A Novel Cargo Delivery System-AnCar-ExoLaIMTS Ameliorates Arthritis via Specifically Targeting Pro-Inflammatory Macrophages.

Macrophages are heterogenic phagocytic cells that play distinct roles in physiological and pathological processes. Targeting different types of macrophages has shown potent therapeutic effects in many diseases. Although many approaches are developed to target anti-inflammatory macrophages, there are few researches on targeting pro-inflammatory macrophages, which is partially attributed to their non-s pecificity phagocytosis of extracellular substances. In this study, a novel recombinant protein is constructed that can be anchored on an exosome membrane with the purpose of targeting pro-inflammatory macrophages via antigen recognition, which is named AnCar-ExoLaIMTS . The data indicate that the phagocytosis efficiencies of pro-inflammatory macrophages for different AnCar-ExoLaIMTS show obvious differences. The AnCar-ExoLaIMTS3 has the best targeting ability for pro-inflammatory macrophages in vitro and in vivo. Mechanically, AnCar-ExoLaIMTS3 can specifically recognize the leucine-rich repeat domain of the TLR4 receptor, and then enter into pro-inflammatory macrophages via the TLR4-mediated receptor endocytosis pathway. Moreover, AnCar-ExoLaIMTS3 can efficiently deliver therapeutic cargo to pro-inflammatory macrophages and inhibit the synovial inflammatory response via downregulation of HIF-1α level, thus ameliorating the severity of arthritis in vivo. Collectively, the work established a novel gene/drug delivery system that can specifically target pro-inflammatory macrophages, which may be beneficial for the treatments of arthritis and other inflammatory diseases.

A brain-tumor neural circuit controls breast cancer progression in mice.

Tumor burden, considered a common chronic stressor, can cause widespread anxiety. Evidence suggests that cancer-induced anxiety can promote tumor progression, but the underlying neural mechanism remains unclear. Here, we used neuroscience and cancer tools to investigate how the brain contributes to tumor progression via nerve-tumor crosstalk in a mouse model of breast cancer. We show that tumor-bearing mice exhibited significant anxiety-like behaviors and that corticotropin-releasing hormone (CRH) neurons in the central medial amygdala (CeM) were activated. Moreover, we detected newly formed sympathetic nerves in tumors, which established a polysynaptic connection to the brain. Pharmacogenetic or optogenetic inhibition of CeMCRH neurons and the CeMCRH→lateral paragigantocellular nucleus (LPGi) circuit significantly alleviated anxiety-like behaviors and slowed tumor growth. Conversely, artificial activation of CeMCRH neurons and the CeMCRH→LPGi circuit increased anxiety and tumor growth. Importantly, we found alprazolam, an antianxiety drug, to be a promising agent for slowing tumor progression. Furthermore, we show that manipulation of the CeMCRH→LPGi circuit directly regulated the activity of the intratumoral sympathetic nerves and peripheral nerve-derived norepinephrine, which affected tumor progression by modulating antitumor immunity. Together, these findings reveal a brain-tumor neural circuit that contributes to breast cancer progression and provide therapeutic insights for breast cancer.

Diverse regulatory manners of human telomerase reverse transcriptase.

Human telomerase reverse transcriptase (hTERT) is the core subunit of human telomerase and plays important roles in human cancers. Aberrant expression of hTERT is closely associated with tumorigenesis, cancer cell stemness maintaining, cell proliferation, apoptosis inhibition, senescence evasion and metastasis. The molecular basis of hTERT regulation is highly complicated and consists of various layers. A deep and full-scale comprehension of the regulatory mechanisms of hTERT is pivotal in understanding the pathogenesis and searching for therapeutic approaches. In this review, we summarize the recent advances regarding the diverse regulatory mechanisms of hTERT, including the transcriptional (promoter mutation, promoter region methylation and histone acetylation), post-transcriptional (mRNA alternative splicing and non-coding RNAs) and post-translational levels (phosphorylation and ubiquitination), which may provide novel perspectives for further translational diagnosis or therapeutic strategies targeting hTERT.

Prolyl isomerase Pin1: a promoter of cancer and a target for therapy.

Pin1 is the only known peptidyl-prolyl cis-trans isomerase (PPIase) that specifically recognizes and isomerizes the phosphorylated Serine/Threonine-Proline (pSer/Thr-Pro) motif. The Pin1-mediated structural transformation posttranslationally regulates the biofunctions of multiple proteins. Pin1 is involved in many cellular processes, the aberrance of which lead to both degenerative and neoplastic diseases. Pin1 is highly expressed in the majority of cancers and its deficiency significantly suppresses cancer progression. According to the ground-breaking summaries by Hanahan D and Weinberg RA, the hallmarks of cancer comprise ten biological capabilities. Multiple researches illuminated that Pin1 contributes to these aberrant behaviors of cancer via promoting various cancer-driving pathways. This review summarized the detailed mechanisms of Pin1 in different cancer capabilities and certain Pin1-targeted small-molecule compounds that exhibit anticancer activities, expecting to facilitate anticancer therapies by targeting Pin1.