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Target identification in natural products plays a critical role in the development of innovative drugs. Bufalin, a compound derived from traditional medicines, has shown promising anti-cancer activity; however, its precise molecular mechanism of action remains unclear. Here, we employ artificial intelligence, molecular docking, and molecular dynamics simulations to elucidate the molecular mechanism of Bufalin. Using an integrated multi-predictive strategy, we identify CYP17A1, ESR1, mTOR, AR, and PRKCD as the potential targets of Bufalin. Subsequent validation via surface plasmon resonance, biotin pulldown, and thermal shift assays confirms Bufalin’s direct binding to ESR1, which encodes estrogen receptor alpha (ERα). Molecular docking analyses pinpoint Bufalin’s selective interaction with Arg394 on ERα. Molecular dynamic simulations further show that Bufalin acts as a molecular glue, enhancing the interaction between ERα and the E3 ligase STUB1, thereby promoting proteasomal degradation of ERα. Given the therapeutic potential of ERα degradation in overcoming endocrine resistance, we investigate the inhibitory effect of Bufalin on endocrine-resistant models and prove Bufalin reverses Tamoxifen resistance in vitro, in vivo, and in patient-derived breast cancer organoids from tamoxifen-relapsed cases. Collectively, our findings indicate that Bufalin functions as a molecular glue to degrade ERα, offering a potential therapeutic strategy for reversing Tamoxifen resistance. Target identification of natural products plays a critical role in the development of innovative drugs. Here, this group integrates molecular docking and molecular dynamics simulations on Bufalin and reports the potential targets as well as its role in reversing endocrine resistance.

In this study, it is found that the lncRNA, DNA damage inducible transcript 4 antisense RNA1 (DDIT4‐AS1), is highly expressed in triple‐negative breast cancer (TNBC) cell lines and tissues due to H3K27 acetylation in the promoter region, and promotes the proliferation, migration, and invasion of TNBC cells via activating autophagy. Mechanistically, it is shown that DDIT4‐AS1 induces autophagy by stabilizing DDIT4 mRNA via recruiting the RNA binding protein AUF1 and promoting the interaction between DDIT4 mRNA and AUF1, thereby inhibiting mTOR signaling pathway. Furthermore, silencing of DDIT4‐AS1 enhances the sensitivity of TNBC cells to chemotherapeutic agents such as paclitaxel both in vitro and in vivo. Using a self‐activatable siRNA/drug core–shell nanoparticle system, which effectively deliver both DDIT4‐AS1 siRNA and paclitaxel to the tumor‐bearing mice, a significantly enhanced antitumor activity is achieved. Importantly, the codelivery nanoparticles exert a stronger antitumor effect on breast cancer patient‐derived organoids. These findings indicate that lncRNA DDIT4‐AS1‐mediated activation of autophagy promotes progression and chemoresistance of TNBC, and targeting of DDIT4‐AS1 may be exploited as a new therapeutic approach to enhancing the efficacy of chemotherapy against TNBC. DNA damage inducible transcript 4 antisense RNA1 (DDIT4‐AS1) is identified as a oncogenic lncRNA in triple‐negative breast cancer (TNBC). Mechanistically, DDIT4‐AS1 stabilizes DDIT4 mRNA via recruiting the RNA binding protein AUF1, which subsequently inactivates mTORC1 and induces cyto‐protective autophagy. A smart metal–organic framework nanosystem is fabricated to effectively load DDIT4‐AS1 siRNA and paclitaxel (PTX) for the treatment of TNBC.

Fermented dairy foods such as yogurt exhibit some beneficial effects on consumers, including relieving the symptoms of hypertension. This study aims to obtain fermented dairy products from a co-starter that have a great flavor and the auxiliary function of reducing blood pressure after longtime consumption. Commercial starter cultures composed of Lactobacillus delbrueckii subsp. bulgaricus CICC 6047 and Streptococcus thermophilus CICC 6038 were combined with Lactobacillus plantarum strains Y44, Y12, and Y16, respectively, as a combined starter culture to ferment the mixed milk of skim milk and soybean milk. The fermented milk produced using the combined starter culture mixed with L. plantarum Y44 showed an angiotensin-converting-enzyme (ACE) inhibitory activity (53.56 ± 0.69%). Some peptides that regulate blood pressure were released in the fermented milk, such as AMKPWIQPK, GPVRGPFPII, LNVPGEIVE, NIPPLTQTPV, and YQEPVL. In spontaneously hypertensive rat (SHR) oral-administration experiments compared with the gavage unfermented milk group, the gavage feeding of SHRs with the fermented milk produced using the combined starter culture mixed with L. plantarum Y44 significantly reduced the blood pressure of the SHRs after long-term intragastric administration, shown with the systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreasing by 23.67 ± 2.49 mmHg and 15.22 ± 2.62 mmHg, respectively. Moreover, the abundance of short-chain fatty acids (SCFA), bacterial diversity in the gut microbiota, and SCFA levels including acetic acid, propionic acid, and butyric acid in the feces of the SHRs were increased via oral administration of the fermented milk produced using the combined starter culture containing L. plantarum Y44. Furthermore, the ACE-angiotensin II (Ang II)-angiotensin type 1 (AT 1) axis was downregulated, the angiotensin-converting-enzyme 2 (ACE 2)-angiotensin(1-7) (Ang1-7)-Mas receptor axis of the SHRs was upregulated, and then the RAS signal was rebalanced. The fermented milk obtained from the combined starter culture shows the potential to be a functional food with antihypertension properties.

Background/Objectives: This study characterized the endogenous peptide profile of human milk from a Chinese multicenter cohort (n = 200 mothers) using the Orbitrap Fusion Lumos LC-MS/MS. Methods: Samples were collected across different lactation stages (2 and 6 months postpartum) and seven geographic regions (Beijing, Chengdu, Guangzhou, Jinhua, Lanzhou, Weihai, and Zhengzhou). Results: In total, 6960 peptides derived from 621 proteins were identified. Peptides from the polymeric immunoglobulin receptor (PIGR) were more abundant in the 2nd month than the 6th month, providing a high antimicrobial activity and immune functions for the infants. Moreover, region-specific variations were observed, with milk from Lanzhou exhibiting significantly higher levels of β-casein (CASB) and butyrophilin subfamily 1 member A1 (BTN1A1) peptides compared to other cities. Conclusions: Furthermore, maternal dietary intake of oils and total fat correlated positively with the intensity of specific antimicrobial peptides, including CASB_199–216, CASB_200–226, and CASB_201–226. Infant growth parameters were inversely correlated with several antimicrobial peptides, although CASB_200–225 demonstrated positive associations. These findings offer novel insights into the dynamics of endogenous peptides in human milk and may guide breastfeeding recommendations and infant formula design.

Protein, as one of the main ingredients for infant formula, may be closely related to the undesirable foam formed during the reconstitution of infant formula. Demineralized whey powder (D70 and D90), whey protein concentrate (WPC), and skimmed milk powder (SMP) are the four protein ingredients commonly used in infant formula formulation. The foaming and physicochemical properties of these four protein ingredients from different manufacturers were analyzed in the present study. Significant differences (p < 0.05) in foaming properties were found between the samples from different manufacturers. SMP showed a highest foaming capacity (FC) and foam stability (FS), followed by D70, D90, and WPC. Although the protein composition was similar based on reducing SDS-PAGE, the aggregates varied based on non-reducing SDS-PAGE, probably resulting in the different foaming properties. Particle size, zeta potential, and solubility of the protein ingredients were assessed. The protein structure was evaluated by circular dichroism, surface hydrophobicity, and free sulfhydryl. Pearson’s correlation analysis demonstrated that FC and FS were positively correlated with random coil (0.55 and 0.74), β-turn (0.53 and 0.73), and zeta potential (0.55 and 0.51) but negatively correlated with β-strand (−0.56 and −0.71), free sulfhydryl (−0.56 and −0.63), particle size (−0.45 and −0.53), and fat content (−0.50 and −0.49). The results of this study could provide a theoretical guidance for reducing formation of foam of infant formula products during reconstitution.

Conventional spectrophotometric methods were unable to accurately detect urea concentrations below 100 μg/L. A modified spectrophotometric method was developed to determine the trace urea in the ultrapure water (UPW) production process of the semiconductor manufacturing industry. This method was optimized based on the dosage of chemical agents, length of the optical path, and mode of the water bath. Metal ions were added to promote the stability of the chromogenic system. A calibration graph was observed with ideal linearity in the range of 0.8–100 μg/L. The detection and quantification limits of urea were 0.24 and 0.80 μg/L, respectively. The distribution of urea in raw water for the UPW production process was observed and the urea in tap water was 10–20 μg/L. The urea of municipal reclaimed water was 24–40 μg/L, which was twice that of industrial reclaimed water at 10–18 μg/L. The total removal rate of urea by the UPW production process was 50–70%. Reverse osmosis membranes played a critical role in the removal of urea (over 30%). The urea in the final UPW produced from tap water was approximately 4.1 μg/L, which creates a potential risk of excessive total organic carbon.

Oncogenic activation of the mTOR signaling pathway occurs frequently in tumor cells and contributes to the devastating features of cancer, including breast cancer. mTOR inhibitors rapalogs are promising anticancer agents in clinical trials; however, rapalogs resistance remains an unresolved clinical challenge. Therefore, understanding the mechanisms by which cells become resistant to rapalogs may guide the development of successful mTOR-targeted cancer therapy. In this study, we found that eEF-2K, which is overexpressed in cancer cells and is required for survival of stressed cells, was involved in the negative-feedback activation of Akt and cytoprotective autophagy induction in breast cancer cells in response to mTOR inhibitors. Therefore, disruption of eEF-2K simultaneously abrogates the two critical resistance signaling pathways, sensitizing breast cancer cells to rapalogs. Importantly, we identified mitoxantrone, an admitted anticancer drug for a wide range of tumors, as a potential inhibitor of eEF-2K via a structure-based virtual screening strategy. We further demonstrated that mitoxantrone binds to eEF-2K and inhibits its activity, and the combination treatment of mitoxantrone and mTOR inhibitor resulted in significant synergistic cytotoxicity in breast cancer. In conclusion, we report that eEF-2K contributes to the activation of resistance signaling pathways of mTOR inhibitor, suggesting a novel strategy to enhance mTOR-targeted cancer therapy through combining mitoxantrone, an eEF-2K inhibitor.

Dysregulated eEF2K expression is implicated in the pathogenesis of many human cancers, including triple‐negative breast cancer (TNBC), making it a plausible therapeutic target. However, specific eEF2K inhibitors with potent anti‐cancer activity have not been available so far. Targeted protein degradation has emerged as a new strategy for drug discovery. In this study, a novel small molecule chemical is designed and synthesized, named as compound C1, which shows potent activity in degrading eEF2K. C1 selectively binds to F8, L10, R144, C146, E229, and Y236 of the eEF2K protein and promotes its proteasomal degradation by increasing the interaction between eEF2K and the ubiquitin E3 ligase βTRCP in the form of molecular glue. C1 significantly inhibits the proliferation and metastasis of TNBC cells both in vitro and in vivo and in TNBC patient‐derived organoids, and these antitumor effects are attributed to the degradation of eEF2K by C1. Additionally, combination treatment of C1 with paclitaxel, a commonly used chemotherapeutic drug, exhibits synergistic anti‐tumor effects against TNBC. This study not only generates a powerful research tool to investigate the therapeutic potential of targeting eEF2K, but also provides a promising lead compound for developing novel drugs for the treatment of TNBC and other cancers. Dysregulated eukaryotic elongation factor 2 kinase (eEF2K) expression is implicated in the pathogenesis of triple‐negative breast cancer (TNBC). Compound C1 is designed and synthesized, which shows potent activity in degrading eEF2K protein. C1 significantly inhibits the proliferation and metastasis of TNBC. These findings provide a promising therapeutic strategy for the development of novel therapeutic drugs for TNBC treatment.

Background Baricitinib, an oral-administrated selective inhibitor of the JAK1 and JAK2, is recently approved for rheumatoid arthritis (RA) treatment. With the aim to provide some insights on the clinical safety, the current study mainly focused on the effect of baricitinib on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels and cardiovascular risk. Methods The net change scores [least squares mean (LSM) and mean change] of LDL-C and HDL-C levels from baseline with the comparison of baricitinib versus placebo were pooled, respectively. Risk rations (RR) of major cardiovascular events (MACEs) and differences of cardiovascular risk scores at the end of treatment across groups were compared. Results Six trials with randomized 3552 patients were finally included in summary analysis. Results showed that baricitinib significantly increased LDL-C levels, the net mean change was 13.15 mg/dl with 95% CI 8.89~17.42 (I 2  = 0) and the net LSM was 11.94 mg/dl with 95% CI 7.52~16.37 (I 2  = 84%). HDL-C also increased obviously with the net LSM change was 7.19 mg/dl (95% CI, 6.05~8.33, I 2  = 47%) and net mean change was 5.40 mg/dl (95% CI, 3.07~7.74, I 2  = 10%). Subgroup and meta-regression analysis demonstrated baricitinib induced LDL-C and HDL-C increases in a dose-response manner. However, both the pooled RRs of MACEs and differences of cardiovascular risk scores were not statistically significant across groups. Conclusion This study confirmed that baricitinib induced a stable dose-response increase in LDL-C and HDL-C levels. Since the causality association between altered lipids and cardiovascular risk was not identified yet, this issue cannot be completely dismissed. Future research is needed to fully dissect the implications of these lipid changes.

BackgroundImmune checkpoint blockade (ICB) targeting programmed death ligand-1 (PD-L1)/programmed cell death protein-1 (PD-1) pathway has become an attractive strategy for cancer treatment; however, unsatisfactory efficacy has limited its clinical benefits. Therefore, a more comprehensive understanding of the regulation of PD-L1 expression is essential for developing more effective cancer immunotherapy. Recent studies have revealed the important roles of eukaryotic elongation factor 2 kinase (eEF2K) in promoting epithelial-mesenchymal transition (EMT), angiogenesis, tumor cell migration and invasion; nevertheless, the exact role of eEF2K in the regulation of tumor immune microenvironment (TIME) remains largely unknown.MethodsIn this study, we used a cohort of 38 patients with melanoma who received anti-PD-1 treatment to explore the association between eEF2K expression and immunotherapy efficacy against melanoma. Immunoprecipitation-mass spectrometry analysis and in vitro assays were used to examine the role and molecular mechanism of eEF2K in regulating PD-L1 expression. We also determined the effects of eEF2K on tumor growth and cytotoxicity of CD8+ T cells in TIME in a mouse melanoma model. We further investigated the efficacy of the eEF2K inhibition in combination with anti-PD-1 treatment in vivo.ResultsHigh eEF2K expression is correlated with better therapeutic response and longer survival in patients with melanoma treated with PD-1 monoclonal antibody (mAb). Moreover, eEF2K protein expression is positively correlated with PD-L1 protein expression. Mechanistically, eEF2K directly bound to and inactivated glycogen synthase kinase 3 beta (GSK3β) by phosphorylating it at serine 9 (S9), leading to PD-L1 protein stabilization and upregulation, and subsequently tumor immune evasion. Knockdown of eEF2K decreased PD-L1 expression and enhanced CD8+ T cell activity, thus dramatically attenuating murine B16F10 melanoma growth in vivo. Clinically, p-GSK3β/S9 expression is positively correlated with the expressions of eEF2K and PD-L1, and the response to anti-PD-1 immunotherapy. Furthermore, eEF2K inhibitor, NH125 treatment or eEF2K knockdown enhanced the efficacy of PD-1 mAb therapy in a melanoma mouse model.ConclusionsOur results suggest that eEF2K may serve as a biomarker for predicting therapeutic response and prognosis in patients receiving anti-PD-1 therapy, reveal a vital role of eEF2K in regulating TIME by controlling PD-L1 expression and provide a potential combination therapeutic strategy of eEF2K inhibition with ICB therapy.