P53 Protein Research Articles

Small molecules that targeting p53 Y220C protein: mechanisms, structures, and clinical advances in anti-tumor therapy.

The p53 protein is regarded as the "Guardian of the Genome," but its mutation is tumor progression and present in more than half of malignant tumors. The pro-metastatic property of mutant p53 makes a strong argument for targeting mutant p53 with new therapeutic strategies. However, mutant p53 was considered as a challenging target for drug discovery due to the lack of small molecular binding pockets. Among them, mutant p53 Y220C creates a narrow crevice since the side chains dynamics on protein surface, which is suitable for designing small molecules to occupy the cavity and recovery the tumor suppressing function. Here, we describe the mechanism of p53 related signal pathway and how p53 Y220C regulate the tumorigenesis. We review the two types of p53 Y220C modulators including restoring the conformation of mutant p53 Y220C protein to wild-type p53 protein and recruiting histone acetyltransferase p300/CBP to acetylate p53 Y220C thus enables p53 Y220C dependent upregulation of apoptotic genes and downregulation of DNA damage response pathways. We also report clinical advances and challenges of these molecules in p53 Y220C medicated tumor therapy.

Ethyl Acetate Extract of Cichorium glandulosum Activates the P21/Nrf2/HO-1 Pathway to Alleviate Oxidative Stress in a Mouse Model of Alcoholic Liver Disease

Background: Alcoholic liver disease (ALD) is a significant global health concern, primarily resulting from chronic alcohol consumption, with oxidative stress as a key driver. The ethyl acetate extract of Cichorium glandulosum (CGE) exhibits antioxidant and hepatoprotective properties, but its detailed mechanism of action against ALD remains unclear. This study investigates the effects and mechanisms of CGE in alleviating alcohol-induced oxidative stress and liver injury. Methods: Ultra-Performance Liquid Chromatography coupled with Quadrupole-Orbitrap Mass Spectrometry (UPLC-Q-Orbitrap-MS) was used to identify CGE components. A C57BL/6J mouse model of ALD was established via daily oral ethanol (56%) for six weeks, with CGE treatment at low (100 mg/kg) and high doses (200 mg/kg). Silibinin (100 mg/kg) served as a positive control. Liver function markers, oxidative stress indicators, and inflammatory markers were assessed. Transcriptomic and network pharmacology analyses identified key genes and pathways, validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Results: UPLC-Q-Orbitrap-MS identified 81 CGE compounds, mainly including terpenoids, flavonoids, and phenylpropanoids. CGE significantly ameliorated liver injury by reducing alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels and enhancing antioxidative markers such as total antioxidant capacity (T-AOC) and total superoxide dismutase (T-SOD) while lowering hepatic malondialdehyde (MDA) levels. Inflammation was mitigated through reduced levels of Tumor Necrosis Factor Alpha (TNF-α), Interleukin-1 Beta (IL-1β), and C-X-C Motif Chemokine Ligand 10 (CXCL-10). Transcriptomic and network pharmacology analysis revealed seven key antioxidant-related genes, including HMOX1, RSAD2, BCL6, CDKN1A, THBD, SLC2A4, and TGFβ3, validated by RT-qPCR. CGE activated the P21/Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1) signaling axis, increasing P21, Nrf2, and HO-1 protein levels while suppressing Kelch-like ECH-associated Protein 1 (Keap1) expression. Conclusions: CGE mitigates oxidative stress and liver injury by activating the P21/Nrf2/HO-1 pathway and regulating antioxidant genes. Its hepatoprotective effects and multi-target mechanisms highlight CGE’s potential as a promising therapeutic candidate for ALD treatment.

Bushen-Huoxue-Mingmu-Formula attenuates pressurization-induced retinal ganglion cell damage by reducing mitochondrial autophagy through the inhibition of the Pink1/Parkin pathway.

Bushen-Huoxue-Mingmu-Formula (MMF) has achieved definite clinical efficacy. However, its mechanism is still unclear. Investigating the molecular mechanism of MMF to protect retinal ganglion cells (RGCs). This study developed a pressurization-induced model of damaged RGCs, which were then treated with a serum supplemented with MMF. The effects of MMF on proliferation, apoptosis, adenosine 5'-triphosphate content, and mitochondrial structure of RGCs were investigated, and the underlying molecular mechanism was explored by RNA interference experiment. In the pressurization-induced RGC injury model, apoptosis rate increased, cell proliferation decreased, adenosine 5'-triphosphate content reduced, mitochondrial structure was disrupted, BCL2-associated X, cleaved caspase-3, and microtubule-associated proteins light chain 3 II/I protein expression enhanced, B cell lymphoma-2 and p62 protein expression decreased, and the Pink1/Parkin pathway was activated. The stress-induced damage to RGCs was, however, reversible following MMF-mediated inhibition of the Pink1/Parkin pathway. Pink1 short-hairpin RNA downregulated Pink1 expression in RGCs, which led to outcomes that aligned with those observed with MMF intervention. MMF altered the expression of apoptosis- and autophagy-related proteins and possibly inhibited the Pink1/Parkin signaling pathway, which led to reduced pressurization-induced mitochondrial autophagy in RGCs. This preventive effect of MMF on RGCs can be potentially useful to preserve the viability of RGCs.

NPA7: A Dual Receptor Activating Peptide That Inhibits Cardiac Oxidative Stress.

Cardiomyocyte oxidative stress significantly contributes to the progression of hypertension-induced heart failure, highlighting the need for targeted therapies. We developed a novel peptide, NPA7, that coactivates the GC-A (guanylyl cyclase A)/cGMP and MasR (Mas receptor)/cAMP pathway. This study aimed to test NPA7's ability to inhibit oxidative stress by modulating the p62-KEAP1 (Kelch-like ECH-associated protein 1)-NRF2 (nuclear factor erythroid 2-related factor 2) pathway in human cardiomyocytes (HCMs) and a rat model of hypertension. Oxidative stress was induced in HCMs using H2O2 with PBS or NPA7 treatment. Intracellular reactive oxygen species levels were assessed via dihydroethidium staining. Western blotting analysis measured p62, KEAP1, and NRF2 protein levels, while GSH/GSSG ratios and antioxidant gene expression were analyzed. HCMs were transfected with siRNA targeting GC-A, MasR, or p62 before NPA7 and H2O2 treatment. In vivo, spontaneously hypertensive rats received saline or NPA7, with normotensive WKY rats as control and cardiac oxidative stress, KEAP1 protein levels, NOX2, and p67 mRNA levels were measured. NPA7 reduced H2O2-induced reactive oxygen species levels and increased GSH/GSSG ratio in HCMs. Silencing GC-A and MasR reversed NPA7's effects. NPA7 activated the KEAP1-NRF2 pathway, enhancing NRF2's antioxidant target gene expression. In p62 knockdown HCMs, NPA7-induced KEAP1 degradation and NRF2 activation were diminished. Reactive oxygen species levels were elevated in spontaneously hypertensive rat versus WKY hearts however, NPA7 treatment reduced myocardial reactive oxygen species, suppressed KEAP1 protein, and decreased NOX2 and p67 mRNA levels. NPA7 exhibits antioxidant properties in HCMs and spontaneously hypertensive rat hearts by targeting GC-A and MasR through the p62-KEAP1-NRF2 pathway, supporting a novel therapeutic approach against cardiovascular disease-related oxidative stress.

Cabozantinib Selectively Induces Proteasomal Degradation of p53 Somatic Mutant Y220C and Impedes Tumor Growth.

Inactivation of p53 by mutations commonly occurs in human cancer. The mutated p53 proteins may escape proteolytic degradation and exhibit high expression in tumors, and acquire gain-of-function activity that promotes tumor progression and chemo-resistance. Therefore, selectively targeting of the gain-of-function p53 mutants may serve as a promising therapeutic strategy for cancer prevention and treatment. In this study, we identified cabozantinib, a multi-kinase inhibitor currently used in clinical treatment of several types of cancer, as a selective inducer of proteasomal degradation of the p53-Y220C mutant. We demonstrate that cabozantinib disrupts the interaction between p53Y220C and USP7, a deubiquitylating enzyme, resulting in the dissociation of p53Y220C protein from its binding with USP7 and subsequent ubiquitination and degradation mediated by CHIP (The carboxyl terminal of Hsp70-interacting protein). We also show that cabozantinib displays preferential cytotoxicity to p53Y220C-harboring cancer cells both in vitro and in vivo. This study demonstrates a novel, p53-Y220C mutant-targeted anticancer action and mechanism for cabozantinib, and provides the rationale for use of this drug in treatment of cancers that carry the p53-Y220C mutation.

Inhibition of ASIC1a reduces ferroptosis in rheumatoid arthritis articular chondrocytes via the p53/NRF2/SLC7A11 pathway.

The activation of acid-sensing ion channel 1a (ASIC1a) in response to extracellular acidification leads to an increase in extracellular calcium influx, thereby exacerbating the degeneration of articular chondrocytes in rheumatoid arthritis (RA). It has been suggested that the inhibition of extracellular calcium influx could potentially impede chondrocyte ferroptosis. The cystine transporter, solute carrier family 7 member 11 (SLC7A11), is recognized as a key regulator of ferroptosis. Recent studies suggest that the tumor suppressor gene p53 facilitates the induction of ferroptosis by suppressing the upregulation of SLC7A11. This process is mediated by the nuclear factor erythroid 2-related factor 2 (NRF2), a key transcription factor integral to the maintenance of cellular redox homeostasis and the regulation of inflammatory responses. This study aims to investigate the role of ASIC1a in the ferroptosis of RA chondrocytes and to determine the involvement of the p53/NRF2/SLC7A11 pathway in its underlying mechanism. Invitro experiments revealed that acidosis induces ferroptosis and reduces the expression of NRF2 and SLC7A11 in chondrocytes. Moreover, acidification significantly increased p53 protein levels in chondrocytes. Pifithrin-α (PFN-α), a p53 inhibitor, mitigated acidosis-induced ferroptosis and restored the diminished expression of NRF2 and SLC7A11. Furthermore, PcTx-1, an ASIC1a inhibitor, inhibited acidification-induced ferroptosis, enhanced the protein levels of SLC7A11 and NRF2, and reduced p53 expression. Invivo experiments demonstrated that the ASIC1a-specific inhibitor PcTx-1 ameliorated histopathological characteristics of ankle joints in collagen-induced arthritis (CIA) mice, decreased p53 expression, and enhanced NRF2 and SLC7A11 expression in chondrocytes. These findings suggest that ASIC1a inhibition may mitigate acidification-induced ferroptosis in articular chondrocytes in RA, potentially via the p53/NRF2/SLC7A11 pathway.

The Anti-Inflammatory Effects of Formononetin, an Active Constituent of Pueraria montana Var. Lobata, via Modulation of Macrophage Autophagy and Polarization.

Pueraria montana var. lobata (Willd.) Maesen & S.M.Almeida ex Sanjappa & Predeep (P. lobata) is a medicinal herb widely used in the food and pharmaceutical industries, and studies have shown that P. lobata possesses significant anti-inflammatory pharmacological activities. In this paper, a total of 16 compounds were isolated and identified from P. lobata, among which compounds 1-3, 7, 14, and 16 were isolated from P. lobata for the first time. The results of an in vitro anti-inflammatory activity screening assay showed that compounds 1, 4, 6, 8, and 15 were able to significantly reduce the levels of pro-inflammatory cytokines IL-6 and IL-1β in LPS-induced RAW264.7 macrophages, with the most obvious effect produced by compound 6 (formononetin), while formononetin was able to significantly reduce the number of macrophages at the site of inflammation in transgenic zebrafish. In addition, network pharmacological analysis revealed that the anti-inflammatory activity of formononetin is closely related to autophagy and polarization targets such as TNF, EGFR, PTGS2, and ESR1. In vitro validation experiments showed that formononetin could enhance the expression of LCII/LCI and reduce the expression of P62 protein, reduce the expression of CD86, and enhance the expression of CD206, which further indicated that formononetin could reduce inflammation by regulating macrophage autophagy and polarization processes.

Molecular analysis of HPV16 and HPV18 oncogenes in oral squamous cell carcinoma: Structural, transcriptomic and in vitro insights.

The present study investigated the involvement of human papillomavirus (HPV)16 and HPV18 in oropharyngeal malignancies in order to understand the oncogenic mechanisms, and to identify biomarkers for early detection and treatment targets. Given the rising incidence of HPV-associated cancer, particularly in India, this holds significance in elucidating the molecular basis of these diseases. Structural validation of HPV16 and 18 oncoproteins E6 and E7 was conducted using computational tools, while gene expression profiles related to oral squamous cell carcinoma (OSCC) were analyzed to assess differential expression. The presence of HPV in patient tissue sections was examined using reverse transcription-PCR. The present study revealed the interactions of HPV16 and 18 E6/E7 oncoproteins, highlighting their role in cancer progression by targeting key tumor suppressors, such as p53 and retinoblastoma protein. Further analysis demonstrated the involvement of HPV16 and 18 E6/E7 oncoproteins in cancer pathways, signaling and telomere regulation, which supports the development of future targeted therapies. HPV16 and 18 E6/E7 represent promising therapeutic targets in OSCC, and provide further insights into potential diagnostic and treatment avenues. The present study contributes to the current understanding of HPV-associated cancer and innovative strategies in disease management.

Unveiling the role of ASPP1 in cancer progression: pan-cancer bioinformatics and experimental validation in colorectal cancer

BackgroundThe Apoptosis-Stimulating Protein of P53 (ASPP) family contributes to apoptosis regulation and tumor suppression, with ASPP1 influencing processes like cancer cell proliferation, invasion, and migration. Its expression varies across cancer types, suggesting a potential role in oncogenesis.MethodsThis study investigates ASPP1’s role across various cancers using a comprehensive bioinformatics approach. Data were extracted from public resources, including The Cancer Genome Atlas (TCGA), GTEx, and the Human Protein Atlas, and analyzed via tools such as cBioPortal, GEPIA, and TIMER2. Statistical and network analyses were performed with R, Cytoscape, and Hiplot. ASPP1’s function in colorectal cancer was further explored through in vitro assays, including qRT-PCR, Western blotting, colony formation, Transwell, and wound healing.ResultsASPP1 expression exhibited significant variability across different cancer types, with marked associations with patient outcomes, particularly overall survival (OS) and disease-specific survival (DSS) across several cancer types. In-depth protein-protein interaction (PPI) analysis revealed ASPP1’s involvement in apoptosis and cancer progression networks. Functional enrichment analysis further linked ASPP1 to key apoptotic signaling pathways and transcriptional regulatory processes, underscoring its potential impact on tumor biology. Additionally, the expression of ASPP1 correlates with immune cell infiltration patterns, including cancer-associated fibroblasts and various immune markers, suggesting roles in immune response modulation. In vitro assays with colorectal cancer cell lines revealed significantly lower ASPP1 expression levels compared to normal colon cells (HCM460), and ASPP1 overexpression experiments showed a marked reduction in colorectal cancer cell proliferation, colony formation, invasion, and migration abilities. These cellular findings align with the bioinformatics predictions, highlighting ASPP1’s role as a suppressor of metastatic traits in colorectal cancer.ConclusionThis study highlights ASPP1 as a forecasting biomarker in the colorectal cancers and potentially across other cancers. The findings support ASPP1’s involvement in tumor biology, particularly regarding cell proliferation and metastatic potential, establishing a foundation for further investigation into its therapeutic relevance.

Mink enteritis virus infection induced cell cycle arrest and autophagy for its replication.

Mink enteritis virus (MEV) is an important pathogen causing mink viral enteritis. The mechanisms of cell cycle arrest induced by MEV infection and the roles of autophagy in MEV replication remain unclear. In this study, the roles of MEV NS1 protein in inducing cell cycle arrest were investigated, using the in vitro CRFK cell models. As a result, MEV infection increased the proportion of the cells in S phase, inducing S phase arrest. MEV NS1 protein also led to cycle arrest in S phase. And the deletions of NLS and TAD significantly weakened the ability of NS1 protein to cause cycle arrest in Sphase, and NLS and TAD were the indispensable domains of NS1 protein. Furthermore, proteome profiling of the cells infected with MEV at the early stage demonstrated that the autophagy-related protein TRIM23 was significantly up-regulated during MEV infection. To investigate the effects of TRIM23 on MEV replication, the cell models were established, using siRNAs targeting TRIM23. The knockdown of TRIM23 resulted in the decreases in the levels of TBK1 protein and the phosphorylated p62 protein, and an increase in the level of p62 protein in the cells infected with MEV, indirectly influencing virus replication. The findings implied that S phase arrest and the up-regulated TRIM23 induced by MEV infection played the important roles in MEV replication.

Drug pairs of Huangqi and Danggui alleviates pyroptosis by promoting autophagy activity via AMPK/mTOR signaling pathway in middle-cerebral artery occlusion/reperfusion in rats

Ethnopharmacological relevanceCerebral ischemia-reperfusion (I/R) injury is a common complication of ischemic stroke, with autophagy and pyroptosis playing key roles. Huangqi and Danggui (HQDG) are a commonly used drug pair of Chinese traditional medicine for clinical treatment of ischemic stroke. Aim of the studyThe study aims to investigate the interaction between autophagy and pyroptosis regulated by HQDG through the AMPK/mTOR signaling pathway during cerebral I/R injury. Materials and methodsModel of middle-cerebral artery occlusion/reperfusion (MCAO/R) in SD rats was established using the Longa suture method. The components of traditional Chinese medicine were detected by liquid chromatography coupled to quadrupole orbitrap high resolution mass spectrometry (LC/MS). Neurological deficits were evaluated by neurological function score. Changes of cerebral blood flow were detected by a laser speckle blood flow imaging instrument. The volume of cerebral infarction was observed by 2,3,5-Chlorotriphenyltetrazolium (TTC) staining. The permeability of the blood-brain barrier was measured by Evans blue test. Neurovascular unit and autophagosomes in brain tissue were assessed by transmission electron microscopy. Neuronal pyroptosis was detected by terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL)/Caspase-1 staining. The expression of autophagy related proteins, pyroptosis related proteins, and AMPK/mTOR pathway related proteins were detected by Western blot. ResultsAfter cerebral I/R injury, autophagy and pyroptosis, were characterized by increased number of autophagosomes and pyroptosis cells, upregulated expression of Beclin 1, LC3-II/LC3-I, NLRP3, cleaved Caspase-1, IL-1beta, IL-18 proteins, and downregulated expression of P62 proteins. HQDG significantly improved neurological function, reduced the volume of cerebral infarction, increased cerebral blood flow, improved blood-brain barrier permeability and the function of neurovascular units. Autophagy was further activated and pyroptosis was significantly inhibited by HQDG, which promoted increased number of autophagosomes, enhanced expression of Beclin 1, LC3-II/LC3-I proteins, reduced expression of P62, NLRP3, cleaved Caspase-1, IL-1beta, and IL-18 proteins, and downregulated the number of pyroptosis cells. On the other hand, after administering 3-Methyladenine (3-MA) to inhibit autophagy, the above effects of HQDG were significantly inhibited. Besides, HQDG promoted AMPK phosphorylation, and weakened mTOR phosphorylation. However, after the administration of AMPK inhibitor Compound C, HQDG caused increase in Beclin 1 and LC3-II/LC3-I, reduced P62 and NLRP3, and cleaved Caspase-1 protein expression, whereas cerebral blood flow decreased. ConclusionHQDG alleviated pyroptosis by promoting autophagy via AMPK/mTOR signaling pathway after middle-cerebral artery occlusion/reperfusion in rats, showing its potential for treatment of cerebral I/R injury in humans.

FLT3 inhibitors induce p53 instability, driven by STAT5/MDM2/p53 competitive interactions in acute myeloid leukemia.

FLT3 mutations are present in one third of patients with Acute myeloid leukemia (AML) and stand as an attractive therapeutic target. Although FLT3 inhibitors demonstrate clinical efficacy, the drug resistance remains challenging attributed to multiple mechanisms. In this study, we found that tyrosine kinase inhibitors (TKIs) targeting FLT3 prompt p53 degradation in AML cells with FLT3-ITD through ubiquitination. STAT5 phosphorylation facilitates its nuclear localization, leading to competitive interactions among STAT5, MDM2, and p53. TKIs blocked STAT5 nuclear entry, amplifying MDM2/p53 binding and subsequent p53 degradation. Additionally, STAT5 overexpression inhibited MDM2-mediated p53 ubiquitination, whereas knock-down of STAT5 destabilizes p53. Co-administration of MDM2 inhibitors stabilizes p53 ubiquitination induced by TKIs, enhancing pro-apoptotic effects on AML cells. Moreover, in mice engrafted with AML cells, gilteritinib treatment results in decreased p53 protein levels and the transcriptional repression of downstream genes in leukemia cells, which are mitigated by the co-administration of MDM2 inhibitors. In conclusion, our study shows that FLT3 TKIs impede STAT5 nuclear translocation, strengthening p53/MDM2 interaction and consequent p53 degradation. This finding reveals a novel mechanism of TKIs resistance and indicates a combination of MDM2 inhibitors with TKIs for AML therapy, offering new insights into effective treatment strategies.

Quinazolinone nitriles and related metabolites from the deep-sea-derived fungus Penicillium viridicatum MCCC 3A00265

New quinazolinone nitriles featuring an unusual nitrile group were isolated from the deep-sea-derived Penicillium viridicatum MCCC 3A00265, exhibiting potent activity in reactivating the mutant p53 protein.

Neuroprotective effects of activated fibroblast growth factor receptor 1 via the suppression of p53 accumulation against poly-PR-mediated toxicity.

A GGGGCC hexanucleotide repeat expansion (HRE) within the C9orf72 gene is a major causative factor in amyotrophic lateral sclerosis (ALS). This aberrant HRE results in the generation of five distinct dipeptide repeat proteins (DPRs). Among the DPRs, poly-PR accumulates in the nucleus and exhibits particularly strong toxicity to motor and cortical neurons. Fibroblast growth factor receptor 1 (FGFR1) is known to promote neurogenesis and inhibit apoptosis in neurons. Nevertheless, there has been no previous report of its neuroprotective effects against poly-PR toxicity. The objective of this study was to investigate the neuroprotective effects of FGFR1 activation in poly-PR-expressing NSC34 motor neuron-like cells. RT-qPCR analysis in NSC34cells showed that Fgfr1 was the most highly expressed member of the Fgfr family in NSC34cells. The activation of FGFR1 by FGF2, a common ligand for all FGFRs, exerted neuroprotective effects against the toxicity of poly-PR. Additionally, FGFR1 activation was observed to enhance cell viability through the PI3K-AKT pathway, while the contribution of the MEK-ERK pathway was found to be limited. Furthermore, FGFR1 activation suppressed the accumulation of p53 protein and promoted its degradation through increased murine double minute 2 (MDM2), an E3 ubiquitin ligase that targets p53. The neuroprotective effects were attenuated by PD173074, a selective FGFR1 inhibitor or Nutlin-3a, an inhibitor of the p53-MDM2 interaction. Overall, these findings suggest that FGFR1 activation provides neuroprotection against poly-PR toxicity. Consequently, this study suggests the potential utility of FGFR1 activation as a therapeutic strategy for ALS.

Uncovering the Natural Inhibitors From Medicinal Plants to Alleviate Human Cancers Targeting the p53 Protein: An In Silico Approach

Uncovering the Natural Inhibitors From Medicinal Plants to Alleviate Human Cancers Targeting the p53 Protein: An In Silico Approach

Centipeda minima extracts and the active sesquiterpene lactones have therapeutic efficacy in non-small cell lung cancer by suppressing Skp2/p27 signaling pathway.

Centipeda minima (L.) A. Braun & Asch (C. minima) was applied to treat nasal allergy, headache, cough, and even nasopharyngeal carcinoma in traditional Chinese medicine. However, the underlying anticancer mechanisms of C. minima and its active components have not been systematically illustrated. The study aims to examine the therapeutic efficacy of the ethanol extract of C. minima (ECM) and its active components in non-small cell lung cancer (NSCLC) and illustrate the underlying mechanisms. The main chemical components in the ethanol extract of C. minima (ECM) and the supercritical CO2 fluid extract of C. minima (CM-SFE) were determined by using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The antitumor effects of ECM and CM-SFE were examined by using NSCLC cell xenografts. The flow cytometry, cell colony formation, wound-healing, transwell assay, and Western blotting were conducted to investigate the anticancer properties of ECM, CM-SFE, and these sesquiterpene lactones that abundantly distributed in these extracts. We first determined that ECM contains high levels of sesquiterpene lactones. ECM can markedly induce cell cycle arrest and suppress migration and invasion of NSCLC cells. Mechanistically, ECM promoted proteasome-dependent degradation of Skp2 protein and induced the accumulation of its substrates p27; whereas Skp2 overexpression can attenuate the inhibitory effects of ECM on NSCLC proliferation and migration. Moreover, ECM at 200-600mg/kg can significantly inhibit tumor growth and metastasis in A549-luciferase cell orthotopic xenografts by suppressing Skp2 expression. The sesquiterpene lactones that abundantly distributed in ECM, including 6-O-angeloylplenolin (6-OAP), arnicolide D (ArD) and arnicolide C (ArC), were also demonstrated to decrease Skp2 while increase p27 protein level, thereby significantly inducing cell cycle arrest and suppressing migration of NSCLC cells. Notably, CM-SFE, which mainly consisted of 6-OAP, ArD and ArC, exhibited much stronger anti-NSCLC activity than that of ECM in A549-luciferase cell orthotopic xenografts. Our results demonstrate that the active components in C. minima possesses potential anti-NSCLC activities by suppressing Skp2/p27 signaling pathway, and these active sesquiterpene lactones can be further developed as potent Skp2 inhibitor to treat NSCLC.

Immunomodulatory lectin from Cordia myxa targets PI3K/AKT signalling mediated apoptosis to regress both in-vitro and in-vivo tumour.

Plant based medicine is gaining recognition as a complementary approach to conventional treatments. Plants contain lectins that bind to carbohydrates and exhibit various biological properties and being used in cancer treatment. In present investigation Cordia myxa fruit was chosen, screen for presence of lectin and explore its biological role. Screening of lectin was conducted through HA activity. Purification and characterization through conventional methods. HI assay to confirm the carbohydrate specificity. Immunomodulatory role by proliferative assays and ELISA. Apoptosis by annexin-V stain, TUNEL, MOMP and COMET assay and in-vivo antitumour activity by EAC induced ascites and solid tumour model. Gene expression through IB and IHC. The results illustrated that, presence of immunostimulant, ̴12 kDa lectin (CML) with strong leucoaggulutination activity having ovalbumin & fetuin specificity. The CML exhibits immune cell proliferation and secretes immune cytokines IL-2, IL-10 & IL-12. The immunomodulatory experiments infer that, CML induces anti-proliferative response against A549 and EAC by inducing apoptosis, which were validated in an in-vitro & in-vivo models. Mechanistically, CML modulates phosphorylation of PI3K/AKT signalling pathways and modulates downstream apoptotic proteins P53, Bax, Bad, Bcl-2, cytochrome-c, caspase-3 and DFF-40. Overall, the study reports the immunomodulatory lectin in Cordia myxa with its potential therapeutic role.

Pharmacokinetic predictions and molecular docking of phytocompounds derived from Carissa edulis on mutant p53 protein in breast cancer

Globally, breast cancer is a leading cause of death, and the current chemotherapeutic agents are not devoid of drawbacks. Nevertheless, the potential of medicinal plants for cancer treatment and prevention remains immense. The current study aimed at elucidating the interactions between phytocompounds identified in Carissa edulis (C. edulis) and mutant p53, drug-likeness and potential toxicity. Molecular docking analysis was employed to analyse the interaction of compounds and the target protein. Lipinski’s Rule of Five was used to analyse drug-likeness properties. Liquid chromatography-mass spectroscopy (LC-MS) and gas chromatography-mass spectroscopy (GC-MS) were employed to detected presence of phytocompounds in the extracts. Quantitative analyses revealed presence of phytocompounds which have been previously reported to have antiproliferative effects. The docked compounds had a binding efficiency ranging from -4.00 to -8.44 kcal/mol. Most of the studied phytocompounds were found to be within the "Rule of 5" without any violation. Regarding toxicity, rutin, catechin, betulin, tocopherol, sitosterol, beta-amyrin, menthol, and epicatechin exhibited no inhibitory effect on CYP450 enzymes. Moreover, most compounds had high intestinal absorption, whereas few compounds cross blood brain barrier. A bioavailability score of 0.55 was exhibited by most bioactive compounds analysed. These results underscore the therapeutic potential of C. edulis for future anticancer drug development.

Recent Perspectives on Anticancer Potential of Coumarin Against Different Human Malignancies: AnUpdated Review.

Coumarins, a group of naturally occurring compounds, have been reported to demonstrate anticancer potential. These substances, distinguished by their combined benzene and α-pyrone rings, have been demonstrated to impact multiple cellular mechanisms essential for the initiation and advancement of cancer. These agents work in different ways that prevent different tumor cells from growing, spreading, and increasing. One of the main anticancer mechanisms of coumarin act is killing cancer cells through apoptosis. This includes changes to pro- and anti-apoptotic proteins like Bcl-2 and Bax, the release of cytochrome c from mitochondria, and the activation of caspases. The tumor suppressor protein p53's expression has been discovered to be upregulated by coumarins such as esculetin and imperatorin, which encourage interrupted cell cycle and death. Additionally, coumarin has anti-angiogenic qualities, which are critical for the development and spread of tumors. It can slow the development of new blood vessels that feed tumors by inhibiting the "vascular endothelial growth factor (VEGF)" route of signaling. Coumarins inhibit the number of signaling pathways that are vital for cell division. For example, they can suppress the "PI3K/mTOR" pathway, which usually impairs the cancer cells and results in decreased cell viability and growth. Finally, coumarins could modulate the response of the immune system to cancerous cells. They have the ability to boost the activity of natural killer cells and cytotoxic T lymphocytes, which aid the immune system in identifying and eliminating cancer cells. Through a variety of mechanisms, such as immune response regulation, angiogenesis reduction, cell growth inhibition, and apoptosis activation, coumarins exhibit their anticancer effects. These molecular pathways demonstrate coumarins' potential as an interesting option for the development of novel anticancer treatments. More studies are needed to completely understand their modes of action and maximize their therapeutic efficacy.

Kelch-like ECH-associated Protein 1/Nuclear Factor Erythroid 2-related Factor 2 Pathway and Its Interplay with Oncogenes in Lung Tumorigenesis.

Nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor regulating cellular redox homeostasis, exhibits a complex role in cancer biology. Genetic mutations in the Kelch-like ECH-associated protein 1 (KEAP1)/NRF2 system, which lead to NRF2 hyperactivation, are found in 20% to 30% of lung cancer cases. This review explores the intricate interplay between NRF2 and key oncogenic pathways in lung cancer, focusing on the interaction of KEAP1/NRF2 system with Kirsten rat sarcoma virus (KRAS), tumor protein P53 (TP53), epidermal growth factor receptor (EGFR), and phosphatidylinositol 3-kinases (PI3K)/AKT signaling. While NRF2 activation alone is insufficient to initiate tumorigenesis, it can significantly impact tumor initiation and progression when combined with oncogenic drivers such as KRAS. The review highlights the context-dependent effects of NRF2, from its protective role against chemical carcinogen-induced tumor initiation to its potential promotion of tumor growth in established cancers. These findings suggest the need for nuanced, stage-specific approaches to targeting the NRF2 pathway in cancer therapy.