Recent Progress in Site-Selective Modification of Peptides and Proteins Using Macrocycles.

Peptides and proteins undergo crucial modifications to alter their physicochemical properties to expand their applications in diverse fields. Various techniques, such as unnatural amino acid incorporation, enzyme catalysis, and chemoselective methods, have been employed for site-selective peptide and protein modification. While traditional methods remain valuable, advancement in host-guest chemistry introduces innovative and promising approaches for the selective modification of peptides and proteins. Macrocycles exhibit robust binding affinities, particularly with natural amino acids, which facilitates their use in selectively binding to specific sequences. This distinctive property endows macrocycles with the potential for modification of target peptides and proteins. This review provides a comprehensive overview of strategies utilizing macrocycles for the selective modification of peptides and proteins. These strategies unlock new possibilities for constructing antibody-drug conjugates and stabilizing volatile medications.

Circ_0002295 facilitated myocardial fibrosis progression through the miR-1287/CXCR2 axis.

Myocardial fibrosis (MF) is involved in hypertension, myocardial infarction and heart failure. It has been reported that circular RNA (circRNA) is a key regulatory factor of MF progression. In this study, we revealed that circ_0002295 and CXCR2 were elevated, and miR-1287 was reduced in MF patients. Knockdown of circ_0002295 effectively suppressed the proliferation, migration and MF progression. Circ_0002295 was the molecular sponge of miR-12878, and miR-1287 inhibitor reversed the biological functions of circ_0002295 on the myocardial fibrosis. CXCR2 was a target gene of miR-1287, and CXCR2 silencing relieved the impacts of miR-1287 inhibitor on cardiac myofibroblasts. Circ_0002295 promoted MF progression by regulating the miR-1287/CXCR2 axis, providing a possible circRNA-targeted therapy for MF.

The Hippo Signaling Core Components YAP and TAZ as New Prognostic Factors in Lung Cancer.

Background: The Hippo pathway is an essential signaling cascade that regulates cell and organ growth. However, there is no consensus about (i) the expression levels of the Hippo signaling core components yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in lung cancer, especially in small cell lung cancer (SCLC), or (ii) their association with the prognosis of patients with SCLC. Methods: We screened relevant articles and identified eligible studies in the PubMed, EMBASE, COCHRANE, and WanFang databases. A combined analysis was performed to investigate (i) the expression levels of the major effectors, YAP and TAZ, in lung cancer and its subsets and (ii) their prognostic role in lung cancer, especially in SCLC. Results: In total, 6 studies related to TAZ and 13 studies concerning YAP were enrolled in this meta-analysis. We found that high TAZ expression was significantly associated with poor overall survival (OS) of patients with non-small cell lung cancer (NSCLC) in the overall population [P h < 0.001, crude hazard ratio (HR) = 1.629, 95% CI = 1.199-2.214 for TAZ expression; P h = 0.029, adjusted HR = 2.127, 95% CI = 1.307-3.460 for TAZ], the Caucasian population (P h = 0.043, crude HR = 1.233, 95% CI = 1.030-1.477 for TAZ expression), and the Asian population (P h = 0.551, adjusted HR = 2.676, 95% CI = 1.798-3.982 for TAZ). Moreover, there was a significant negative association between YAP expression and an unsatisfactory survival of patients with lung cancer (P h = 0.327, crude HR = 1.652, 95% CI = 1.211-2.253 for YAP expression) and patients with NSCLC [disease-free survival (DFS): Ph = 0.693, crude HR = 2.562, 95% CI = 1.876-3.499 for YAP expression; Ph = 0.920, crude HR = 2.617, 95% CI = 1.690-4.052 for YAP-mRNA; OS: Ph = 0.878, crude HR = 1.777, 95% CI = 1.233-2.562 for YAP expression], especially in the Asian population (DFS: P h = 0.414, crude HR = 2.515, 95% CI = 1.755-3.063; OS: P h = 0.712, crude HR = 1.772, 95% CI = 1.214-2.587). However, no association was observed in the multivariate combined analysis. High YAP expression was significantly associated with short OS of patients with SCLC in our combined multivariate analysis in the Asian population (P h = 0.289, crude HR = 4.482, 95% CI = 2.182-9.209), but not with crude data (P h = 0.033, crude HR = 1.654, 95% CI = 0.434-6.300). Conclusion: The Hippo pathway is involved in carcinogenesis and progression of NSCLC and SCLC, and high expression levels of YAP and TAZ are independent and novel prognostic factors for lung cancer.

Silencing of the CrkL gene reverses the doxorubicin resistance of K562/ADR cells through regulating PI3K/Akt/MRP1 signaling.

BACKGROUND: Doxorubicin is a first-line chemotherapy agent on human myelogenous leukemia clinical treatment, but the development of chemoresistance has largely limited curative effect. In this study, we aimed to evaluate the biological function and molecular mechanisms of CrkL to Doxorubicin resistance. METHODS: Quantitative reverse transcription-PCR (qRT-PCR) assay was performed to examine the expression of CrkL in K562 and K562/ADR cells. The expression of CrkL was silenced through RNA interference technology. MTT assay and flow cytometry were performed to detect the proliferation inhibition and apoptosis rate after CrkL siRNA transfection. The protein expression changes of PI3K/AKT/MRP1 pathway induced by CrkL siRNA were observed by Western Blot assay. Xenograft tumor model was carried out to observe tumor growth in vivo. RESULTS: We observed that silencing of CrkL could effectively increase apoptosis rate induced by doxorubicin and dramatically reversed doxorubicin resistance in K562/ADR cells. Further studies revealed knockdown CrkL expression suppressed PI3K/Akt/MRP1 signaling, which indicated CrkL siRNA reversed doxorubicin effect through regulating PI3K/Akt/MRP1 pathway. In addition, overexpression of MRP1 could evidently reduce apoptosis rate and reversed the inhibitory effects of doxorubicin resistance caused by CrkL siRNA on K562/ADR cells. Finally, in vivo experiments revealed that CrkL silencing acted a tumor-suppressing role in myelogenous leukemia via regulating PI3K/Akt/MRP1 signaling. CONCLUSION: Together, we indicated that CrkL is up-regulated in myelogenous leukemia cells and silencing of CrkL could reverse Doxorubicin resistance effectively. These results show a potential novel strategy for intervention chemoresistance in myelogenous leukemia during chemotherapy.