Emerging clinical and experimental evidence demonstrates that neuroinflammation plays an important role in cognitive impairment associated with neuropathic pain. However, how peripheral nerve challenge induces remote inflammation in the brain remains largely unknown. Methods: The circulating leukocytes and plasma C-X-C motif chemokine 12 (CXCL12) and brain perivascular macrophages (PVMs) were analyzed by flow cytometry, Western blotting, ELISA, and immunostaining in spared nerve injury (SNI) mice. The memory function was evaluated with a novel object recognition test (NORT) in mice and with Montreal Cognitive Assessment (MoCA) in chronic pain patients. Results: The classical monocytes and CXCL12 in the blood, PVMs in the perivascular space, and gliosis in the brain, particularly in the hippocampus, were persistently increased following SNI in mice. Using the transgenic CCR2 RFP/+ and CX3CR1 GFP/+ mice, we discovered that at least some of the PVMs were recruited from circulating monocytes. The SNI-induced increase in hippocampal PVMs, gliosis, and memory decline were substantially prevented by either depleting circulating monocytes via intravenous injection of clodronate liposomes or blockade of CXCL12-CXCR4 signaling. On the contrary, intravenous injection of CXCL12 at a pathological concentration in naïve mice mimicked SNI effects. Significantly, we found that circulating monocytes and plasma CXCL12 were elevated in chronic pain patients, and both of them were closely correlated with memory decline. Conclusion: CXCL12-mediated monocyte recruitment into the perivascular space is critical for neuroinflammation and the resultant cognitive impairment in neuropathic pain.

Cholangiocarcinoma (CCA) is an aggressive and multifactorial malignancy of the biliary tract. The carcinogenesis of CCA is associated with genomic and epigenetic abnormalities, as well as environmental effects. However, early clinical diagnosis and reliable treatment strategies of CCA remain unsatisfactory. Multiple compartments of the tumor microenvironment significantly affect the progression of CCA. Tumor-associated macrophages (TAMs) are a type of plastic immune cells that are recruited and activated in the CCA microenvironment, especially at the tumor invasive front and perivascular sites. TAMs create a favorable environment that benefits CCA growth by closely interacting with CCA cells and other stromal cells via releasing multiple protumor factors. In addition, TAMs exert immunosuppressive and antichemotherapeutic effects, thus intensifying the malignancy. Targeting TAMs may provide an improved understanding of, and novel therapeutic approaches for, CCA. This review focuses on revealing the interplay between TAMs and CCA.

Intestinal epithelium serves as the first barrier against the infections and injuries that mediate colonic inflammation. Colorectal cancer is often accompanied with chronic inflammation. Differed from its well-known oncogenic role in many malignancies, we present here that Golgi membrane protein 1 (GOLM1, also referred to as GP73) suppresses colorectal tumorigenesis via maintenance of intestinal epithelial barrier. GOLM1 deficiency in mice conferred susceptibility to mucosal inflammation and colitis-induced epithelial damage, which consequently promoted colon cancer. Mechanistically, depletion of GOLM1 in intestinal epithelial cells (IECs) led to aberrant Notch activation that interfered with IEC differentiation, maturation, and lineage commitment in mice. Pharmacological inhibition of Notch pathway alleviated epithelial lesions and restrained pro-tumorigenic inflammation in GOLM1-deficient mice. Therefore, GOLM1 maintains IEC homeostasis and protects against colitis and colon tumorigenesis by modulating the equilibrium of Notch signaling pathway.

Glutamate is an excitatory neurotransmitter that has been shown to regulate the proliferation, migration and survival of neuronal progenitors in the central nervous system through its action on metabotropic and ionotropic glutamate receptors (GluRs). Antagonists of ionotropic GluRs have been shown to cause a rapid and reversible change in melanocyte dendritic morphology, which is associated with the disorganization of actin and tubulin microfilaments in the cytoskeleton. Intracellular expression of microtubule-associated protein (MAP) 2a affects the assembly, stabilization and bundling of microtubules in melanoma cells; stimulates the development of dendrites; and suppresses melanoma cell migration and invasion. In this study, we investigated the relationship between glutamate-mediated signalling and microtubules, cell dendritic morphology and melanoma cell motility. We found that metabotropic GluR1 and N-methyl-d-aspartate receptor antagonists increased dendritic branching and inhibited the motility, migration and proliferation of melanoma cells. We also demonstrated that the invasion and motility of melanoma cells are significantly inhibited by the combination of increased expression of MAP2a and either metabotropic GluR1 or N-methyl-d-aspartate receptor antagonists. Moreover, the blockade of glutamate receptors inhibited melanoma growth in vivo. Collectively, these results demonstrate the importance of glutamate signalling in human melanoma and suggest that the blockade of glutamate receptors is a promising novel therapy for treating melanoma.

Salicylic acid (SA) is an important signalling molecule that is synthesized by plants and induces the expression of resistance genes. The SA pathway is typically activated by DNA viruses as well as RNA viruses. Here, we demonstrated that heper-component protease (HC-Pro) encoded by tobacco vein banding mosaic virus (TVBMV) decreases in DNA methylation at the promoters of the regulators ACD6 and NPR1 in the SA pathway. We found that the overexpression of HC-Pro increases the expression of components in the SA pathway in plants. The results revealed that HC-Pro interferes in DNA methylation and activates the SA pathway in the HC-Pro transgenic plants and TVBMV-infected plants. We further found that the accumulation of siRNAs derived from the promoter repeats of ACD6 and NPR1 is greatly reduced in the HC-Pro plants. Our results suggested that HC-Pro-mediated interference with DNA methylation is likely caused by a reduction in accumulation of siRNAs.

Hepatocellular carcinoma (HCC) is characterized by alterations in multiple genes. High expression of CD147 on the surface of HCC cells promotes proliferation. The monoclonal antibody HAb18 recognizes CD147. We constructed an oncolytic adenoviral vector to express HAb18 (ZD55-HAb18) in HCC cells. Interleukin 24 (IL24) was co-expressed through the use of an F2A linker. ZD55-HAb18-IL24 decreased HCC cell viability to a greater degree than either ZD55-HAb18 or ZD55-IL24 alone. ZD55-HAb18-IL24 also induced apoptosis and autophagy in PLC/PRF/5 HCC cells. Intratumoral injection of ZD55-HAb18-IL24 repressed tumor growth in a PLC/PRF/5 xenograft model. Our results suggest that antibody-antitumor gene conjugation elicited a stronger antitumor effect than the antibody alone, and that this strategy could broaden the applications of antibody-based therapies in HCC.

Accumulating evidence shows that inhibition of glycogen synthase kinase-3beta (GSK-3β) ameliorates cognitive impairments caused by a diverse array of diseases. Our previous work showed that spared nerve injury (SNI) that induces neuropathic pain causes short-term memory deficits. Here, we reported that GSK-3β activity was enhanced in hippocampus and reduced in spinal dorsal horn following SNI, and the changes persisted for at least 45 days. Repetitive applications of selective GSK-3β inhibitors (SB216763, 5 mg/kg, intraperitoneally, three times or AR-A014418, 400 ng/kg, intrathecally, seven times) prevented short-term memory deficits but did not affect neuropathic pain induced by SNI. Surprisingly, we found that the repetitive SB216763 or AR-A014418 induced a persistent pain hypersensitivity in sham animals. Mechanistically, both β-catenin and brain-derived neurotrophic factor (BDNF) were upregulated in spinal dorsal horn but downregulated in hippocampus following SNI. Injections of SB216763 prevented the BDNF downregulation in hippocampus but enhanced its upregulation in spinal dorsal horn in SNI rats. In sham rats, SB216763 upregulated both β-catenin and BDNF in spinal dorsal horn but affect neither of them in hippocampus. Finally, intravenous injection of interleukin-1beta that induces pain hypersensitivity and memory deficits mimicked the SNI-induced the differential regulation of GSK-3β/β-catenin/BDNF in spinal dorsal horn and in hippocampus. Accordingly, the prolonged opposite changes of GSK-3β activity in hippocampus and in spinal dorsal horn induced by SNI may contribute to memory deficits and neuropathic pain by differential regulation of BDNF in the two regions. GSK-3β inhibitors that treat cognitive disorders may result in a long-lasting pain hypersensitivity.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a new tick-borne pathogen that can cause severe hemorrhagic fever. Fever with thrombocytopenia syndrome caused by SFTSV is a new infectious disease that has posed a great threat to public health. Therefore, a fast, sensitive, low-cost, and field-deployable detection method for diagnosing SFTSV is essential for virus surveillance and control. In this study, we developed a rapid, highly sensitive, instrument-flexible SFTSV detection method that utilizes recombinase polymerase amplification and the CRISPR/Cas12a system. We found that three copies of the L gene from the SFTSV genome per reaction were enough to ensure stable detection within 40 min. The assay clearly showed no cross-reactivity with other RNA viruses. Additionally, our method demonstrated 100% agreement with Q-PCR detection results for SFTSV in 46 clinical samples. We simplified the requirements for on-site detection instruments by combining the CRISPR/Cas12a tool and immunochromatographic strips to create a system that can reliably detect one copy/μl sample of the L gene, which showed extremely high sensitivity and specificity for detecting the virus. Taken together, these findings indicate that the new SFTSV detection method is a powerful and effective tool for on-site detection, which can contribute to diagnosing SFTSV quickly and sensitively.