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Manypeptide-based therapeutics have short circulatory half-lives.We report here that the pharmacokinetics of an anti-HIV peptide drugenfuvirtide (ENF) can be dramatically improved by a chemical glycosylationapproach. A set of glycosylated ENFs with varying glycosylation sitesand glycan structures were synthesized. Among these, a sialic acid-introducedpeptide (SL-ENF) demonstrated a 15-fold extended half-life in ratsrelative to ENF (T1/2: 23.1 vs 1.5 h),and its antiviral potency was comparable to that of ENF (EC50: 2 vs 3 nM). SL-ENF bound to a functional fragment of the HIV fusogenicprotein gp41 and formed complexes with high affinity and α-helicity,revealing the mechanism behind its potent antiviral activity. Becauseit is widely accepted in biology that glycosylation protects proteinsfrom denaturation and proteases, our approach may be useful for thedevelopment of novel protein and peptide drugs with enhanced pharmaceuticalproperties. [ABSTRACT FROM AUTHOR]

Objective: Numerous studies have reported that metformin can reduce the risk of tumor development. However, some of the results of these studies are conflicting, necessitating a more reliable evaluation., Methods: We conducted a Mendelian randomization phenome-wide association study (MR-PheWAS) of tumors to explore the causal relationship between metformin and tumors. Two cohorts of patients taking metformin were obtained from the UK Biobank. Complete phenotype data of the tumors were obtained from FinnGen_R10. We elucidated the causal relationship using a two-sample Mendelian randomization (MR) analysis. More importantly, we conducted a meta-analysis to ensure relatively unbiased results. In the MR analysis, we used the inverse-variance weighted (IVW) method as the main outcome indicator. Subsequently, two cohorts were integrated for the meta-analysis. Finally, we investigated the mechanisms through mediational MR analysis., Results: MR analysis revealed that metformin might have a causal relationship with 13 tumor-associated phenotypes in the training cohort. Four phenotypes were validated in the testing cohort. In the training and testing cohorts, metformin exhibited a protective effect against brain meningiomas and malignant neoplasms of the breast (HER-positive), oral cavity, tonsils, and the base of the tongue. Intriguingly, after integrating the results of the two cohorts for the meta-analysis, 12 results were statistically significant. Mediational MR analysis suggested that the effects of metformin on brain meningiomas may be weakened by the presence of the family Oxalobacteraceae., Conclusion: Metformin exhibits potential preventive and therapeutic effects on four types of tumors: brain meningioma, malignant neoplasms of the breast (HER-positive), oral cavity and tonsils, and the base of the tongue. Large randomized controlled trials are required to confirm these findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Wu, Wu, He, Chang, Deng, Zhou, Chen and Zhang.)

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has emerged as a significant obstacle in managing patients with EGFR-mutant non-small-cell lung cancer (NSCLC), necessitating the exploration of novel therapeutic approaches. Tanreqing injection (TRQ) is a kind of Chinese patent medicine known for its heat-clearing and detoxifying properties. Studies have shown a correlation between tumor drug resistance and enrichment of cancer stem cells (CSCs). We aim to investigate the feasibility of TRQ enhancing sensitivity to gefitinib by targeting CSCs and reactive oxygen species (ROS). In our study, TRQ significantly inhibited cell proliferation in gefitinib-resistant non-small-cell lung cancer (NSCLC) models including 2D cell lines, 3D cell spheres, tumor-bearing animal and organoids. Compared with the gefitinib group alone, addition of TRQ elevated ROS levels, attenuated upregulation of the protein levels of sex-determining region Y-box 2 (SOX2) and aldehyde dehydrogenase 1 family member A1 (ALDH1A1) induced by gefitinib treatment, and inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Scavenging ROS could restore tumor stemness, attenuate the inhibitory effect on the phosphorylation of STAT3, and promote cell proliferation. These results suggested that TRQ could enhance sensitivity of NSCLC models to gefitinib, providing a new combined treatment strategy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)