Myeloid-derived growth factor ameliorates dextran sodium sulfate-induced colitis by regulating macrophage polarization.

Inflammatory bowel disease (IBD) is characterized by inflammatory conditions in the gastrointestinal tract. According to reports, IBD prevalence is increasing globally, with heavy economic and physical burdens. Current IBD clinical treatment is limited to pharmacological methods; therefore, new strategies are needed. Myeloid-derived growth factor (MYDGF) secreted by bone marrow-derived mononuclear macrophages has beneficial effects in multiple inflammatory diseases. To this end, the present study aimed to establish an experimental IBD mouse model using dextran sulfate sodium in drinking water. MYDGF significantly alleviated DSS-induced colitis, suppressed lymphocyte infiltration, restored epithelial integrity in mice, and decreased apoptosis in the colon tissue. Moreover, the number of M1 macrophages was decreased and that of M2 macrophages was increased by the action of MYDGF. In MYDGF-treated mice, the NF-κB and MAPK pathways were partially inhibited. Our findings indicate that MYDGF could mitigate DSS-induced mice IBD by reducing inflammation and restoring epithelial integrity through regulation of intestinal macrophage polarization via NF-κB and MAPK pathway inhibition. KEY MESSAGES: MYDGF alleviated DSS-induced acute colitis. MYDGF maintains colon epithelial barrier integrity and relieves inflammation. MYDGF regulates colon macrophage polarization. MYDGF partially inhibited the activation of NF-κB and MAPK pathway.

Dental pulp stem cells accelerate wound healing through CCL2-induced M2 macrophages polarization.

The crosstalk between mesenchymal stem cells (MSCs) and the host immune function plays a key role in the efficiency of tissue regeneration and wound healing. However, the difference in immunological modulation and tissue regeneration function between MSCs from different sources remains unclear. Compared to PDLSCs, BMMSCs, and ADSCs, DPSCs exhibited greater tissue regeneration potential and triggered more M2 macrophages in vivo. DPSCs elicited the polarization of M2a macrophages by conditioned medium and transwell assay and exhibited higher expression levels of C-C motif chemokine ligand 2 (CCL2). Specific blocking of CCL2 could significantly inhibit the DPSCs-induced polarization of M2 macrophages. DPSCs promoted wound healing of the palatal mucosa and M2 macrophages polarization in vivo, which could be significantly impaired by CCL2-neutralized antibody. Our data indicate that DPSCs exert better tissue regeneration potential and immunoregulatory function by secreting CCL2, which can enhance MSCs-mediated tissue regeneration or wound healing.

Transient Activation of Hedgehog Signaling Inhibits Cellular Senescence and Inflammation in Radiated Swine Salivary Glands through Preserving Resident Macrophages.

Salivary gland function is commonly and irreversibly damaged by radiation therapy for head and neck cancer. This damage greatly decreases the patient's quality of life and is difficult to remedy. Previously, we found that the transient activation of Hedgehog signaling alleviated salivary hypofunction after radiation in both mouse and pig models through the inhibition of radiation-induced cellular senescence that is mediated by resident macrophages in mouse submandibular glands. Here we report that in swine parotid glands sharing many features with humans, the Hedgehog receptor PTCH1 is mainly expressed in macrophages, and levels of PTCH1 and multiple macrophage markers are significantly decreased by radiation but recovered by transient Hedgehog activation. These parotid macrophages mainly express the M2 macrophage marker ARG1, while radiation promotes expression of pro-inflammatory cytokine that is reversed by transient Hedgehog activation. Hedgehog activation likely preserves parotid macrophages after radiation through inhibition of P53 signaling and consequent cellular senescence. Consistently, VEGF, an essential anti-senescence cytokine downstream of Hedgehog signaling, is significantly decreased by radiation but recovered by transient Hedgehog activation. These findings indicate that in the clinically-relevant swine model, transient Hedgehog activation restores the function of irradiated salivary glands through the recovery of resident macrophages and the consequent inhibition of cellular senescence and inflammation.

Total body irradiation-induced colon damage is prevented by nitrate-mediated suppression of oxidative stress and homeostasis of the gut microbiome.

Inorganic dietary nitrate plays vital roles in biological functions via the exogenous NO3-/NO2-/NO pathway under hypoxia and ischemia. We previously verified the antioxidative effects of inorganic nitrate in a mouse model of total body irradiation (TBI). Accordingly, in this study, we evaluated the effects of inorganic nitrate on prevention of TBI-induced colon injury and dysbiosis of the gut microbiome. Nitrate significantly rescued the abnormal biological indexes (body weight, white blood cell, red blood cell, platelet, hemoglobin level and intestinal canal lengths) induced by TBI. Then, we detected oxidative stress and DNA damage indexes (phospho-histone H2AX and p53 binding protein 1), which were both increased by irradiation (IR) and alleviated by nitrate. IR-induced apoptosis and senescence were ameliorated by inorganic nitrate. The distribution of the gut microbiome differed for mice with TBI and those receiving inorganic nitrate. The average abundance of Lactobacillus significantly increased, and that of Bacteroidales decreased at the genus level in the nitrate group compared with that in the IR alone group. At 30 days after TBI, the abundances of Bacteroides and Faecalibaculum decreased, whereas that of Lactobacillus increased in the IR + nitrate group compared with that in the IR alone group. Inorganic nitrate efficiently prevents TBI-induced colon epithelium injury and maintains the homeostasis of the gut microbiome. Thus, our results showed that inorganic nitrate might be a promising treatment for TBI induced colon injury.

Silencing of CCR7 inhibits the growth, invasion and migration of prostate cancer cells induced by VEGFC.

Early in prostate cancer development, tumor cells express vascular endothelial growth factor C (VEGF-C), a secreted molecule that is important in angiogenesis progression. CC-chemokine receptor 7 (CCR7), another protein involved in angiogenesis, is strongly expressed in most human cancers, where it activated promotes tumor growth as well as favoring tumor cell invasion and migration. The present study aimed to investigate the effect of down-regulating CCR7 expression on the growth of human prostate cancer cells stimulated by VEGFC. The CCR7-specific small interfering RNA (siRNA) plasmid vector was constructed and then transfected into prostate cancer cells. The expression of CCR7 mRNA and protein was detected by quantitative polymerase chain reaction and western blot analysis, respectively. Cell proliferation, apoptosis, cell cycle distribution and cell migration were assessed following knockdown of CCR7 by RNA interference (RNAi). Western blot analysis was used to identify differentially expressed angiogenesis- and cell cycle-associated proteins in cells with silenced CCR7. The expression levels of CCR7 in prostate cancer cells transfected with siRNA were decreased, leading to a significant inhibition of prostate cancer cell proliferation, migration and invasion induced by VEGFC. Western blot analysis revealed that silencing of CCR7 may inhibit vascular endothelial growth factor, matrix metalloproteinase (MMP)-2 and MMP-9 protein expression. In conclusion, the present study demonstrated that RNAi can effectively silence CCR7 gene expression and inhibit the growth of prostate cancer cells, which indicates that there is a potential of targeting CCR7 as a novel gene therapy approach for the treatment of prostate cancer.