RESUMO
Interleukin-37b (hereafter called IL-37) was identified as fundamental inhibitor of natural and acquired immunity. The molecular mechanism and function of IL-37 in colorectal cancer (CRC) has been elusive. Here, we found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and suffered from dramatically increased tumor burdens in colon. Nevertheless, IL-37 is dispensable for intestinal mutagenesis, and CRC cell proliferation, apoptosis, and migration. Notably, IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models. CD8+ T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice, enabling tumor evasion of immune surveillance. The dysfunction led by IL-37 antagonizes IL-18-induced proliferation and effector function of CD8+ T cells, which was dependent on SIGIRR (single immunoglobulin interleukin-1 receptor-related protein). Finally, we observed that IL-37 levels were significantly increased in CRC patients, and positively correlated with serum CRC biomarker CEA levels, but negatively correlated with the CD8+ T cell infiltration in CRC patients. Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancer-immunity cycle as therapeutic targets in CRC.
Assuntos
Carcinogênese/imunologia , Colite/imunologia , Neoplasias Colorretais/imunologia , Interleucina-1/imunologia , Proteínas de Neoplasias/imunologia , Receptores de Interleucina-1/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Carcinogênese/genética , Colite/genética , Colite/patologia , Neoplasias Colorretais/genética , Interleucina-1/genética , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Receptores de Interleucina-1/genéticaRESUMO
Previous studies suggested that oxidative stress is related to the onset and development of osteoporosis. Moreover, it was demonstrated that berberine has a protective effect against oxidative stress-induced injuries. In this study, we aimed to investigate the effect and mechanism of action of berberine on rats with induced osteoporosis. Sixty 8-week-old female Wistar rats were randomly divided into the following 6 groups: control saline-treated, osteoporosis saline-treated, 3 osteoporosis berberine-treated groups (Ber 5, 10, and 20 mg/kg/body weight, respectively), and osteoporosis alendronate-treated (ALD) group. Osteoporosis was induced by bilateral ovariectomy. All treatments were performed for 8 weeks. The bone mineral density (BMD), serum alkaline phosphatase (ALP), osteocalcin, calcium, phosphorus, superoxide dismutase (SOD), methylenedioxyamphetamine (MDA), and glutathione peroxidase (GSH-Px) level was determined in the rat femur tissue. The gene and protein expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) was analyzed by quantitative reverse transcription PCR and Western blot, respectively. The BMD, SOD and GSHâPx levels, and the expression of OPG were significantly lower in osteoporosis compared to control group (all p < 0.05). The serum levels of osteocalcin, ALP, and MDA, and the expression of RANKL were significantly higher in osteoporosis compared to control group (all p < 0.05). Berberine, especially the high doses of berberine, effectively increased SOD, GSHâPx, and OPG levels as well as decreased serum osteocalcin, ALP, MDA and RANKL levels in berberine-treated osteoporosis groups (all p < 0.05). To conclude, oxidative stress may promote the development of osteoporosis in rats through the RANK/RANKL/OPG pathway. The antioxidative effect of berberine reduces the development of osteoporosis in rats to some extent.
Assuntos
Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Berberina/farmacologia , Berberina/uso terapêutico , NF-kappa B/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Osteoprotegerina/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Ligante RANK/biossíntese , Animais , Peso Corporal , Densidade Óssea/efeitos dos fármacos , Feminino , Fêmur/patologia , Osteoporose/patologia , Osteoprotegerina/efeitos dos fármacos , Osteoprotegerina/genética , Ligante RANK/efeitos dos fármacos , Ligante RANK/genética , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Rapid angiogenesis is one of the major issues in the field of tissue engineering, and it is an urgent problem to be solved. The process and related mechanism of angiogenesis have been deeply researched. Meanwhile, various methods or strategies for promoting angiogenesis, involving the application of stem cells and growth factors, and construction and modification of biomaterial scaffolds, have also been reported. On one hand, many remarkable advances in the field of promoting angiogenesis have been achieved; on the other hand, the complexity of mechanism and regulation of angiogenesis have gradually been recognized and emphasized. This paper presents a comprehensive overview of advances in research of the strategies for promoting angiogenesis in the field of tissue engineering.
