The development of biomaterials with the potential to accelerate wound healing is a great challenge in biomedicine. In this study, four types of samples including pepsin soluble collagen sponge (PCS), acid soluble collagen sponge (ACS), bovine collagen electrospun I (BCE I) and bovine collagen electrospun II (BCE II) were used as wound dressing materials. We showed that the PCS, ACS, BCE I and BCE II treated rats increased the percentage of wound contraction, reduced the inflammatory infiltration, and accelerated the epithelization and healing. PCS, ACS, BCE I, and BCE II significantly enhanced the total protein and hydroxyproline level in rats. ACS could induce more fibroblasts proliferation and differentiation than PCS, however, both PCS and ACS had a lower effect than BCE I and BCE II. PCS, ACS, BCE I, and BCE II could regulate deposition of collagen, which led to excellent alignment in the wound healing process. There were similar effects on inducing the level of cytokines including EGF, FGF, and vascular endothelial marker CD31 among these four groups. Accordingly, this study disclosed that collagens (PCS and ACS) from tilapia skin and bovine collagen electrospun (BCE I and BCE II) have significant bioactivity and could accelerate wound healing rapidly and effectively in rat model.

Non-small cell lung cancer (NSCLC) is one of the most common malignancies in the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been used as a first-line treatment for patients harboring with EGFR mutations in advanced NSCLC. Nevertheless, the drug resistance after continuous and long-term chemotherapies considerably limits its clinical efficacy. Therefore, it is of great importance to develop new chemotherapeutic agents and treatment strategies to conquer the drug resistance. FGFC1 (Fungi fibrinolytic compound 1), a type of bisindole alkaloid from a metabolite of the rare marine fungi Starchbotrys longispora. FG216, has exhibited excellent fibrinolytic and anti-inflammatory activity. However, the potent efficacy of FGFC1 in human cancer therapy requires further study. Herein, we demonstrated that FGFC1 selectively suppressed the growth of NSCLC cells with EGFR mutation. Mechanistically, FGFC1 treatment significantly induced the apoptosis of erlotinib-resistant NSCLC cells H1975 in a dose-dependent manner, which was proved to be mediated by mitochondrial dysfunction and elevated accumulation of intracellular reactive oxygen species (ROS). Scavenging ROS not only alleviated FGFC1-induced apoptosis but also relieved the decrease of phospho-Akt. We further confirmed that FGFC1 significantly decreased the phosphorylation of protein EGFR, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR) in H1975 cells. Notably, PI3K inhibitor (LY294002) could promote the accumulation of ROS and the expression levels of apoptosis-related proteins induced by FGFC1. Molecular dynamics simulations indicated that FGFC1 can inhibit EGFR and its downstream PI3K/Akt/mTOR pathway through directly binding to EGFR, which displayed a much higher binding affinity to EGFR^T790M/L858R than EGFR^WT. Additionally, FGFC1 treatment also inhibited the migration and invasion of H1975 cells. Finally, FGFC1 effectively inhibited tumor growth in the nude mice xenograft model of NSCLC. Taken together, our results indicate that FGFC1 may be a potential candidate for erlotinib-resistant NSCLC therapy.

Colorectal cancer (CRC), the third most common cancer worldwide, remains highly lethal as the disease only becomes symptomatic at an advanced stage. Growing evidence suggests that histone deacetylases (HDACs), a group of epigenetic enzymes overexpressed in precancerous lesions of CRC, may represent promising molecular targets for CRC treatment. Histone deacetylase inhibitors (HDACis) have gradually become powerful anti-cancer agents targeting epigenetic modulation and have been widely used in the clinical treatment of hematologic malignancies, while only few studies on the benefit of HDACis in the treatment of CRC. In the present study, we designed a series of small-molecule Thiazole-based HDACis, among which HR488B bound to HDAC1 with a high affinity and exerted effective anti-CRC activity both in vitro and in vivo. Moreover, we revealed that HR488B specifically suppressed the growth of CRC cells by inducing cell cycle G0/G1 arrest and apoptosis via causing mitochondrial dysfunction, reactive oxygen species (ROS) generation, and DNA damage accumulation. Importantly, we noticed that HR488B significantly decreased the expression of the E2F transcription factor 1 (E2F1), which was crucial for the inhibitory effect of HR488B on CRC. Mechanistically, HR488B obviously decreased the phosphorylation level of the retinoblastoma protein (Rb), and subsequently prevented the release of E2F1 from the E2F1/Rb/HDAC1 complex, which ultimately suppressed the growth of CRC cells. Overall, our study suggests that HR488B, a novel and efficient HDAC1 inhibitor, may be a potential candidate for CRC therapy in the future. Furthermore, targeting the E2F1/Rb/HDAC1 axis with HR488B provides a promising therapeutic avenue for CRC.

FGFC1, an active compound isolated from the culture of marine fungi Stachybotrys longispora FG216, elicits fibrinolytic, anti-oxidative, and anti-inflammatory activity. We have previously reported that FGFC1 inhibited the proliferation, migration, and invasion of the non-small cell lung cancer (NSCLC) cells in vitro. However, the precise mechanisms of FGFC1 on NSCLC and its anti-cancer activity in vivo remains unclear. Hence, this study was focused to investigate the effects and regulatory mechanisms of FGFC1 on two NSCLC cell lines, EGFR-mutant PC9 (ex19del) and EGFR wild-type H1299. Results suggested that FGFC1 significantly inhibited proliferation, colony formation, as well as triggered G0/G1 arrest and apoptosis of PC9 cells in a dose- and time-dependent manner, but no obvious inhibitory effects were observed in H1299 cells. Subsequently, transcriptome analysis revealed that FGFC1 significantly down-regulated 28 genes related to the NF-κB pathway, including IL-6, TNF-α, and ICAM-1 in the PC9 cells. We further confirmed that FGFC1 decreased the expression of protein p-IKKα/β, p-p65, p-IκB, IL-6, and TNF-α. Moreover, NF-κB inhibitor PDTC could strengthen the effects of FGFC1 on the expression of CDK4, Cyclin D1, cleaved-PARP-1, and cleaved-caspase-3 proteins, suggesting that the NF-κB pathway plays a major role in FGFC1-induced cell cycle arrest and apoptosis. Correspondingly, the nuclear translocation of p-p65 was also suppressed by FGFC1 in PC9 cells. Finally, the intraperitoneal injection of FGFC1 remarkably inhibited PC9 xenograft growth and decreased the expression of Ki-67, p-p65, IL-6, and TNF-α in tumors. Our results indicated that FGFC1 exerted anti-cancer activity in PC9 cells via inhibiting the NF-κB signaling pathway, providing a possibility for FGFC1 to be used as a lead compound for the treatment of NSCLC in the future.

Introduction: Previous observational studies have found an increased risk of frailty in patients with stroke. However, evidence of a causal relationship between stroke and frailty is scarce. The aim of this study was to investigate the potential causal relationship between stroke and frailty index (FI). Methods: Pooled data on stroke and debility were obtained from genome-wide association studies (GWAS).The MEGASTROKE Consortium provided data on stroke (N = 40,585), ischemic stroke (IS,N = 34,217), large-vessel atherosclerotic stroke (LAS,N = 4373), and cardioembolic stroke (CES,N = 7 193).Summary statistics for the FI were obtained from the most recent GWAS meta-analysis of UK BioBank participants and Swedish TwinGene participants of European ancestry (N = 175,226).Two-sample Mendelian randomization (MR) analyses were performed by inverse variance weighting (IVW), weighted median, MR-Egger regression, Simple mode, and Weighted mode, and heterogeneity and horizontal multiplicity of results were assessed using Cochran’s Q test and MR-Egger regression intercept term test. Results: The results of the current MR study showed a significant correlation between stroke gene prediction and FI (odds ratio 1.104, 95% confidence interval 1.064 − 1.144, P < 0.001). In terms of stroke subtypes, IS (odds ratio 1.081, 95% confidence interval 1.044 − 1.120, P < 0.001) and LAS (odds ratio 1.037, 95% confidence interval 1.012 − 1.062, P = 0.005). There was no causal relationship between gene-predicted CES and FI. Horizontal multidimensionality was not found in the intercept test for MR Egger regression (P > 0.05), nor in the heterogeneity test (P > 0.05). Conclusions: This study provides evidence for a causal relationship between stroke and FI and offers new insights into the genetic study of FI.