Murine Double Minute Research Articles

Exploration of marine natural compounds as promising MDM2 inhibitors for treating triple-negative breast cancer: insights from molecular docking, ADME/T studies, molecular dynamics simulation and MM-PBSA binding free energy calculations

Triple-negative breast cancer (TNBC), the most aggressive form of breast cancer, presents a significant mortality risk owing to its elevated potential for metastasis. The overexpression of Murine Double Minute 2 homolog (MDM2) protein, a key suppressor of tumour suppressor p53, in TNBC amplifies its growth, advancement, and invasiveness. Thus, inhibiting MDM2 protein emerges as a compelling strategy to enhance the efficacy of TNBC treatment. We aimed to identify novel potential MDM2 inhibitors from natural marine compounds, known for their distinctive chemical structures and heightened anticancer activities, utilizing molecular docking, ADME/T analysis, molecular dynamics (MD) simulations, MM-PBSA calculations, and in silico PASS predictions. A marine compound library was constructed for initial screening purpose and the molecular docking analysis revealed that two marine compounds, namely 10,11-dihydrosodwanone B and sodwanone T, exhibited significantly higher binding affinity (− 9.6 kcal/mol and − 9.1 kcal/mol, respectively) compared to the established inhibitor nutlin-3a (− 8.4 kcal/mol). ADME/T investigations were conducted to ensure the drug-likeness properties and safety of these compounds. Additionally, in silico PASS tool predicted that both compounds possess a heightened potential for anticancer activities. Molecular dynamics simulations (100 ns) and MM-PBSA calculations indicated that sodwanone T formed a relatively more stable complex and had a higher binding-free energy with MDM2, respectively. In conclusion, this research suggests sodwanone T as a promising candidate for further testing and development as an MDM2 inhibitor for potential therapeutic applications against TNBC. Nevertheless, substantial experimental and clinical investigations are necessary to enhance its applicability in clinical settings.Graphical abstract

Low-Level MDM2 Amplification by FISH: An Institutional Experience With a Diagnostic Dilemma.

Background: MD M2 (murine double minute-2) amplification via fluorescence in-situ hybridization (FISH) is the gold standard test used for confirming the diagnosis of atypical lipomatous tumor/well differentiated liposarcoma and dedifferentiated liposarcoma. It is also used as a screening test in high grade spindle cell or pleomorphic neoplasms. MDM2 FISH is considered positive for amplification when the MDM2/CEP12 ratio is greater than 2; however, a ratio between 2 and 3 is considered a "low-level" amplification and raises the possibility of a false positive result; thus, posing a diagnostic dilemma. Another molecular modality, next generation sequencing (NGS) assay, can help in such situations in confirming or excluding the M D M 2 amplification status. Confronted by a number of neoplastic specimens at our institution with "low-level" MDM2 amplification via FISH, we aimed to assess the specificity of fluorescence in situ hybridization (FISH) in such tumors by comparing their NGS assay results and determine an accurate MDM2 amplification status that further aids in diagnosis. Methods: Tumors with "low-level" MDM2 amplification via FISH, defined as MDM2/CEP12 ratio between 2 and 3, and harboring a high grade and/or pleomorphic morphology were retrospectively retrieved from our institutional archives from the last five years. The retrieved specimens were evaluated for concordant retrospective Oncomine v3 analysis. Oncomine v3 is an institutional NGS assay that covers 161 genes and assesses for DNA mutations, RNA fusions, and copy number alterations including MDM2 gene gain or amplification. The tumors with Oncomine v3 results were compared and the FISH specificity was calculated. Results: Twenty-seven high grade and/or pleomorphic tumors with "low-level" MDM2 amplification were retrieved. Eight out of twenty-seven tumors had Oncomine v3 performed on them. The tumors correlated to neoplasms from different lineage types including undifferentiated melanoma, sarcomatoid squamous cell carcinoma, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, and high-grade poorly differentiated pleomorphic neoplasm. All 8 tumors had a low-level MD M2 amplification ratio ranging between 2.09 and 2.84. Seven out of eight had no MD M2 copy number alteration. One only (leiomyosarcoma) demonstrated MD M2 copy number gain (∼5 copies) that did not qualify as amplification due to the "6 copy number" gain cutoff. TP53, CDKN2A/B, PIKC3, and PTEN alterations were the most common genetic aberrations detected by Oncomine v3. Conclusion: We demonstrated the absence of MDM2 amplification via Oncomine in all our 8 "low-level" MDM2 FISH amplification specimens confirming the FISH results as "false positive" with a corresponding FISH specificity rate of 0%. Laboratory measures and utilizing NGS assay when needed, could be implemented when encountering such problematic "low-level" MDM2 amplification specimens to avoid misdiagnosis and misuse of targeted therapy. Future studies are needed to better characterize and investigate such findings.

MDM2 interacts with PTEN to inhibit endothelial cell development and promote deep vein thrombosis via the JAK/STAT signaling pathway.

Deep vein thrombosis (DVT) is a prevalent clinical condition, which markedly affects patients' quality of life, commonly leading to post‑thrombotic syndrome. The present study aimed to elucidate the intricate interplay between murine double minute‑2 (MDM2) and phosphatase and tensin homolog (PTEN), thus shedding new light on their role in the pathogenesis of DVT. The results showed that both MDM2 and PTEN were upregulated in venous blood samples obtained from patients with DVT. However, MDM2 or PTEN knockdown markedly increased the proliferation, migration, invasion, apoptosis and angiogenesis of oxidized low‑density lipoprotein‑treated human umbilical vein endothelial cells (HUVECs). Furthermore, MDM2 silencing downregulated PTEN. The association between MDM2 and PTEN was verified through comprehensive analyses, including Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analysis and co‑immunoprecipitation assays. The effect of PTEN on DVT was evaluated by Kyoto Encyclopedia of Genes and Genomes and STRING analysis, which demonstrated that PTEN displayed an inhibitory role in the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Notably, treatment with AG‑490, an inhibitor of JAK/STAT signaling, reversed the protective effect of PTEN knockdown on the behavior of HUVECs. In summary, the results of the current study indicated that both MDM2 and PTEN were upregulated in patients with DVT. The interaction between MDM2 and PTEN was also verified, thus providing novel insights into their potential collaborative role in the development of DVT. Overall, MDM2 and PTEN may interact to inhibit endothelial cell development and promote the occurrence of DVT via inhibiting the JAK/STAT signaling pathway.

MDM2 drives resistance to Osimertinib by contextually disrupting FBW7-mediated destruction of MCL-1 protein in EGFR mutant NSCLC

BackgroundOvercoming resistance to Osimertinib in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) is clinically challenging because the underlying mechanisms are not fully understood. The murine double minute 2 (MDM2) has been extensively described as a tumor promotor in various malignancies, mainly through a negative regulatory machinery on the p53 tumor suppressor. However, the significance of MDM2 on the sensitivity to Osimertinib has not been described.MethodsOsimertinib resistant cells were generated by standard dose escalation strategy and individual resistant clones were isolated for MDM2 testing. The MDM2 and its mutant constructs (ΔPBD, ΔRING, C464A) were introduced into PC-9, HCC827 and H1975 cells and evaluated for the sensitivity to Osimertinib by MTT assay, colony formation, EdU assay and TUNEL assay. MDM2 expression in resistant cells was manipulated by pharmacological and molecular approaches, respectively. Proteins that were implicated in PI3K/Akt, MAPK/Erk and apoptosis signaling were measured by Western blot analysis. Candidate proteins that interacted with MDM2 were captured by immunoprecipitation and probed with indicated antibodies.ResultsIn comparison with parental PC-9 cells, the PC-9 OR resistant cells expressed high level of MDM2. Ectopic expression of MDM2 in PC-9, HCC827 and H1975 sensitive cells generated an Osimertinib resistant phenotype, regardless of p53 status. MDM2 promoted resistance to Osimertinib through a PI3K/Akt and MAPK/Erk-independent machinery, in contrast, MDM2 selectively stabilized MCL-1 protein to arrest Osimertinib-induced cancer cell apoptosis. Mechanistically, MDM2 acted as a E3 ligase to ubiquitinate FBW7, a well-established E3 ligase for MCL-1, at Lys412 residue, which resulted in FBW7 destruction and MCL-1 stabilization. Targeting MDM2 to augment MCL-1 protein breakdown overcame resistance to Osimertinib in vitro and in vivo. Finally, the clinical relevance of MDM2-FBW7-MCL-1 regulatory axis was validated in mouse xenograft tumor model and in NSCLC specimen.ConclusionOverexpression of MDM2 is a novel resistant mechanism to Osimertinib in EGFR mutant NSCLC. MDM2 utilizes its E3 ligase activity to provoke FBW7 destruction and sequentially leads to MCL-1 stabilization. Cancer cells with aberrant MDM2 state are refractory to apoptosis induction and elicit a resistant phenotype to Osimertinib. Therefore, targeting MDM2 would be a feasible approach to overcome resistance to Osimertinib in EGFR mutant NSCLC.

USP22 promotes gefitinib resistance and inhibits ferroptosis in non-small cell lung cancer by deubiquitination of MDM2.

The emergence of chemoresistance markedly compromised the treatment efficiency of human cancer, including non-small cell lung cancer (NSCLC). In the present study, we aimed to explore the effects of ubiquitin-specific peptidase 22 (USP22) and murine double minute 2 (MDM2) in gefitinib resistance in NSCLC. Immunohistochemistry (IHC) assay, quantitative real-time polymerase chain reaction (qRT-PCR) assay and western blot assay were carried out to determine the expression of USP22 and MDM2. Transwell assay and flow cytometry analysis were performed to evaluate cell migration and apoptosis. Cell Counting Kit-8 (CCK-8) assay was employed to assess gefitinib resistance. The phenomenon of ferroptosis was estimated by related commercial kits. The oxidized C11-BODIPY fluorescence intensity by C11-BODIPY staining. The relation between USP22 and MDM2 was analyzed by ubiquitination assay and co-immunoprecipitation (Co-IP) assay. USP22 was abnormally upregulated in NSCLC tissues and cells, and USP22 silencing markedly repressed NSCLC cell migration and facilitated apoptosis and ferroptosis. Moreover, our results indicated that ferroptosis could enhance the suppressive effect of gefitinib on NSCLC cells. Besides, USP22 overexpression enhanced gefitinib resistance and ferroptosis protection in NSCLC cells. Mechanically, USP22 stabilized MDM2 and regulated MDM2 expression through deubiquitination of MDM2. MDM2 deficiency partially restored the effects of USP22 on gefitinib resistance and ferroptosis in NSCLC cells. Of note, we validated the promotional effect of USP22 on gefitinib resistance in NSCLC in vivo through establishing the murine xenograft model. USP22/MDM2 promoted gefitinib resistance and inhibited ferroptosis in NSCLC, which might offer a novel strategy for overcoming gefitinib resistance in NSCLC.

Design of Murine Double Minute 2 Proteolysis Targeting Chimera Degraders with a Built-In Tumor-Targeting Ability.

Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules to induce the proteasomal degradation of target proteins. Currently, there are no tumor-targeting PROTACs for modulating oncogenic murine double minute 2 (MDM2). AS1411 is a tumor-targeting aptamer that specifically recognizes nucleolin (NCL) overexpressed on the surface of tumor cells. We recently repurposed AS1411 as an MDM2 recruiter since it could form an NCL-bridged ternary complex with MDM2. In this study, we design a PROTAC molecule AS1411-VH032 via conjugating AS1411 with a recruiter of von Hippel-Lindau (VHL) ligase VH032. AS1411-VH032 facilitates tumor-selective degradation of MDM2, leading to tumor shrinkage with no detectable toxicity. Besides being a molecular target, MDM2 also serves as an E3 ligase harnessed by PROTACs. Thus, we developed an AS1411-based homo-PROTAC homoAS1411, which induces tumor-specific suicide degradation of MDM2 and prevents tumor progression without causing side effects. Both AS1411-VH032 and homoAS1411 are promising MDM2 degraders with built-in tumor-targeting ability, which balances the antitumor efficacy with a favorable safety profile.

A structure-based virtual screening identifies a novel MDM2 antagonist in the activation of the p53 signaling and inhibition of tumor growth.

p53, a tumor suppressor protein, has a vital role in the regulation of the cell cycle, apoptosis, and DNA damage repair. The degradation of p53 is predominantly controlled by the murine double minute 2 (MDM2) protein, a ubiquitin E3 ligase. The overexpression or amplification of MDM2 is commonly observed in various human cancers bearing wild-type p53 alleles, leading to the rapid degradation of the p53 protein and the attenuation of p53 tumor suppression functions. Thus, a major effort in p53-based cancer therapy has been to research MDM2 antagonists that specifically stabilize and activate p53, leading to the suppression of tumor growth. However, despite numerous efforts to develop MDM2 antagonists, to date they have failed to reach clinical use, largely because of the cytotoxicity associated with these small molecules. This study used our newly designed structure-based virtual screening approach on a commercial compound library to identify a novel compound, CGMA-Q18, which directly binds to MDM2, leading to the activation of p53, the induction of apoptosis, and cell cycle arrest in cancer cells. Notably, CGMA-Q18 significantly inhibited tumor xenograft growth in nude mice without observable toxicity. These findings highlight our useful virtual screening protocol and CGMA-Q18 as a putative MDM2 antagonist.

Impaired SUMOylation of FoxA1 promotes nonalcoholic fatty liver disease through down-regulation of Sirt6

Abnormal SUMOylation is implicated in non-alcoholic fatty liver disease (NAFLD) progression. Forkhead box protein A1 (FoxA1) has been shown to protect liver from steatosis, which was down-regulated in NAFLD. This study elucidated the role of FoxA1 deSUMOylation in NAFLD. NAFLD models were established in high-fat diet (HFD)-induced mice and palmitate acid (PAL)-treated hepatocytes. Hepatic steatosis was evaluated by biochemical and histological methods. Lipid droplet formation was determined by BODIPY and Oil red O staining. Target molecule levels were analyzed by RT-qPCR, Western blotting, and immunohistochemistry staining. SUMOylation of FoxA1 was determined by Ni-NTA pull-down assay and SUMOylation assay Ultra Kit. Protein interaction and ubiquitination were detected by Co-IP. Gene transcription was assessed by ChIP and dual luciferase reporter assays. Liver FoxA1 knockout mice developed severe liver steatosis, which could be ameliorated by sirtuin 6 (Sirt6) overexpression. Nutritional stresses reduced Sumo2/3-mediated FoxA1 SUMOylation at lysine residue K6, which promoted lipid droplet formation by repressing fatty acid β-oxidation. Moreover, Sirt6 was a target gene of FoxA1, and Sirt6 transcription activity was restrained by deSUMOylation of FoxA1 at site K6. Furthermore, nutritional stresses-induced deSUMOylation of FoxA1 promoted the ubiquitination and degradation of FoxA1 with assistance of murine double minute 2 (Mdm2). Finally, activating FoxA1 SUMOylation delayed the progression of NAFLD in mice. DeSUMOylation of FoxA1 at K6 promotes FoxA1 degradation and then inhibits Sirt6 transcription, thereby suppressing fatty acid β-oxidation and facilitating NAFLD development. Our findings suggest that FoxA1 SUMOylation activation might be a promising therapeutic strategy for NAFLD.

Cellular, Structural Basis, and Recent Progress for Targeting Murine Double Minute X (MDMX) in Tumors.

Murine double minute X (MDMX) is an oncoprotein that mainly has a negative regulatory effect on the tumor suppressor p53 to induce tumorigenesis. As MDMX is highly expressed in various types of tumor cells, targeting and inhibiting MDMX are becoming a promising strategy for treating cancers. However, the high degree of structural homology between MDMX and its homologous protein murine double minute 2 (MDM2) is a great challenge for the development of MDMX-targeted therapies. This review introduces the structure, distribution, and regulation of the MDMX, summarizes the structural features and structure-activity relationships (SARs) of MDMX ligands, and focuses on the differences between MDMX and MDM2 in these aspects. Our purpose of this work is to propose potential strategies to achieve the specific targeting of MDMX.

A metabolic crosstalk between liposarcoma and muscle sustains tumor growth

Dedifferentiated and Well-differentiated liposarcoma are characterized by a systematic amplification of the Murine Double Minute 2 (MDM2) oncogene. We demonstrate that p53-independent metabolic functions of chromatin-bound MDM2 are exacerbated in liposarcoma and mediate an addiction to serine metabolism to sustain tumor growth. However, the origin of exogenous serine remains unclear. Here, we show that elevated serine levels in mice harboring liposarcoma-patient derived xenograft, released by distant muscle is essential for liposarcoma cell survival. Repressing interleukine-6 expression, or treating liposarcoma cells with Food and Drugs Administration (FDA) approved anti-interleukine-6 monoclonal antibody, decreases de novo serine synthesis in muscle, impairs proliferation, and increases cell death in vitro and in vivo. This work reveals a metabolic crosstalk between muscle and liposarcoma tumor and identifies anti-interleukine-6 as a plausible treatment for liposarcoma patients.

Platinum-Selenopeptide Interfaces in Support of High Fidelity Electrochemical Biomarker Quantification in Complex Biological Matrices.

The real world applications of conventional antifouling biosensors based on gold-thiol (Au-S) interfaces are hampered by the progressive competitive displacement of key functionality by ubiquitous biothiols. To overcome this limitation, we introduce here novel platinum-selenium (Pt-Se) interfaces. Thiol displacement tests, antifouling analyses, and density functional theory calculations confirm markedly improved interfacial stability. This was then leveraged through the application of a seleno-multifunctional peptide platform, tailored to the detection of murine double minute 2, in biological samples. A derived amperometric sensing platform exhibited a notably lower detection limit and more accurate target quantification than that supported by analogous Au-S and Pt-S interfaces. We believe that this work broadens the scope of electrochemical sensor construction and holds significant promise for the development of high-fidelity impactful bioassay platforms.

Genetic polymorphisms in FABP2, CYP2E1, and TP53 genes are potentially associated with colorectal cancer susceptibility

Colorectal cancer (CRC) is among the most prevalent cancers with a high mortality rate. Both genetic and environmental factors contribute to CRC development. This study aimed to assess the association of single nucleotide polymorphisms (SNPs) in the fatty acid binding protein-2 (rs1799883), Cytochrome P450 2E1 (rs3813865), TP53 (rs1042522), and Murine double minute 2 (rs1042522) genes with CRC. A cross-sectional case–control study was conducted at the Institute of Molecular Biology and Biotechnology from May 2020 to March 2021, involving CRC patients (N = 100) and controls (N = 100) recruited from the Multan district in Pakistan. Polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) and tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) were employed to investigate the studied SNPs. The association of SNPs in all genes with CRC was examined either individually or in various combinations. Genotypes at three SNPs, rs1799883 in FABP2, rs3813865 in CYP2E1, and rs1042522 in TP53, were found to be associated with the development of CRC, while rs1042522 in MDM2 was not. Patients who were married, smoked, lacked exercise habits or had a family history of CRC were at a greater risk of acquiring the disease. FABP2 gene rs1799883, CYP2E1 gene rs3813865, and TP53 gene rs1042522 polymorphisms are significant in the development of CRC in Pakistani participants.

Esophageal dedifferentiated liposarcoma resected by the cervical approach: a case report

BackgroundWhile liposarcomas tend to mainly occur in the soft tissues of the extremities and retroperitoneum, esophageal liposarcoma is rare. Herein, we report a case of a patient who underwent complete resection of an esophageal dedifferentiated liposarcoma via the cervical approach, leading to the preservation of the esophagus.Case presentationA 69-year-old man underwent an upper gastrointestinal endoscopy, as a result of which a submucosal-like tumor was observed. Upper gastrointestinal imaging showed a 12-cm tumor with a stalk arising from the esophageal entrance, extending to the middle intrathoracic esophagus, with a normal surface mucosa. Endoscopic ultrasound-fine needle aspiration biopsy showed that the nuclei of tumors cells were positive for murine double minute (MDM) and weakly positive for cyclin-dependent kinase 4 (CDK4). We diagnosed the tumor as the esophageal dedifferentiated liposarcoma, and planed tumor resection via the cervical approach. The tumor was successfully resected and the postoperative course was uneventful.ConclusionThis case report highlights the use of tumor resection via the cervical approach as a good option for esophageal liposarcoma.

A comprehensive view on the fisetin impact on colorectal cancer in animal models: Focusing on cellular and molecular mechanisms.

Flavonoids, including fisetin, have been linked to a reduced risk of colorectal cancer (CRC) and have potential therapeutic applications for the condition. Fisetin, a natural flavonoid found in various fruits and vegetables, has shown promise in managing CRC due to its diverse biological activities. It has been found to influence key cell signaling pathways related to inflammation, angiogenesis, apoptosis, and transcription factors. The results of this study demonstrate that fisetin induces colon cancer cell apoptosis through multiple mechanisms. It impacts the p53 pathway, leading to increased levels of p53 and decreased levels of murine double minute 2, contributing to apoptosis induction. Fisetin also triggers the release of important components in the apoptotic process, such as second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI and cytochrome c. Furthermore, fisetin inhibits the cyclooxygenase-2 and wingless-related integration site (Wnt)/epidermal growth factor receptor/nuclear factor kappa B signaling pathways, reducing Wnt target gene expression and hindering colony formation. It achieves this by regulating the activities of cyclin-dependent kinase 2 and cyclin-dependent kinase 4, reducing retinoblastoma protein phosphorylation, decreasing cyclin E levels, and increasing p21 levels, ultimately influencing E2 promoter binding factor 1 and cell division cycle 2 (CDC2) protein levels. Additionally, fisetin exhibits various effects on CRC cells, including inhibiting the phosphorylation of Y-box binding protein 1 and ribosomal S6 kinase, promoting the phosphorylation of extracellular signal-regulated kinase 1/2, and disrupting the repair process of DNA double-strand breaks. Moreover, fisetin serves as an adjunct therapy for the prevention and treatment of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA)-mutant CRC, resulting in a reduction in phosphatidylinositol-3 kinase (PI3K) expression, Ak strain transforming phosphorylation, mTOR activity, and downstream target proteins in CRC cells with a PIK3CA mutation. These findings highlight the multifaceted potential of fisetin in managing CRC and position it as a promising candidate for future therapy development.

Membranous translocation of murine double minute 2 promotes the increased renal tubular immunogenicity in ischemia-reperfusion-induced acute kidney injury.

Kidneys from donors with prolonged warm and cold ischemia are prone to posttransplant T cell-mediated rejection (TCMR) due to ischemia-reperfusion injury (IRI). However, the precise mechanisms still remain obscure. Renal tubular epithelial cells (TECs) are the main target during IRI. Meanwhile, we have previously reported that murine double minute 2 (MDM2) actively participates in TEC homeostasis during IRI. In this study, we established a murine model of renal IRI and a cell model of hypoxia-reoxygenation by culturing immortalized rat renal proximal tubule cells (NRK-52E) in a hypoxic environment for different time points followed by 24 h of reoxygenation and incubating NRK-52E cells in a chemical anoxia-recovery environment. We found that during renal IRI MDM2 expression increased on the membrane of TECs and aggregated mainly on the basolateral side. This process was accompanied by a reduction of a transmembrane protein, programmed death ligand 1 (PD-L1), a coinhibitory second signal for T cells in TECs. Using mutant plasmids of MDM2 to anchor MDM2 on the cell membrane or nuclei, we found that the upregulation of membrane MDM2 could promote the ubiquitination of PD-L1 and lead to its ubiquitination-proteasome degradation. Finally, we set up a coculture system of TECs and CD4+ T cells in vitro; our results revealed that the immunogenicity of TECs was enhanced during IRI. In conclusion, our findings suggest that the increased immunogenicity of TECs during IRI may be related to ubiquitinated degradation of PD-L1 by increased MDM2 on the cell membrane, which consequently results in T-cell activation and TCMR.NEW & NOTEWORTHY Ischemic acute kidney injury (AKI) donors can effectively shorten the waiting time for kidney transplantation but increase immune rejection, especially T cell-mediated rejection (TCMR), the mechanism of which remains to be elucidated. Our study demonstrates that during ischemia-reperfusion injury (IRI), the translocation of tubular murine double minute 2 leads to basolateral programmed death ligand 1 degradation, which ultimately results in the occurrence of TCMR, which may provide a new therapeutic strategy for preventing AKI donor-associated TCMR.

Ursodeoxycholic acid inhibits the uptake of cystine through SLC7A11 and impairs de novo synthesis of glutathione

Ursodeoxycholic acid (UDCA) is a naturally occurring, low-toxicity, and hydrophilic bile acid (BA) in the human body that is converted by intestinal flora using primary BA. Solute carrier family 7 member 11 (SLC7A11) functions to uptake extracellular cystine in exchange for glutamate, and is highly expressed in a variety of human cancers. Retroperitoneal liposarcoma (RLPS) refers to liposarcoma originating from the retroperitoneal area. Lipidomics analysis revealed that UDCA was one of the most significantly downregulated metabolites in sera of RLPS patients compared with healthy subjects. The augmentation of UDCA concentration (≥25 μg/mL) demonstrated a suppressive effect on the proliferation of liposarcoma cells. [15N2]-cystine and [13C5]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione (GSH) synthesis. Mechanistically, UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis, leading to reactive oxygen species (ROS) accumulation and mitochondrial oxidative damage. Furthermore, UDCA can promote the anti-cancer effects of ferroptosis inducers (Erastin, RSL3), the murine double minute 2 (MDM2) inhibitors (Nutlin 3a, RG7112), cyclin dependent kinase 4 (CDK4) inhibitor (Abemaciclib), and glutaminase inhibitor (CB839). Together, UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity, and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA. More importantly, in combination with other antitumor chemotherapy or physiotherapy treatments, UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.

Unraveling the Role of TP53 in Colorectal Cancer Therapy: From Wild-Type Regulation to Mutant.

The p53, a pivotal tumor suppressor, regulates various cellular responses, including DNA repair and apoptosis. Normally, p53 levels are low due to murine double minute clone 2 (MDM2) mediated polyubiquitination. However, stress signals disrupt p53-MDM2 interaction, stabilizing p53 and activating target genes. Dysfunctional p53 is common in cancers, especially colorectal cancer (CRC), with TP53 mutations in 43% of tumors. These mutations impair wild-type p53 function or confer novel activities, promoting cancer progression. Despite drugs targeting p53 entering trials, understanding wild-type and mutant p53 functions is crucial for novel CRC therapies. P53 mutations not only impact DNA repair and apoptosis but also play a crucial role in tumor immunotherapy. While rendering tumors resistant to chemotherapy, p53 mutations provide opportunities for immunotherapy due to neoantigen-rich tumors. Additionally, p53 mutations influence tumor microenvironment cells, such as fibroblasts and immunosuppressive cells, through p53-mediated signaling pathways. Investigating p53 mutations in tumor therapy is vital for personalized medicine and immunotherapy. In cancer treatment research, scientists explore drugs and strategies to restore or enhance p53 function. Targeting wild-type p53 aims to restore DNA repair and cell cycle control, while targeting mutant p53 seeks new drugs to inhibit its detrimental effects, advancing tumor treatment. Understanding p53 drugs and strategies is crucial for cancer therapy progress.

Anticancer activity of Aucklandia costus Falc. terpenes: Targeting MDM2 protein inhibition for therapeutic advancements

Context: Protein 53 (p53) is a well-known tumor suppressor protein, while murine double minute 2 (MDM2) acts as a negative regulator of p53, leading to p53 inactivation and cancer development. Aucklandia costus Falc. or Saussurea lappa contains bioactive compounds, particularly terpenoids, known for their anticancer activity against various cancer cells. Targeting the p53-MDM2 protein interaction and inhibiting MDM2 are crucial strategies in cancer therapy. Aims: To analyze the anticancer properties of A. costus terpenes against MDM2 protein. Methods: The compounds costunolide, dehydrocostus lactone, lappadilactone, and cynaropicrin were docked with MDM2 (PDB ID: 4HG7) using AutoDockTools 1.5.6. Additionally, the physicochemical, pharmacokinetic, and toxicity properties were predicted using pkCSM. Results: Lappadilactone exhibited the highest binding energy value, surpassing both the control and the native ligand. Following lappadilactone, cynaropicrin, costunolide, and dehydrocostus lactone displayed decreasing binding energies. When assessing ADMET properties with pkCSM, all compounds exhibited good permeability, suggesting their ability to penetrate intestinal cell membranes, and showed no signs of hepatotoxicity. Conclusions: Lappadilactone emerges as a promising candidate with high intestinal absorption, distinctive distribution characteristics, and a lack of mutagenic or hepatotoxic effects.

Preoperative Contrast-Enhanced CT-Based Deep Learning Radiomics Model for Distinguishing Retroperitoneal Lipomas and Well‑Differentiated Liposarcomas

ObjectivesTo assess the efficacy of a preoperative contrast-enhanced CT (CECT) –based deep learning radiomics nomogram (DLRN) for predicting murine double minute 2 (MDM2) gene amplification as a means of distinguishing between retroperitoneal well-differentiated liposarcomas (WDLPS) and lipomas. MethodsThis retrospective multi-centre study included 167 patients (training/external test cohort, 104/63) with MDM2-positive WDLPS or MDM2-negative lipomas. Clinical data and CECT features were independently measured and analyzed by two radiologists. A clinico-radiological model, radiomics signature (RS), deep learning and radiomics signature (DLRS), and a DLRN incorporating radiomics and deep learning features were developed to differentiate between WDLPS and lipoma. The model utility was evaluated based on the area under the receiver operating characteristic curve (AUC), accuracy, calibration curve, and decision curve analysis (DCA). ResultsThe DLRN showed good performance for distinguishing retroperitoneal lipomas and WDLPS in the training (AUC, 0.981; accuracy, 0.933) and external validation group (AUC, 0.861; accuracy, 0.810). The DeLong test revealed the DLRN was noticeably better than clinico-radiological and RS models (training: 0.981 vs. 0.890 vs. 0.751; validation: 0.861 vs. 0.724 vs. 0.700; both P < 0.05); however, no discernible difference in performance was seen between the DLRN and DLRS (training: 0.981 vs. 0.969; validation: 0.861 vs. 0.837; both P > 0.05). The calibration curve analysis and DCA demonstrated that the nomogram exhibited good calibration and offered substantial clinical advantages. ConclusionsThe DLRN exhibited strong predictive capability in predicting WDLPS and retroperitoneal lipomas preoperatively, making it a promising imaging biomarker that can facilitate personalized management and precision medicine.

Murine Double Minute 2–Positive Primary Pulmonary Artery Intimal Sarcoma Diagnosed by Pulmonary Arterial Catheter Aspiration After Emergency Admission

Murine Double Minute 2–Positive Primary Pulmonary Artery Intimal Sarcoma Diagnosed by Pulmonary Arterial Catheter Aspiration After Emergency Admission