Identification of a suitable nonhuman primate (NHP) model of COVID-19 remains challenging. Here, we characterized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in three NHP species: Old World monkeys Macaca mulatta (M. mulatta) and Macaca fascicularis (M. fascicularis) and New World monkey Callithrix jacchus (C. jacchus). Infected M. mulatta and M. fascicularis showed abnormal chest radiographs, an increased body temperature and a decreased body weight. Viral genomes were detected in swab and blood samples from all animals. Viral load was detected in the pulmonary tissues of M. mulatta and M. fascicularis but not C. jacchus. Furthermore, among the three animal species, M. mulatta showed the strongest response to SARS-CoV-2, including increased inflammatory cytokine expression and pathological changes in the pulmonary tissues. Collectively, these data revealed the different susceptibilities of Old World and New World monkeys to SARS-CoV-2 and identified M. mulatta as the most suitable for modeling COVID-19.

Neurological manifestations are frequently reported in the COVID-19 patients. Neuromechanism of SARS-CoV-2 remains to be elucidated. In this study, we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19. In rhesus monkey, SARS-CoV-2 invades the CNS primarily via the olfactory bulb. Thereafter, viruses rapidly spread to functional areas of the central nervous system, such as hippocampus, thalamus, and medulla oblongata. The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons, microglia, and astrocytes in the CNS. Consistently, SARS-CoV-2 infects neuro-derived SK-N-SH, glial-derived U251, and brain microvascular endothelial cells in vitro. To our knowledge, this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model, which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.

Radioresistance hampers success in the treatment of patients with advanced colorectal cancer (CRC). Improving our understanding of the underlying mechanisms of radioresistance could increase patients’ response to irradiation (IR). MicroRNAs are a class of small RNAs involved in tumor therapy response to radiation. Here we found that miR-214 was markedly decreased in CRC cell lines and blood of CRC patients after IR exposure. Meanwhile, autophagy was enhanced in irradiated CRC cells. Mechanically, ATG12 was predicted and identified as a direct target of miR-214 by dual luciferase assay, qPCR, and Western blot. In vitro and in vivo experiments showed that miR-214 promoted radiosensitivity by inhibiting IR-induced autophagy. Restoration of ATG12 attenuated miR-214-mediated inhibition of cell growth and survival in response to IR. Importantly, miR-214 was highly expressed in radiosensitive CRC specimens and negatively correlated with plasma level of CEA. Moreover, ATG12 and LC3 expressions were increased in radioresistant CRC specimens. Our study elucidates that miR-214 promotes radiosensitivity by inhibition of ATG12-mediated autophagy in CRC. Importantly, miR-214 is a determinant of CRC irradiation response and may serve as a potential therapeutic target in CRC treatment.

Breast cancer (BC) is a common malignancy worldwide. More than 3 700 000 women die of BC every year. DSCAM-AS1 was overexpressed several kinds of cancer and miR-204-5p was lowly expressed, which indicated that miR-204-5p had anti-tumor activity and DSCAM-AS1 had pro-tumor activity. We intended to analyze DSCAM-AS1, miR-204-5p, and ribonucleotide reductase M2 (RRM2). Microarray analysis and quantitative Real Time fluorescence Polymerase Chain Reaction (qRT-PCR) were employed to determine DSCAM-AS1 and miR-204-5p expression. Luciferase reporter assay was applied to examine the target relationship between DSCAM-AS1, miR-204-5p, and RRM2. Cell Counting Kit-8 (CCK-8 assay), transwell assay, and flow cytometry were used to detect cell proliferation, invasion, and apoptosis. The expression of DSCAM-AS1, miR-204-5p, and RRM2 were confirmed by Western blot. We also conducted in vivo assay to verify the effect of DSCAM-AS1. DSCAM-AS1 was up-regulated, while miR-204-5p was down-regulated in BC tissues and cells. DSCAM-AS1 directly targeted miR-204-5p. DSCAM-AS1 promoted the proliferation and invasion of BC cells by reducing miR-204-5p and inhibiting miR-204-5p expression. DSCAM-AS1 expression was related to the expression of RRM2, and miR-204-5p could reverse the function of DSCAM-AS1. RRM2 was up-regulated in BC cells, and miR-204-5p inhibited RRM2 expression by targeting RRM2. Overexpression of RRM2 stimulated proliferation and cell invasion and impeded apoptosis. In vivo experiments showed that knockdown of DSCAM-AS1 decreased the tumorigenesis of BC cells, increased the expression of miR-204-5p. DSCAM-AS1 promoted proliferation and impaired apoptosis of BC cells by reducing miR-204-5p and enhancing RRM2 expression. DSCAM-AS1/miR-204-5p/RRM2 may serve as novel therapeutic targets for BC. K E Y W O R D S Breast cancer, DSCAM-AS1, miR-204-5p, RRM2

Imbalances in intestinal bacteria correlate with colitis-associated colorectal cancer (CAC). Traditional Chinese medicines have been used to adjust the gut microbiota, and isoliquiritigenin (ISL), a flavonoid extracted from licorice, has shown antitumor efficacy. In this study, the effects of ISL on CAC development and the gut microbiota were evaluated using an azoxymethane and dextran sulphate sodium (AOM/DSS)-induced mouse model of CAC (CACM). Histopathological analysis suggested that ISL reduced tumor incidence in vivo. Moreover, high-throughput sequencing and terminal restriction fragment length polymorphism (T-RFLP) studies of the bacterial 16S rRNA gene revealed that the structure of the gut microbial community shifted significantly following AOM/DSS treatment, and that effect was alleviated by treatment with high-dose ISL (150 mg/kg). Compared to the microbiota in the control mice (CK), the levels of Bacteroidetes decreased and the levels of Firmicutes increased during CAC development. ISL reversed the imbalance at the phylum level and altered the familial constituents of the gut microbiota. Specifically, the abundance of Helicobacteraceae increased after treatment with high-dose ISL, while the abundance of Lachnospiraceae and Rikenellaceae decreased. At the genus level, ISL reduced the abundance of opportunistic pathogens (Escherichia and Enterococcus), and increased the levels of probiotics, particularly butyrate-producing bacteria (Butyricicoccus, Clostridium, and Ruminococcus). Thus, ISL protects mice from AOM/DSS-induced CAC, and ISL and the gut microbiota may have synergistic anti-cancer effects.

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The increased expression of microRNA-145 promotes media remodeling through TGF-b1 in the aortic aneurysm wall.