Biomolecules & Therapeutics最新文献

Topically applied hyaluronic acid (HA) hydrates the skin without efficient penetration. This study compared the penetration efficiency of liposomal hyaluronic acid (LPS-HA) against that of conventional HA across different models. Dynamic light scattering revealed that particles of LPS-HA (226.1 nm, PDI 0.2898) were smaller than those of HA (798.4 nm, PDI 0.8709). In Strat-M® membrane assays, permeability over 24 h was higher with LPS-HA (629.37 ± 103.26%) than that of HA (508.04 ± 93.80%; p<0.05). In keratinocytes, LPS-HA increased differentiation markers filaggrin and caspase-14 in a concentration-dependent manner, with maximal induction at 1% (186.6 ± 6.99% and 249.3 ± 8.60%) vs. HA (117.9 ± 7.64% and 130.1 ± 2.90%; p<0.05). In fibroblasts, LPS-HA increased the expression of type I and type III collagens (138.4 and 133.6%) without increasing that of elastin (68.3-94.7%) and reduced UVB-induced IL-6 (79.1-90.2% of UVB; p<0.05). Ex vivo, LPS-HA enhanced HAS-3 mRNA (3.03 ± 0.19-fold vs. 1.31 ± 0.13-fold with HA; p<0.05) and increased epidermal hyaluronan staining. In PM10-treated human skin, LPS-HA reduced inflammatory cytokines (TNF-α, IL-6, IL-8, and IL-1β) and suppressed mast cell degranulation, similar to dexamethasone, and reduced ROS formation (124.46 ± 8.45% vs. 169.35 ± 9.40% in PM10-only, p<0.01) without histological abnormalities. In a 20-subject clinical study, corneometric hydration with LPS-HA was higher than that of control (96.99% vs. 36.31%; RM-ANOVA, p<0.001). Collectively, LPS-HA enhanced skin permeation, hydration, and anti-inflammatory responses, supporting its potential as a cosmetic moisturizing ingredient.

Ubiquitination of RIPK1 serves as a critical regulatory switch in determining the outcome of prosurvival NF-κB signaling by linking the TNFR1 signaling complex to upstream IKK activation. Therefore, identifying bioactive compounds that modulate RIPK1 ubiquitination has emerged as a promising strategy to enhance the therapeutic efficacy of TNF, particularly in cancers with constitutively active NF-κB signaling. In our previous in vitro phytochemical study, we demonstrated that brazilin, isolated from Caesalpinia sappan L., inhibits the catalytic activity of the IKK complex during TNF-mediated NF-κB activation without affecting RIPK1 ubiquitination at high concentrations (~50 μM), raising concerns about off-target effects. In this study, we now report that brazilein, an oxidized derivative of brazilin, acts as a potent inhibitor of RIPK1-dependent NF-κB activation upon TNFR1 engagement. Our findings reveal that brazilein markedly suppresses upstream IKK signaling events, including TNFR1-associated RIPK1 polyubiquitination and its interaction with IKKβ. In contrast, brazilein does not affect NIK/IKKα-mediated non-canonical NF-κB activation induced by LIGHT, indicating its specificity for the canonical NF-κB pathway. Moreover, brazilein not only sensitizes cells to TNF-induced apoptosis but also induces apoptosis in A20-deficient and oncogenically transformed cells with constitutive NF-κB activity. Taken together, these results suggest a novel mechanism by which brazilein exerts anti-IKK activity through inhibition of RIPK1 ubiquitination, highlighting its potential as a candidate for NF-κB-targeted cancer therapy.

Obesity is a global health problem associated with several metabolic disorders. Conventional dietary supplements such as Garcinia cambogia, catechin, and conjugated linoleic acid (GC complex) are widely used for weight loss but raise concerns about long-term efficacy and safety. Recent advances in nutritional research suggest that combining dietary mineral elements might enhance obesity therapeutic outcomes. The objective of this study is to investigate the potential synergistic effects of potassium in combination with GC complex in a mouse model of high-fat diet (HFD)-induced obesity. When administered daily orally for 12 weeks, the HFD+GC+Potassium group exhibited synergistically reduced adipocyte size in both white and brown adipose tissue compared to the HFD group, indicating a reduction in fat storage. In addition, HFD+GC+Potassium group exhibited a marked improvement in metabolic profiles, characterized by reduced fasting glucose and total cholesterol levels without toxicity, compared with HFD group. Histological analyses confirmed the effectiveness of the treatment, showing marked reductions in hepatic steatosis and lipid accumulation, as evidenced by H&E and Oil Red-O staining in the HFD+GC+Potassium group. Significantly, the study showed that potassium supplementation in combination with GC complex improved lipid metabolism and energy expenditure by increasing the expression of phosphorylated acetyl-CoA carboxylase 1 (p-ACC1) and carnitine palmitoyltransferase I (CPT1), while decreasing the levels of fatty acid synthase (FAS) and sterol regulatory element-binding protein 1 (SREBP1) through IGF1R/PI3K/AKT/GSK3β axis. These findings suggest that the combination of GC complex and dietary potassium may offer a synergistic effect and a safe strategy for managing obesity by reducing fat accumulation and enhancing metabolic health.

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.