A cardiotoxicity-eliminated ACE2 variant as a pan-inhibitor against coronavirus cell invasion.

Human recombinant ACE2 (hrACE2) has been highly anticipated as a successful COVID-19 treatment; however, its potential to cause cardiac side effects has given rise to many concerns. Here, we developed a cardiotoxicity-eliminated hrACE2 variant, which had four mutation sites within hrACE2 (H345L, H374L, H378L, H505L) and was named as hrACE2-4mu. hrACE2-4mu has a consistent binding affinity with the variant SARS-CoV-2 spike proteins (SPs) and an efficient ability to block SP-induced SARS-CoV-2 entry into cells. In golden hamsters, injection of purified wild-type (WT) hrACE2 rescues the early stages of pneumonia caused by the SPs of the WT, delta, and omicron variants with reduced inflammatory cell infiltration. However, long-term injection of WT hrACE2 induces undesired cardiac fibrosis, as demonstrated by upregulated fibronectin and collagen expression. Our newly developed hrACE2-4mu showed similar protective abilities against a series of coronavirus cell invasions as WT hrACE2, meanwhile it did not cause apparent cardiac side effects. Thus, we generated a cardiotoxicity-eliminated variant of hrACE2 as a pan-inhibitor against coronavirus cell invasion, providing a potential novel strategy for the treatment of COVID-19 and other coronaviruses.

Curcumin promotes cancer-associated fibroblasts apoptosis via ROS-mediated endoplasmic reticulum stress.

Cancer-associated fibroblasts (CAFs) play an important role in tumorigenesis, development, and migration. Eliminating CAFs or reducing their tumor-promoting activity is beneficial for tumor immunotherapy. Curcumin is a natural polyphenol derived from turmeric, which has been shown to inhibit the growth of many types of tumor. In this study, we explored the effect of curcumin on prostate-CAFs and its underlying molecular mechanism. The effect of curcumin on CAFs was measured using MTT assay and plate colony formation assay. Flow cytometry was used to detect cell apoptosis, ROS, Cell cycle, and mitochondrial membrane potential (ΔΨm) changes after curcumin treatment. Western Blot was used to detect changes in expression levels of related proteins in CAFs after curcumin stimulation. Colorimetry was used to detect the change of caspase 3 activity. The mRNA levels of Bims, Puma, ATF4 and CHOP were determined by qRT-PCR. We found that curcumin induced the apoptosis and cell cycle arrest of CAFs, which is mainly caused by the ROS-mediated endoplasmic reticulum stress pathway. For mechanism, the up-regulation of ROS caused by curcumin triggers endoplasmic reticulum stress of CAFs through the PERK-eIF2α-ATF4 axis. Our study suggests that curcumin selectively inhibits prostate-CAFs by inducing apoptosis and cell cycle arrest in G2-M phase, indicating a novel application of curcumin in tumor therapy.

Cross-kingdom regulation by plant-derived miRNAs in mammalian systems.

MicroRNAs (miRNAs) are small noncoding RNA molecules ubiquitously distributed across diverse organisms, serving as pivotal regulators of genetic expression. Notably, plant-derived miRNAs have been demonstrated to have unique bioactivity and certain stability in mammalian systems, thereby facilitating their capacity for cross-kingdom modulation of gene expression. While there is substantial evidence supporting the regulation of mammalian cells by plant-derived miRNAs, several questions remain unanswered. Specifically, a comprehensive investigation of the mechanisms underlying the stability and transport of plant miRNAs and their cross-kingdom regulation of gene expression in mammals remains to be done. In this review, we summarized the origin, processing, and functional mechanisms of plant miRNAs in mammalian tissues and circulation, emphasizing their greater resistance to mammalian digestion and circulation systems compared to animal miRNAs. Additionally, we introduce four well-known plant miRNAs that have been extensively studied for their functions and mechanisms in mammalian systems. By delving into these aspects, we aim to offer a fundamental understanding of this intriguing field and shed light on the complex interactions between plant miRNAs and mammalian biology.