Cell Biochemistry and Function最新文献

Cancer is a global health issue with a high mortality rate, and early detection significantly improves patient survival rates. Currently, the primary methods for cancer detection include imaging examination and tissue biopsy. However, due to technical limitations, early detection can result in invasiveness, false positives, and other complications for patients. Therefore, there is an urgent need for new cancer biomarkers to address these challenges and enhance the accuracy and non-invasiveness of detection. With advances in molecular biology, nucleic acid biomarkers have become invaluable for early cancer diagnosis, prognosis assessment, and therapeutic monitoring. Epigenetic biomarkers, such as DNA methylation and non-coding RNA, play a crucial role in tumorigenesis by regulating related gene expression. However, although they offer significant potential for early warning, the complexity of the detection process coupled with tissue specificity makes the interpretation of results challenging. Liquid biopsy, such as circulating tumor DNA (ctDNA), provide a non-invasive method for dynamic tumor monitoring. However, its applicability is limited due to low sensitivity and high cost. Combining these two approaches can help address their individual shortcomings. CtDNA methylation enhances screening specificity, while multimodal strategies are expected to overcome the limitations of single techniques. The purpose of this review is to explore the role of cancer nucleic acid markers in cancer diagnosis and prognosis, examine their molecular mechanisms, and evaluate the advantages and limitations of these markers. Additionally, it will discuss biomarkers related to the tumor microenvironment and immune response, and their interactions with nucleic acids.

This study uncovers a novel post-translational regulatory mechanism through which MDM2 stabilizes IL-33 via K63-linked ubiquitination, thus facilitating the progression of gastric cancer. Using MKN45 and AGS gastric cancer cells, we conducted MDM2 knockdown followed by qPCR and Western blot to evaluate IL-33 regulation. Co-IP and cycloheximide chase assays verified MDM2-IL-33 binding and stabilization. Ubiquitination assays using WT and mutant (K63R/K48-only) ubiquitin identified MDM2-dependent K63-linked polyubiquitination of IL-33. A subcutaneous xenograft tumor model in nude mice was established to validate the oncogenic role of the MDM2-IL-33 axis in vivo. Functional assays (CCK-8, colony formation, Transwell, and wound healing) revealed MDM2's requirement for IL-33-mediated oncogenic effects. Western blots showed MDM2-IL-33 axis modulates apoptosis (Bcl-2/Bax/Caspase-3) and ERK signaling (p-ERK/p-JNK). We have demonstrated that knocked down MDM2 significantly decreases IL-33 protein levels without influencing its mRNA expression, suggesting that the regulation occurred at the post-translational stage. Co-immunoprecipitation assays have confirmed the physical interaction between MDM2 and IL-33 in gastric cancer cell lines, namely MKN45 and AGS. Meanwhile, ubiquitination assays have revealed that MDM2 specifically mediated the K63-linked polyubiquitination of IL-33, thereby enhancing its stability. Functionally, overexpressing IL-33 promoted malignant phenotypes in gastric cancer cells, such as increased cell viability, enhanced clonogenic growth, and augmented invasion and migration capabilities. Intriguingly, depleting MDM2 effectively abolished these promoting effects. Mechanistically, the MDM2-IL-33 axis exerted its influence by suppressing apoptosis through modulating the expression of Bcl-2/Bax/Caspase-3, and by activating the oncogenic ERK/JNK signaling pathway. Crucially, MDM2 overexpression promoted tumor growth, which was effectively reversed by transfection with si-MDM2. These findings firmly established MDM2 as a crucial regulator of IL-33 stability and highlighted the significant therapeutic potential of targeting the MDM2-IL-33 interaction to impede gastric cancer progression.

6-MP and 5-FU are effective anticancer drugs; still, their efficacy is limited by inadequate solubility and dose-dependent toxicity. Propolis, high in bioactive chemicals, was investigated for its synergistic effects to improve efficacy. GC-MS analysis found 20 bioactive chemicals that were docked against cyclin-dependent kinase 2 and aromatase. Compounds 1,3-dipalmitin and rac-1-oleoyl-3-linoleoylglycerol demonstrated the highest affinities (− 10.93 to −13.18 kcal/mol), indicating possible inhibition of cell cycle and estrogen biosynthesis regulators. Co-treatment with propolis and chemotherapeutic exhibited a marked reduction of IC₅₀ values in both MCF-7 and HepG2 cells, with the most significant reduction for the 5-FU–propolis combination (IC₅₀ of 12.0 µg/mL) compared with 5-FU alone (26.2 µg/mL in MCF-7 and 15.8 µg/mL in HepG2). The Chou–Talalay analysis confirmed synergy (CI < 1), for 5 FU with propolis (CI = 0.46 in MCF 7). Combination therapy elicited S-phase arrest, also impairing mitochondrial membrane potential and altering the path of cell death toward necrosis and late-stage apoptosis. Propolis serves as a prospective chemotherapeutic adjuvant that enhances the anticancer efficacy of 6-MP and 5-FU, allowing dose reduction, minimizing toxicity, and potentially overcoming drug resistance in breast cancer treatment. However, the therapeutic use of this synergistic technique requires confirmation via pharmacokinetic profiling, extensive vivo research, and considered clinical trials.

Cadmium exposure is a known disruptor of ovarian redox homeostasis and steroidogenesis, with clinically relevant implications for fertility and pregnancy outcomes. We hypothesized that date seed extract (DS), rich in antioxidant constituents, and low-dose gamma radiation (LDR) could synergistically counteract Cd-induced ovarian toxicity. (1) To assess whether DS and/or low-dose γ-radiation mitigate Cd-induced oxidative stress, inflammatory signaling, and impairment of steroidogenesis; (2) to determine whether the combination of DS + LDR offers superior protection relative to single treatments; and (3) to evaluate whether biochemical improvements translate to preservation of ovarian histology. The present study highlights the combinatorial approach (DS + LDR) as a potential, novel intervention for reducing Cd-associated gonadotoxicity. Forty-eight female Swiss albino rats were allocated to eight groups (n = 6): Control; DS; R; DS + R; Cd; Cd + DS; Cd + R; Cd + DS + R. Treatments were administered for 21 days (DS) and 2 weeks (Cd exposure) with ongoing γ-radiation where indicated. Outcomes included: (i) oxidative stress markers (SOD, GSH); (ii) steroidogenic axis components (StAR, CYP11A1, 3β-HSD, 17β-HSD) at the ovarian level; (iii) hormonal profiles (e.g., estrogen, progesterone, and relevant gonadotropins); (iv) inflammatory signaling (NF-κβ); and (v) histopathology of ovarian sections. Cd exposure caused a significant decline in ovarian antioxidants (SOD, GSH) and a reduction in steroidogenic enzyme expression, accompanied by hormonal disturbances and prominent NF-κβ–driven inflammatory changes. Histologically, Cd induced cortical and follicular disruption with increased degenerative changes. DS and LDR mitigated these effects, with the combination DS + LDR showing the most robust rescue: antioxidant defenses and steroidogenic enzyme expression nearly normalized, hormonal levels stabilized, NF-κβ signaling reduced, and ovarian architecture preserved. Statistical significance was achieved for most endpoints (p < 0.05) and trends supported additive or synergistic benefits for DS + LDR. The combination of DS and low-dose γ-radiation offers superior protection against Cd-induced ovarian toxicity by restoring redox balance, downregulating inflammatory pathways, normalizing steroidogenesis, and preserving ovarian histology. These findings support further exploration of DS + R as a potential therapeutic strategy to mitigate heavy metal–related reproductive damage.

Many epigenetic drugs lack specificity, which may lead to drug resistance and long-term safety concerns. There is an urgent need to develop more precise nuclear-targeted drugs to reduce adverse reactions and harmful effects. The development of nuclear drugs relies on the exploration of new nuclear targeting mechanisms. This review delves into nuclear protein posttranslational modifications (PTMs), highlighting their roles in nuclear function and influence on cell fate. It showcases the diversity of PTMs, including acetylation, novel acylations, phosphorylation, ubiquitylation, oxidative modifications, itaconation, and citrullination, and differentiates the roles of these modifications between nuclear and non-nuclear proteins. The review partially highlights how nuclear PTMs impact key biological processes, gene expression, and cell function by interacting with cell metabolism. Additionally, it explores the regulatory mechanisms of nuclear PTMs and their implications in diseases such as cancers, and degenerative, metabolic, and inflammatory conditions, suggesting nuclear protein PTMs as potential therapeutic targets. It underscores the need for precise techniques and treatments to study PTMs and introduces the “metabolite-nuclear protein PTM-genome” axis as a novel conceptual framework for future research and therapeutic strategies.

Silent mating type information regulation 2 homolog (SIRT1), a key protein involved in cellular regulation, exhibits altered expression in breast cancer. The study aimed to assess serum Sirtuin 1 level, investigate SIRT1 gene polymorphisms, and examine their association with breast cancer. One hundred seventy-two breast cancer patients and 78 healthy age-matched females were included in the study. Genetic variants of the SIRT1 gene were identified using Polymerase Chain Reaction—Restriction Fragment Length Polymorphism/Sanger Sequencing and serum SIRT1 levels using Enzyme-Linked Immuno Sorbent Assay. Serum SIRT1 levels were significantly higher in breast cancer patients [0.822 (0.72–0.96)] than controls [0.752 (0.66–0.86)], p = 0.0027. Subgroup analyses revealed notable increases in Human epidermal growth factor receptor 2-positive (p = 0.0016), hormone-positive (p = 0.0232), and Triple Negative Breast Cancer groups (p = 0.4426) compared to the control group. The SIRT1 levels were also significantly associated with breast cancer (p = 0.0252). SIRT1 exhibited an Area Under Curve (AUC) of 0.618, with 58% sensitivity and specificity at a cutoff of 0.797, showing poor discriminative ability. rs141528984 had a significant difference in allele frequency between patient group and control group (OR = 3.48, 95% CI: 1.896–6.516), p < 0.0001. There were no significant associations between SIRT1 gene polymorphisms and serum Sirtuin 1 levels in breast cancer patients. The proliferation marker Ki67 showed a significant association (p = 0.0428) with specific SIRT1 variants, rs777323664, rs757804740, and rs184282868. SIRT1 levels are elevated in breast cancer patients indicate its potential as a diagnostic marker. Mutant alleles of rs141528984 were more common in controls compared to case group, indicating its protective function. Ki67 expression was associated with rs777323, rs757804740, and rs1842828683 which may contribute to tumor aggressiveness.

4-hydroxy-2-nonenal (4HNE), a reactive aldehyde produced during lipid peroxidation, reduces angiogenesis in cultured mouse coronary endothelial cells (MCECs). In our previous studies, we found that 4HNE lowers both mRNA and protein levels of vascular endothelial growth factor receptor 2 (VEGFR2), a key regulator of angiogenesis. Since VEGFR2 transcription is regulated by nuclear factor kappa B (NFκB)—a well-known transcription factor—and aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme that detoxifies 4HNE, we sought to investigate how the interaction between ALDH2, 4HNE, and NFκB and VEGFR2 affects angiogenesis. Given that coronary endothelial cell rarefaction contributes to cardiometabolic conditions such as heart failure with preserved ejection fraction (HFpEF), it is imperative to study the underlying signaling mechanisms regulating coronary angiogenesis. In this study, we hypothesized that activation of ALDH2 enhances NFκB signaling, thereby preventing the 4HNE-induced reduction in VEGFR2 expression and restoring angiogenesis. To test this, MCECs were treated with disulfiram (DSF; 2.5 μM), an ALDH2 inhibitor; Alda-1 (10 μM), an ALDH2 activator; and prostratin (10 μM), an NFκB activator, prior to 4HNE (75 μM) exposure. Prostratin treatment increased both cellular and nuclear levels of NFκB across all conditions. Alda-1 pretreatment significantly rescued 4HNE-induced impairment of angiogenesis (p < 0.005 vs. 4HNE), while prostratin further enhanced Alda-1's effects (p < 0.005 vs. Alda-1 alone). Alda-1 restored VEGFR2 levels suppressed by 4HNE, and this effect was further potentiated by prostratin (p < 0.0005 vs. Alda1). In conclusion, NFκB activation enhances the protective effect of ALDH2 against 4HNE-induced angiogenic dysfunction by restoring VEGFR2 expression.