Biomolecules & Therapeutics最新文献

Steroid receptor coactivator-1 (SRC-1) is documented in various cancers and primarily mediates tumor growth and metastasis. Nevertheless, the specific effects and underlying mechanisms of SRC-1 in lung cancer have not been fully explored. This study aims to elucidate the role of SRC-1 in lung cancer progression and its impact on cancer stemness. In this study, we found that SRC-1 was expressed higher in human lung cancer tissues compared to normal lung tissues, with a positive correlation between SRC-1 expression and rates of distant metastasis and lymph node involvement. High SRC-1 expression was correlated with a poor prognosis of lung cancer. In vitro, silencing SRC-1 in lung cancer cell lines repressed cell proliferation, invasion, migration, and enhanced the sensitivity of lung cancer cells to gefitinib. In vivo, silencing SRC-1 in lung cancer cells decreased tumor size and weight in a subcutaneous xenograft mouse model. Furthermore, SRC-1 knockdown inhibited the lung metastasis and reduced twist1 expression. Mechanistically, SRC-1 promoted sphere formation and induced increased expression of the markers of cancer stem cells in lung cancer cells. Besides, SRC-1 positively correlated with c-Myc in human lung cancer. Overexpression of SRC-1 in lung cancer cell lines up-regulated mRNA and protein expression of c-Myc, suggesting that SRC-1 may enhance lung cancer stemness via up-regulating c-Myc. This study demonstrated that aberrantly high levels of SRC-1 in lung cancer contribute to tumor growth and metastasis by enhancing cancer stemness, suggesting that targeting SRC-1 could be a novel potential therapeutic strategy in the treatment of lung cancer.

Gnetofuran A, a newly extracted compound from Gnetum latifolium, possesses anti-inflammatory effects by inhibiting TNF-α activity. However, the function and mechanism of Gnetofuran A in osteoblast differentiation remain unknown. In this study, we found that Gnetofuran A enhanced osteoblast differentiation and upregulated the mRNA levels of osteogenic genes, including alkaline phosphatase (ALP) and osteocalcin (OC). Meanwhile, Gnetofuran A improved protein levels of Runt-related gene 2 (Runx2) and Osterix, the key transcription factors in osteoblast differentiation. Furthermore, we discovered that p38 MAPK signaling is involved in Gnetofuran A-induced osteoblast differentiation. A docking analysis showed the potential interaction between Gnetofuran A and p38. Taken together, our study provides a new biological function of Gnetofuran A and a therapeutic candidate for osteoporosis.

Ovarian cancer is the leading cause of death among gynecological malignancies worldwide. Surgery and chemotherapy are the primary treatment modalities; however, their effectiveness significantly diminishes in the advanced stages of the disease. There is emerging evidence suggesting that natural products, including phytochemicals, could be beneficial in treating ovarian cancer. In this study, we employed SKOV3 cells to investigate the anticancer activity and the specific mechanisms of corylin, a principal flavonoid isolated from the fruit of Psoralea corylifolia. Corylin inhibited SKOV3 cell proliferation and colony formation in a dose-dependent manner. It also induced apoptosis through the activation of caspases and disruption of the mitochondrial membrane potential. Moreover, corylin caused G0/G1 cell cycle arrest by modifying the levels of cyclin D1 and the phosphorylated retinoblastoma protein. Further mechanistic studies demonstrated a marked downregulation of Signal transducer and activator of transcription 3 (STAT3) phosphorylation, nuclear localization, and target gene expression in corylin-treated SKOV3 cells. These findings suggest that corylin is a promising therapeutic agent for inhibiting cancer cell proliferation by targeting STAT3 in ovarian cancer.

B cells are essential for the defense against various infectious agents including severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) causing coronavirus disease 2019 (COVID-19). COVID-19 is caused by interaction of the spike protein (SP) with the receptor-binding domain (RBD) and its receptor, angiotensin converting enzyme 2 (ACE2). Bisphenol A (BPA), a plasticizer and endocrine-disrupting chemical, can enter the human body through several exposure routes. Previously, we reported human B cell death by BPA treatment via autophagy induction. Here, we investigated whether the exposure to BPA affects B cell susceptibility to SP of COVID-19 and how to interfere the interaction of SP and ACE2. We observed an increase in ACE2 gene expression in human B cells by BPA treatment and more SP binding in BPA-treated B cells. Our data also showed more B cell death accompanying increased autophagic puncta count and lysosomal intracellular activity by co-treatment with BPA and SP compared to those in BPA treatment alone. Ursodeoxycholic acid (UDCA) reduced SP binding in B cells in BPA-exposed B cells. UDCA treatment also inhibited B cell death and lysosomal enzyme activity which were enhanced by co-treatment of BPA and SP. Taken together, results demonstrate that BPA-exposed B cells are more susceptible to COVID-19. It also suggests that UDCA could be protective to SP-responding B cells exposed to BPA.

Disruptor of Telomeric Silencing 1-Like (DOT1L) has emerged as a critical epigenetic regulator in cancer, primarily because of its role as the sole histone methyltransferase responsible for histone H3 at lysine 79 methylation. This modification affects transcriptional activation, DNA repair, and cell cycle progression. Its dysregulation is associated with both hematological and solid tumors. In Mixed-lineage leukemia (MLL)-rearranged leukemia, DOT1L maintains aberrant gene expression patterns at loci such as HOXA and MEIS1, supporting leukemic stem cell survival and driving oncogenesis. In solid tumors, DOT1L influences diverse processes, including epithelial-mesenchymal transition, angiogenesis, and cell cycle regulation, contributing to tumor growth and metastasis. Therapeutic strategies targeting DOT1L using inhibitors, such as EPZ-5676, have shown promise in preclinical and clinical studies, highlighting their potential as versatile targets for precision oncology. This review summarizes the recent findings on DOT1L's involvement in cancer development and its potential as a therapeutic target.

N-Acetyldopamine oligomers are typically biosynthesized as racemic mixtures, yet enantiomers can differ markedly in pharmacological efficacy and safety. In this study, we isolated a pair of enantiomers of an N-acetyldopamine dimer (compound 1) from Cicadidae Periostracum, a traditional medicinal substance, and characterized their structures using mass spectrometry and 1D/2D NMR spectroscopy. The absolute configurations of the enantiomers-1a (2S,3R,1''R) and 1b (2R,3S,1''S)-were determined for the first time through a combination of electronic circular dichroism and Mosher's esterification analysis. Biological evaluation revealed striking differences in activity between the two enantiomers. Specifically, 1a exhibited significant neuroprotective effects against rotenone-induced cytotoxicity in SH-SY5Y neuroblastoma cells, while 1b was inactive. Compound 1a attenuated oxidative stress by reducing intracellular and mitochondrial reactive oxygen species and elevating glutathione levels. Mechanistically, only 1a activated nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant defenses. Molecular docking studies further indicated a stronger interaction of 1a with Keap1, the repressor of Nrf2, suggesting a structural basis for the enantioselective activation of the pathway. To our knowledge, this is the first report to assign the absolute configuration at C-1'' of this class of compounds and to demonstrate enantioselective neuroprotective activity mediated by the Nrf2 pathway. These findings underscore the therapeutic potential of insect-derived chiral natural products and provide a rationale for developing stereochemically defined neuroprotective agents for the treatment of neurodegenerative diseases such as Parkinson's disease.

Many chemotherapeutic agents exert their cytotoxic effects primarily by inducing DNA damage. In response to DNA damage, cells activate a signaling cascade known as DNA damage response (DDR) to repair the damage and promote cell survival. Accordingly, the capacity of the DDR in cancer cells is a critical factor that influences their sensitivity to chemotherapy. Here, we identified a role for interferon γ-inducible protein 16 (IFI16) in modulating the DDR and chemosensitivity of breast cancer cells. Depletion of IFI16 in MDA-MB-231 cells conferred resistance to the DNA-damaging agents doxorubicin and 5-fluorouracil, as evidenced by increased cell viability and reduced caspase-3 cleavage compared to control cells. Mechanistically, IFI16 interacted with the MRE11-RAD50-NBS1 complex and disrupted the interaction between NBS1 and ataxia telangiectasia mutated (ATM), a critical step for ATM activation. In vivo, xenograft tumors derived from IFI16 knockout cells exhibited diminished responses to doxorubicin treatment, characterized by decreased apoptotic cell death and reduced expression of DSB marker proteins, such as γH2AX and 53BP1. Furthermore, analysis of breast cancer patient datasets revealed that high IFI16 expression correlated with an improved pathological complete response rate following chemotherapy. Our findings suggest that IFI16 could serve as both a predictive biomarker for chemotherapy response and a potential therapeutic target for enhancing the efficacy of DNA-damaging agents.

Diabetes mellitus (DM) is a disorder characterized by hyperglycemia, inflammation, and impaired metabolic activities. This study investigated the effects of sialyllactose (SL), a subgroup of human milk oligosaccharides, on streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) in vivo. Male ICR mice were preadministered SL followed by a single intraperitoneal injection of STZ to establish the T1DM model. The evaluation was conducted through biochemical analyses, glucose and insulin tolerance tests, histological assessments, qRT-PCR, and western blotting. We found that SL pretreatment improved body weight, glucose tolerance, and fasting blood glucose levels in mice. SL mitigated STZ-induced organ injury, as evidenced by histological analysis and serum markers of liver, pancreas, kidney, and skeletal muscle damage. SL also improved electrolyte and lipid profiles, indicating its role in metabolism. Notably, SL exhibited strong anti-inflammatory properties by inhibiting hepatic TNF-α and MCP-1 mRNA expression and reducing inducible nitric oxide synthase protein expression. Taken together, our findings suggest that SL is a promising candidate for DM management based on its beneficial effects on inflammation and metabolic modulation.

Microglia have emerged as key regulators in Alzheimer's disease (AD), yet the molecular factors driving their dysfunction remain unclear. Through integrative transcriptomic and proteomic analyses, we identified PLXDC2, a transmembrane receptor, as a protein consistently upregulated in the AD brain and cerebrospinal fluid. Single-nucleus RNA-seq confirmed its microglia-specific enrichment, particularly in lipid-processing, phagocytic, and inflammatory subclusters. Functional assays revealed that PLXDC2 overexpression in BV2 microglial cells impaired Aβ uptake and suppressed pro-inflammatory cytokines Il-6 and Il-1β, without altering lipid droplet formation. These findings indicate that PLXDC2 plays a regulatory role in critical microglial functions and may drive AD pathogenesis by disrupting phagocytic activity and immune responses.

Human chimeric antigen receptor T (hCAR-T) cells are highly potent cellular therapeutics, but their clinical utility depends on stable long-term preservation due to high production costs and lengthy manufacturing processes. Cryopreservation is essential for ensuring the quality and logistics of these therapies. However, current commercial cryoprotectants such as CellBanker^® are limited by high cost, undisclosed composition, and lack of flexibility for optimization. This study aimed to evaluate defined sugar-based cryoprotectants-trehalose, sucrose, and glucose-as potential alternatives for hCAR-T cell preservation. hCAR-T cells were cryopreserved using various concentrations of the three sugars in combination with DMSO. Post-thaw evaluations included viability, recovery, apoptosis, proliferative capacity, and immunophenotypic analysis. At 18 h after thawing, glucose 50 mM significantly improved recovery (1.03 ± 0.29 vs. 1.59 ± 0.20×10⁶ cells) and reduced apoptosis (52.58 ± 7.31% vs. 39.50 ± 2.16%) compared with DMSO alone. These results were comparable to, and in some cases exceeded, those obtained with the commercial product CellBanker^®. Moreover, glucose at 50 mM exhibited approximately 1.9-fold higher cell proliferation after three days of culture compared to CellBanker^®, while preserving a stable CD4⁺/CD8⁺ ratio and central memory T cell (T_CM) profile. These findings indicate that sugar-based cryoprotectants, particularly glucose at 50 mM, can support post-thaw survival and function of hCAR-T cells. Given their defined composition, lower cost, and comparable efficacy, sugar-based formulations represent promising alternatives to commercial cryopreservation agents for advanced cell therapies.