the phosphorylated expression of STAT6, and M2 macrophages treated by it had a weakened ability to promote malignant behavior of MFC. According to the results of in vitro experiments, GAN could inhibit tumor growth, suppress the tissue infiltration of CD206 cells, and inhibit the phosphorylated expression of STAT6. CONCLUSION: Our results show that GAN can inhibit the M2 macrophage polarization in gastric cancer microenvironment, whose mechanism of action is associated with the regulation of STAT6 phosphorylation.

Polystyrene microplastics exposure aggravates acute liver injury by promoting Kupffer cell pyroptosis.

OBJECTIVE: To investigate the long-term effects of polystyrene (PS) exposure on acute liver injury. METHODS: The carbon tetrachloride-induced acute injury mouse model was subjected to long-term PS exposure. Pyroptosis was inhibited by knocking out Gsdmd in mice or treating with the Gsdmd inhibitor necrosulfonamide (NSA) to evaluate the effect of PS on liver injury. Kupffer cells were used as a cellular model to examine the effects of PS on cell pyroptosis, lactate dehydrogenase release rate, structural integrity (propidium iodide staining), and inflammatory factor levels. RESULTS: In mice, PS exposure exacerbated acute liver injury, which was mitigated upon Gsdmd knockout (KO) or NSA treatment along with the downregulation of tissue inflammatory response. In vitro studies demonstrated that PS promoted Kupffer cell pyroptosis, which was suppressed upon Gsdmd KO or NSA treatment along with the alleviation of inflammation. CONCLUSION: These results suggest that long-term PS exposure exacerbates acute liver injury by promoting Kupffer cell pyroptosis, which is one of the hepatotoxic mechanisms of PS.

Meniscal fibrocartilage regeneration inspired by meniscal maturational and regenerative process.

Meniscus is a complex and crucial fibrocartilaginous tissue within the knee joint. Meniscal regeneration remains to be a scientific and translational challenge. We clarified that mesenchymal stem cells (MSCs) participated in meniscal maturation and regeneration using MSC-tracing transgenic mice model. Here, inspired by meniscal natural maturational and regenerative process, we developed an effective and translational strategy to facilitate meniscal regeneration by three-dimensionally printing biomimetic meniscal scaffold combining autologous synovium transplant, which contained abundant intrinsic MSCs. We verified that this facilitated anisotropic meniscus-like tissue regeneration and protected cartilage from degeneration in large animal model. Mechanistically, the biomechanics and matrix stiffness up-regulated Piezo1 expression, facilitating concerted activation of calcineurin and NFATc1, further activated YAP-pSmad2/3-SOX9 axis, and consequently facilitated fibrochondrogenesis of MSCs during meniscal regeneration. In addition, Piezo1 induced by biomechanics and matrix stiffness up-regulated collagen cross-link enzyme expression, which catalyzed collagen cross-link and thereby enhanced mechanical properties of regenerated tissue.

Enhanced osteochondral repair with hyaline cartilage formation using an extracellular matrix-inspired natural scaffold.

Osteochondral defects pose a great challenge and a satisfactory strategy for their repair has yet to be identified. In particular, poor repair could result in the generation of fibrous cartilage and subchondral bone, causing the degeneration of osteochondral tissue and eventually leading to repair failure. Herein, taking inspiration from the chemical elements inherent in the natural extracellular matrix (ECM), we proposed a novel ECM-mimicking scaffold composed of natural polysaccharides and polypeptides for osteochondral repair. By meticulously modifying natural biopolymers to form reversible guest-host and rigid covalent networks, the scaffold not only exhibited outstanding biocompatibility, cell adaptability, and biodegradability, but also had excellent mechanical properties that can cater to the environment of osteochondral tissue. Additionally, benefiting from the drug-loading group, chondrogenic and osteogenic drugs could be precisely integrated into the specific zone of the scaffold, providing a tissue-specific microenvironment to facilitate bone and cartilage differentiation. In rabbit osteochondral defects, the ECM-inspired scaffold not only showed a strong capacity to promote hyaline cartilage formation with typical lacuna structure, sufficient mechanical strength, good elasticity, and cartilage-specific ECM deposition, but also accelerated the regeneration of quality subchondral bone with high bone mineralization density. Furthermore, the new cartilage and subchondral bone were heterogeneous, a trait that is typical of the natural landscape, reflecting the gradual progression from cartilage to subchondral bone. These results suggest the potential value of this bioinspired osteochondral scaffold for clinical applications.

3D Printing of Microenvironment-Specific Bioinspired and Exosome-Reinforced Hydrogel Scaffolds for Efficient Cartilage and Subchondral Bone Regeneration.

In clinical practice, repairing osteochondral defects presents a challenge due to the varying biological properties of articular cartilages and subchondral bones. Thus, elucidating how spatial microenvironment-specific biomimetic scaffolds can be used to simultaneously regenerate osteochondral tissue is an important research topic. Herein, a novel bioinspired double-network hydrogel scaffold produced via 3D printing with tissue-specific decellularized extracellular matrix (dECM) and human adipose mesenchymal stem cell (MSC)-derived exosomes is described. The bionic hydrogel scaffolds promote rat bone marrow MSC attachment, spread, migration, proliferation, and chondrogenic and osteogenic differentiation in vitro, as determined based on the sustained release of bioactive exosomes. Furthermore, the 3D-printed microenvironment-specific heterogeneous bilayer scaffolds efficiently accelerate the simultaneous regeneration of cartilage and subchondral bone tissues in a rat preclinical model. In conclusion, 3D dECM-based microenvironment-specific biomimetics encapsulated with bioactive exosomes can serve as a novel cell-free recipe for stem cell therapy when treating injured or degenerative joints. This strategy provides a promising platform for complex zonal tissue regeneration whilst holding attractive clinical translation potential.

Triterpene acid from Antrodia camphorata alleviates inflammation in acute liver injury.

This study aimed to investigate the role and mechanism of Anctin A, the Antrodia camphorata terpene component, in resisting liver injury. Network pharmacology analysis revealed that MAPK3 was the major action target of Antcin A. Furthermore, experimental research suggested that Antcin A suppressed mouse liver injury, reduced the inflammatory factor levels, and enhanced the anti-oxidative capacity. Meanwhile, it suppressed the expression of MAPK3 and the downstream NF-κB signal, while it did not significantly affect the expression of MAPK1. Based on network pharmacology method, this study discovers that the anti-liver injury effect of Antcin A is mainly related to MAPK3, and that Antcin A can suppress the activation of MAPK3 and its downstream NF-κB to inhibit mouse ALI.

Double-negative T cells regulate the progression of liver fibrosis through Th9 cells differentiation.

Our previous study found that double negative T cells (DNTs) could promote the NLRP3 activation through high expression of TNF-α, thereby leading to hepatic fibrosis progression. We focused on investigating the role and mechanism of DNTs in regulating the Th9 cells differentiation in liver fibrosis. In our results, among patients with liver fibrosis, the proportions of peripheral blood DNTs and Th9 cells were up-regulated and positively correlated. While promoting the progression of liver fibrosis in mice, DNTs could elevate the proportion of Th9 cells and activate the TNFR2-STAT5-NF-κB pathway. The use of IL-9 and TNF-α monoclonal antibodies (mAbs) inhibited the effect of DNTs and lowered the proportion of Th9 cells in tissues. In vitro experiments showed that DNTs could promote the Th9 cells differentiation of Naive T cells, while TNF-α mAbs could inhibit such effect of DNTs to lower the proportion of Th9 cells. We found that DNTs can activate TNFR2-STAT5-NF-κB pathway by secreting TNF-α, thereby promoting the Th9 Cells differentiation to facilitate the progression of liver fibrosis. There is interaction between DNTs and Th9 cells.

Imidacloprid activates Kupffer cells pyroptosis to induce liver injury in mice via P2X7.

AIM: This work aimed to investigate the mechanism by which the environmental poison imidacloprid (IMI) induced liver injury. METHODS: First of all, IMI at the ED50 = 100 µM was added to treat mouse liver Kupffer cells, thereafter, the occurrence of pyroptosis was detected by flow cytometry (FCM), transmission electron microscope (TEM), immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), RT-QPCT and Western-Blot (WB) assay. Furthermore, P2X7 expression was knocked out in Kupffer cells, and cells were treated with the P2X7 inhibitor, so as to observe the pyroptosis level induced by IMI after P2X7 suppression. In animal experiments, IMI was used to induce mouse liver injury, then the P2X7 inhibitor and pyroptosis inhibitor were added to treat the mice, respectively, so as to observe the effect on liver injury. RESULTS: IMI induced Kupffer cell pyroptosis, P2X7 knockout or P2X7 inhibitor treatment suppressed the effect of IMI and reduced the pyroptosis level. In animal experiments, the application of both P2X7 inhibitor and pyroptosis inhibitor decreased the cell injury level. CONCLUSION: IMI induces Kupffer cell pyroptosis via P2X7 and induce liver injury, and inhibiting the occurrence of pyroptosis can suppress the hepatotoxicity of IMI.

Environmental toxin chlorpyrifos induces liver injury by activating P53-mediated ferroptosis via GSDMD-mtROS.

AIM: We investigate the mechanism whereby chlorpyrifos (CHI), an environmental toxin, causes liver injury by inducing ferroptosis in hepatocytes. METHODS: The toxic dose (LD50 = 50 µM) of CHI for inducing AML12 injury in normal mouse hepatocytes was determined, and the ferroptosis-related indices were measured, including the levels of SOD, MDA and GSH-Px, as well as the cellular content of iron ions. JC-1 and DCFH-DA assays were employed to detect the mtROS levels, the levels of mitochondrial proteins (GSDMD, NT-GSDMD), as well as the cellular levels of ferroptosis-related proteins (P53, GPX4, MDM2, SLC7A11). We knocked out the GSDMD and P53 in AML12 and observed the CHI-induced ferroptosis of ALM12 after applying YGC063, an ROS inhibitor. In animal experiments, we explored the effect of CHI on liver injury by using conditional GSDMD-knockout mice (C57BL/6 N-GSDMDem1(flox)Cya) and ferroptosis inhibitor Fer-1. Small molecule-protein docking and Pull-down assay were employed to verify the association between CHI and GSDMD. RESULTS: We found that CHI could induce ferroptosis of AML12. CHI promoted the cleavage of GSDMD, leading to upregulation of mitochondrial NT-GSDMD expression, as well as ROS levels. P53 activation promoted the ferroptosis. Knock out of GSDMD and P53 could inhibit the CHI-induced ferroptosis, and YGC063 could also inhibit ferroptosis. In mice experiments, GSDMD knockout or Fer-1 intervention could significantly inhibit the CHI-induced liver injury. CHI promoted the cleavage of GSDMD by binding to its SER234 site. CONCLUSION: CHI can bind to GSDMD to promote its cleavage, while NT-GSDMD can open mitochondrial membrane to promote the mtROS release. Cytoplasmic upregulation of ROS levels can facilitate the P53-mediated ferroptosis. GSDMD-mtROS is the primary mechanism whereby CHI induces ferroptosis in hepatocytes.

TFAP4 promotes the progression of liver fibrosis through regulating double-negative T cell differentiation via OX40.

This work aimed to investigate the role of transcription factor TFAP4-OX40 in promoting the differentiation of double-negative T cells (DNTs). Through prediction and experimental analysis, it was discovered that TFAP4 was the transcription factor of OX40. Therefore, OX40 neutralizing antibody and TFAP4 overexpression transfection were adopted to investigate the role of TFAP4-OX40 in DNTs differentiation, and the effect of differentiated DNTs on hepatic stellate cell (HSC) activation. Moreover, the impact of TFAP4 on liver fibrosis and DNTs in liver tissue was explored using mice with myeloid specific TFAP4 knockout by TFAP4 neutralizing antibody treatment. TFAP4 is the transcription regulatory factor for OX40, which promoted OX40 transcription expression to accelerate DNTs differentiation. Treatment with OX40 neutralizing antibody suppressed DNTs differentiation, while TFAP4 overexpression promoted DNTs differentiation. DNTs produced from the TFAP4 induced differentiation promoted HSC activation. Myeloid specific TFAP4 knockout delayed the progression of liver fibrosis and decreased DNTs in tissue, while treatment with TFAP4 neutralizing antibody suppressed liver fibrosis and DNTs in liver tissue. According to our results, TFAP4 is the transcription factor of OX40, which promotes DNTs differentiation via the OX40 signal, thus promoting the progression of liver fibrosis.

Earlier and More Severe Cartilage Degeneration Occurs After Meniscal Tears in Juvenile Rabbits Compared with Adults.

OBJECTIVE: To compare the severity of cartilage degeneration after meniscal tears between juvenile and adult rabbits. DESIGN: This study included 20 juvenile rabbits (2 weeks after birth) and 20 adult rabbits (6 months after birth). Meniscal tears were prepared in the anterior horn of medial menisci of right knees. Rabbits were sacrificed at 1, 3, 6, and 12 weeks postoperatively. Cartilage degenerations in the medial femoral condyle and medial tibial plateau were evaluated macroscopically and histologically. The semiquantitative assessment of cartilage degeneration was graded by macroscopic Outerbridge scoring system and histological Osteoarthritis Research Society International (OARSI) scoring system. RESULTS: In juvenile rabbits, the morphologically intact cartilage and normal extracellular matrix architecture were observed at the first week postoperatively. Mild uneven cartilage surface and toluidine blue depletion in the medial femoral condyle were observed on histological assessment at 3 weeks postoperatively. The worsened cartilage deterioration demonstrating chondral fibrillation, prominent cell death, and glycosaminoglycan (GAG) release was observed at 6 and 12 weeks postoperatively. In adult rabbits, only mild cartilage degeneration was observed in the medial femoral condyle at 12 weeks postoperatively. The outcomes of Outerbridge and OARSI scores were consistent with the aforementioned findings in juvenile and adult rabbits. CONCLUSIONS: Our study validated that earlier and more severe cartilage degenerations were observed in juvenile rabbits after meniscal tears compared with adult rabbits. Moreover, the post-tear cartilage degeneration demonstrated regional specificity corresponded to the tear position. However, caution is warranted when extrapolating results of animal models to humans.