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Cardiac fibrosis is a severe condition with limited therapeutic options and often occurs in chronic cardiovascular diseases such as hypertension and myocardial infarction. There is currently a clear need to identify novel mediators of cardiac fibrosis to facilitate the development of more effective therapeutic strategies targeting cardiac fibrosis. Integrin subunit β-like 1 (ITGBL1), an extracellular matrix protein, has previously been implicated in various fibrotic diseases. However, the precise role of ITGBL1 in regulating myocardial fibrosis remains unknown. The present study was designed to investigate whether ITGBL1 regulates angiotensin II (Ang II)-induced myocardial fibrosis in vitro and in vivo and the possible mechanism of action. It was found that the protein expressions of ITGBL1, Forkhead box Q1 (FOXQ1), and Snail were all increased significantly in fibrotic heart tissues from Ang II-infused mice and Ang II-stimulated cardiac fibroblasts, all of which were inhibited by the Ang II type I (AT1) receptor antagonist losartan. Silencing the ITGBL1/FOXQ1/Snail axis with specific siRNAs reversed Ang II-induced fibrotic effects and upregulation of FOXQ1 and Snail expressions in cardiac fibroblasts. FOXQ1 siRNA inhibited Snail expression in Ang II-induced cardiac fibroblasts. Furthermore, ITGBL1/FOXQ1 interacted with the TGF-β1 signaling to form a positive feedback loop. Our findings suggest that the extracellular matrix protein ITGBL1 mediates Ang II-induced cardiac fibrosis via the FOXQ1/Snail axis, which identifies ITGBL1 as a novel mediator of cardiac fibrosis and represents a potential therapeutic target for cardiac fibrosis. [Display omitted] • Extracellular matrix protein ITGBL1 mediates Ang II-induced cardiac fibrosis. • ITGBL1 regulates the FOXQ1/Snail axis to mediate cardiac fibrosis. • Inhibition of the FOXQ1/Snail axis prevents Ang II-induced fibrotic response. [ABSTRACT FROM AUTHOR]

The facile Mn(OAc) 2 -promoted [3+2] cycloaddition reaction of enaminones with isocyanoacetate was disclosed, that delivered a diversity of 3-aroyl pyrrole-2-carboxylic esters with excellent the anti-cancer activity. Notably, compound 2n demonstrate the most potent activity, favorable anti-migration activity and drug-like properties. [Display omitted] • Functionalized pyrrole-2-carboxylic acid derivatives were rapidly constructed. • Most of the newly synthesized compounds display moderate to high toxicity against four cancer cells. • Compound 2n exhibit potent antiproliferative activity, favorable anti-migration activity and drug-like properties. The practical and facile Mn(OAc) 2 -promoted [3+2] cycloaddition reaction of enaminones with isocyanoacetate was developed, that delivered a diversity of 3-aroyl pyrrole-2-carboxylic esters with broad substrates scope. The most of the newly synthesized compounds exhibit moderate antiproliferative activity against four cancer cells. Notably, compound 2n demonstrate the most potent activity with average IC 50 values of 5.61 μM against four distinct cancer cell lines. Moreover, 2n exhibit favorable anti-migration activity and drug-like properties. The further investigation suggests that compound 2n possesses the ability to inhibit ERK5 activity and exhibits effective binding with the ERK5 protein , making it a promising candidate as a lead compound for a new class of ERK5 inhibitors discovery. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Tissue scaffolds with three-dimensional (3D) nanofibrous biomimetic structures have attracted attention in the field of bone regeneration. In recent years, emerging strategies based on electrospinning technologies have facilitated the preparation of 3D nanofibrous scaffolds. Based on these developments, in this study, 3D scaffolds possessing both nanofibrous morphologies and interconnected pores were fabricated for their potential in bone tissue engineering. By combining homogenizing, freeze-drying, and thermal crosslinking techniques, nano-hydroxyapatite/PLLA/gelatin (nHA/PLA/GEL) 3D nanofibrous scaffolds were prepared using pre-fabricated electrospun nanofibers. Then, utilizing a polydopamine (pDA)-assisted coating strategy, bone morphogenetic protein-2 (BMP-2)-derived peptides were further immobilized onto the 3D scaffolds to obtain the resulting nano-hydroxyapatite/PLLA/gelatin-peptide (nHA/PLA/GEL-PEP) 3D nanofibrous scaffolds capable of sustained release. Bone mesenchymal stem cells (BMSCs) were cultured on the 3D nanofibrous scaffolds, then relative cell viability, alkaline phosphatase (ALP) activity, and gene expression assays were performed to study the effects of the scaffolds on cell growth and osteogenic differentiation in vitro. Furthermore, the ability of bone formation in vivo was evaluated using a rat cranial bone defect model. In vitro and in vivo results demonstrated that the 3D nanofibrous scaffolds incorporated with nHA and BMP-2 peptides exhibited favorable biocompatibility and osteoinductivity. Therefore, these nanofibrous scaffolds have excellent potential in bone regenerative medicine. [ABSTRACT FROM AUTHOR]

Poly ADP-ribose polymerase (PARP) plays a critical role in many cellular processes such as DNA damage repair, gene transcription and cell apoptosis. Therefore, targeting PARP represents a promising strategy for cancer therapy. To date, numerous small molecule PARP1 inhibitors have been identified, but many of them suffer from limited clinical efficacy and serious toxicity. Hence, PARP1 inhibitor-based combination therapies, and other PARP1 modulators (e.g. PROTAC degraders, dual acting agents) have attracted great attention with significant advancements achieved in the past few years. In this review, we overviewed the recent progress on PARP1-based drug discovery with a focus on PARP1 inhibitor-based drug combination therapy and other PARP1-targeting strategies (e.g. selective PARP1 inhibitors, PARP1-based dual-target inhibitors, PROTAC PARP1 degraders, and prodrugs of PARP1 inhibitors). In addition, we also summarized the reported co-crystal structures of PARP1 inhibitors in complex with their target proteins as well as the binding interactions. Finally, the challenges and future directions for PARP-based drug discovery in cancer therapy are also discussed in detail. [Display omitted] • Recent progress on PARP-based drug discovery was reviewed. • The structure and biological functions of PARP-1 were elucidated. • PARP modulators (PARP-1 inhibitors, dual inhibitors, PROTAC degraders, prodrugs) were overviewed. • Crystal structures of inhibitors with PARP-1 proteins were summarized. • Prospects and future directions of PARP-targeting cancer therapy were discussed. [ABSTRACT FROM AUTHOR]

This study shown that phenanthroimidazole derivatives could bind and stabilize c-myc G-quadruplex DNA to inhibit the growth of CNE-1 nasopharyngeal carcinoma cells through DNA damage mediated mitochondrial apoptotic pathway. • The single crystal structure of phenanthroimidazole derivatives (4–6). • Excellent inhibition of 4 against CNE-1 cells in vitro and in vivo. • Great affinity and stability of phenanthroimidazole derivatives with G4 DNA. • Apoptosis induced by 4 via ROS-mediated DNA damage and mitochondrial dysfunction. Phenanthroimidazole derivatives containing phenanthroline and imidazole heterocyclic aromatic rings are effective agents to inhibit tumor cell growth. Herein, halogen element-modified imidazo[4,5 f [1,10]phenanthroline derivatives 1–6 (1 , 4-fluorophenyl; 2 , 4-chlorophenyl; 3 , 4-bromobenyl; 4 , 2,3-dichlorophenyl; 5 , 3,4-dichlorophenyl; and 6 , 2,4-dichlorophenyl) were synthesized, and their antitumor activities were investigated. All of the compounds, especially 4 , exhibited an excellent inhibitory effect against nasopharyngeal carcinoma CNE-1 cells. This effect was better than that of doxorubicin. Compound 4 also markedly blocked the proliferation of the CNE-1 cells in a zebrafish xenograft model. The antitumor mechanisms might be attributed to apoptosis induction, which triggered ROS-mediated DNA damage and generated mitochondrial dysfunction by stabilizing c-myc G-quadruplex DNA structure. Results indicated that phenanthroimidazole derivatives could act as promising anticancer agents. [ABSTRACT FROM AUTHOR]