Pterostilbene is a natural polyphenolic compound that is primarily found in fruits, such as blueberries and has a similar structure to resveratrol. Pterostilbene exhibits antioxidant, anti-inflammatory and antitumor activity but the effects of pterostilbene on drug-resistant oral cancer cells and its underlying mechanisms of action have not yet been explored. Therefore, the present study was performed to clarify the anticancer effects of pterostilbene on cisplatin-resistant human oral cancer CAR cells. The results demonstrated that CAR cells exhibited marked shrinkage, cell membrane breakage and autophagic vacuole formation following treatment with pterostilbene. Pterostilbene also effectively inhibited cell viability and suppressed cell confluence in a time- and concentration-dependent manner. Probing with acridine orange, monodansylcadaverine and LysoTracker Red demonstrated that the number of acidic vesicular organelles was increased, indicating increased autophagy. Furthermore, Heochst 33342 staining determined that DNA condensation, a characteristic of apoptosis, was enhanced following treatment with pterostilbene. Furthermore, pterostilbene upregulated mRNA levels of LC3-II and Atg12, as well as the expression of Atgs/Beclin-1/LC3-associated signaling, suggesting that it enhances autophagy. The autophagy inhibitors 3-methyladenine and chloroquine were used to confirm that pterostilbene induces autophagy. It was also determined that pterostilbene triggered caspase-dependent apoptosis by directly testing DNA breakage and using the pan-caspase inhibitor carbobenzoxyvalyl-alanyl-aspartyl fluoromethyl ketone. The results demonstrated that pterostilbene mediates the apoptosis of CAR cells via the intrinsic apoptotic cascade. In addition, pterostilbene inhibited MDR1 expression and the phosphorylation of AKT on the Ser473 site in CAR cells. Therefore, pterostilbene may elicit an oral anticancer response in drug-resistant cells and may be used as a chemotherapeutic adjuvant to treat patients with oral cancer.

Background: Several studies have suggested that drug resistance in colon cancer patients with diabetes may be associated with long-term insulin administration, which in turn decreases the survival rate. Metformin is a commonly used drug to treat diabetes but has been recently demonstrated to have a potential therapeutic effect on colon cancer. This study aimed to elucidate the underlying mechanism by which metformin reverts insulin-induced oxaliplatin resistance in human colon cancer HCT116 cells. Methods: Two colon cancer cell lines (HCT116 and LoVo) were used to verify whether the expression of insulin receptor substrate 1 (IRS-1) could impact the half maximal inhibitory concentration (IC50) of oxaliplatin after chronic insulin treatment. The IC50 of oxaliplatin in both cell lines was measured to identify metformin sensitization to oxaliplatin. The adenosine monophosphate-activated protein kinase (AMPK) inhibitor, namely AMPK small interfering RNA, was used to block AMPK activation to identify critical proteins in the AMPK/Erk signaling pathway. Bcl-2 is a vital antiapoptotic protein involved in the mitochondrial apoptosis pathway. Finally, immunofluorescence and electron microscopy were performed to investigate how metformin affects the ultrastructural integrity of mitochondria. Results: The IC50 of oxaliplatin in HCT116 cells was noticeably increased. After the cells were treated with metformin, oxaliplatin resistance was reversed. According to the results of the western blotting assay of vital proteins involved in the classical apoptosis pathway, cleaved caspase-9 was noticeably upregulated, suggesting that the mitochondrial apoptosis pathway was activated. These results were verified by imaging of mitochondria using electron microscopy. The AMPK/Erk signaling pathway experiments revealed that the upregulation of Bcl-2 induced by insulin through Erk phosphorylation was inhibited by metformin and that such inhibition could be mitigated by the inhibition of AMPK. Conclusions: Insulin-induced oxaliplatin resistance was reversed by metformin-mediated AMPK activation. Accordingly, metformin is likely to sensitize patients with diabetes to chemotherapeutic drugs used to treat colon cancer. |

Endometrial cancer (EC) is one of the most common malignancies of the female reproductive system, and metastasis is a major cause of mortality. In this study, we aimed to explore the role of CP-31398 in the migration, invasion and apoptosis of EC cells by its regulation of the expression of the murine double minute 2 (MDM2) gene. For this purpose, EC tissues and adjacent normal tissues were collected, and the positive expression rate of MDM2 in these tissues was assessed. Subsequently, the cellular 50% inhibitory concentration (IC50) of CP-31398 was measured. The EC RL95-2 and KLE cell lines had a higher MDM2 expression and were thus selected for use in subsequent experiments. The EC cells were then treated with CP-31398 (2 µg/ml), and were transfected with siRNA against MDM2 or an MDM2 overexpression plasmid in order to examine the effects of CP-31398 and MDM2 on EC cell activities. The expression of p53, p21, Bad, Bax, B-cell lymphoma-2 (Bcl-2), cytochrome c (Cyt-c), caspase-3, Cox-2, matrix metalloproteinase (MMP)-2 and MMP-9 was measured to further confirm the effects of CP-31398 on cell migration, invasion and apoptosis. Our results indicated that MDM2 was highly expressed in EC tissues. Notably, EC cell viability decreased with the increasing concentrations of CP-31398. The EC cells treated with CP-31398 or siRNA against MDM2 exhibited an increased apoptosis and a suppressed migration and invasion, corresponding to an increased expression of p53, p21, Bad, Bax, Cyt-c and caspase-3, as well as to a decreased expression of Bcl-2, Cox-2, MMP-2 and MMP-9. Moreover, treatment with CP-31398 and siRNA against MDM2 further enhanced these effects. Taken together, the findings of this study indicate that the CP-31398-mediated downregulation of MDM2 may suppress EC progression via its inhibitory role in EC cell migration, invasion and resistance to apoptosis. Therefore, treatment with CP-31398 may prove to be possible therapeutic strategy for EC.

Mutation in the tumor suppressor gene p53 is the most frequent molecular defect in endometrial carcinoma (EC). Recently, CP‐31398, a p53‐stabilizing compound, has been indicated to possess the ability to alter the expression of non‐p53 target genes in addition to p53 downstream genes in tumor cells. Herein, we explore the alternative mechanisms underlying the restoration of EC tumor suppressor function in mutant p53 by CP‐31398. A p53‐mutated EC cell was constructed in AN3CA cells with restored or partial loss of Slug using lentiviral vectors, followed by treatment with 25 μM CP‐31398. A p53‐independent mechanism of CP‐31398 was confirmed by the interaction between mouse double minute 2 homolog (MDM2) and Slug AN3CA cells treated with IWR‐1 (inhibitor of Wnt response 1). Furthermore, the AN3CA cells were treated with short hairpin RNA against Slug, Wnt‐specific activators (LiCl) or inhibitors (XAV‐939) followed by CP‐31398 treatment. Moreover, AN3CA cell proliferation and apoptosis were examined. A tumorigenicity assay was conducted in nude mice. CP‐31398 could promote the apoptosis of p53‐mutated EC cells, while Slug reversed this effect. Slug ubiquitination was found to occur via binding of Slug to MDM2 in AN3CA cells. We found that CP‐31398 increased the GSK‐3ß, p‐Slug, Puma, Wtp53, and Bax expressions whereas Wnt, Mtp‐53, Slug, Bcl‐2, and Ki‐67 expressions were decreased. However, these findings were reversed following the activation of the Wnt pathway and overexpression of Slug. Finally, the in vivo experimental evidence confirmed that CP‐31398 with depleted Slug suppressed tumor growth by downregulating the Slug. Collectively, CP‐31398‐regulated Slug downregulation represses the p53‐mutated EC via the p53/Wnt/Puma pathway.

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The way that males and females react to environmental exposures and negative impacts on their neurological systems is often different. Although previous research has examined the cognitively impairing effects of solitary metal exposures, the relationship between metal mixtures and cognitive function, particularly when considering an individual’s sex, remains elusive. This study aimed to investigate the sex differences in the association between multiple metal combinations and cognitive function in older Americans. This research employed the 2011–2014 NHANES survey of elderly Americans. The association between five mixed metals and four cognitive tests (the animal fluency test (AFT), the digit symbol substitution test (DSST), the instant recall test (IRT), and the delayed recall test (DRT)) were investigated with generalized linear regression model (GLM), Bayesian kernel machine regression model (BKMR), weighted quantile sum regression model (WQS), and quantile g-computation regression model (Qgcomp). A total of 1833 people, including 883 males and 950 females, enrolled in this cross-sectional study. We discovered that blood lead and blood cadmium were negatively associated with cognitive performance, while blood selenium demonstrated a positive association with cognitive function in older people. The negative relationship of heavy metal combinations on cognitive function might be somewhat reduced or even reversed via selenium. The IRT, AFT, and DSST are three of the four cognitive tests where men had more dramatic positive or negative results. There was a sex-specific connection between blood metal ratios and cognitive function among older Americans, as evidenced by the more significant relationship between mixed metals and cognitive performance in men (either positively or negatively). These results emphasize the impacts of ambient heavy metal exposure on cognitive function by employing sex-specific methods.

Post-translational modification of proteins increases their diversity and maintains the stability of the intracellular environment. Protein arginine methyltransferases (PRMTs) are an important family of epigenetic modification enzymes, which play a critical role in post-translational modification. In recent years, with the in-depth study of the role of epigenetics, the structure and function of PRMTs have been gradually understood. PRMT enzymatic activity is related to a variety of cellular processes in digestive system malignancies, such as inflammation and immune response, activation of cell cycle and proliferation, inhibition of apoptosis, DNA damage repair, epithelial-mesenchymal transition (EMT). A variety of chemical tools are developed to inhibit PRMT activity, which have been verified by tumor models and clinical trials. This review summarizes the structure and functions of PRMTs as a prelude to our further studies on their role in tumors. The involvement of different PRMTs in the pathogenesis of gastrointestinal tumors is then reviewed. In addition, the application of PRMT inhibitors as therapeutic agents for digestive system cancers is highlighted. In conclusion, PRMTs play an important role in the pathogenesis of gastrointestinal tumors, and their prognostic and therapeutic potential warrants further investigation.

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