•Native fucosylated chondroitin sulfates (FCS) and their derivatives were prepared.•Their chemical structures of FCSs and their derivatives were analyzed.•Their relationships between structures and anticoagulant activities were elucidated.•Bleeding risk and factor XII and platelet activation of native FCS were eliminated.•FCS oligosaccharides may be novel drug candidates as selective Xase inhibitors.Fucosylated chondroitin sulfate (FCS), a structurally unusual glycosaminoglycan, has distinct anticoagulant properties, and is an especially strong inhibitor of the intrinsic factor Xase (anti-Xase). To obtain a highly selective inhibitor of human Xase, we purified six native FCSs with various sulfation patterns, prepared a series of FCS derivatives, and then elucidated the relationship between the structures and the anticoagulant activities of FCSs. FCSs 1–3 containing higher Fuc2S4S exhibit stronger AT-dependent anti-IIa activities, whereas 4–6 containing more Fuc3S4S produce potent HCII-dependent anti-IIa activities. Saccharides containing a minimum of 6–8 trisaccharide units, free carboxyl groups, and full fucosylation of GlcA may be required for potent anti-Xase activity, and approximately six trisaccharide units and partial fucosylation of GlcA may contribute to potent HCII-dependent activity. Decreasing of the molecular weights markedly reduces their AT-dependent anti-IIa activities, and even eliminates human platelet and factor XII activation. Furthermore, in vitro and in vivo studies suggested that fractions of 6–12 kDa may be very promising compounds as putative selective intrinsic Xase inhibitors with antithrombotic action, but without the consequences of major bleeding and factor XII activation.

Cardiac fibrosis is involved in a lot of cardiovascular pathological processes. Cardiac fibrosis can block conduction, cause hypoxia, strengthen myocardial stiffness, create electrical heterogeneity, and hamper systolic ejection, which is associated with the development of arrhythmia, heart failure and sudden cardiac death. Besides the initial stimulating factors, the cardiac fibroblasts (CFs) are the principal responsible cells in the fibrogenesis cascade of events. TRPM7, a member of the TRPM (Melastatin) subfamily, is a non-selective cation channel, which permeates both Ca2+ and Mg2+. Here we demonstrated TRPM7 expression in CFs, and 2-APB (TRPM7 inhibitor), inhibited Ang II-induced CTGF, α-SMA expression and CFs proliferation. Besides, knocking down TRPM7 by shRNA, we proved that TRPM7 mediated both calcium and magnesium changes in cardiac fibroblasts which contribute to fibrosis progress. This study suggested that TRPM7 should play a pivotal role in cardiac fibroblast functions associated to cardiac fibrosis development.

•Bradykinin promoted migration and invasion of HepG2 cells through TRPM7 and MMP2.•The effect of Bradykinin on NMHC-IIA Ser-1943 was similar to EGF's.•Ser-1943 could be an overlooked phosphorylation site on NMHC-IIA for TRPM7.•Both NM-IIA and calpains were important for migrating cancer cells.•Src regulated the invadopodia formation and MMP2 secretion of HepG2 cells.Tumor metastasis is the main reason of death for hepatocellular carcinoma (HCC) patients. Cell migration and invasion are two prerequisites for tumor metastasis, in which TRPM7 and MMPs play an important role. In our study, we found that bradykinin (BK) could upregulate the expression of TRPM7 and dynamically regulate the phosphorylation of non-muscle myosin IIA heavy chain (NMHC-IIA) Ser-1943 in HepG2 cells. The influx of Ca2+ via TRPM7 was necessary for elevating the activity of m-calpain and μ-calpain. Additionally, we observed that BK stimulated HepG2 cells to secrete more MMP2 but not MMP9. Src was critical in the process of MMP2 secretion and invadopodia formation. The heat map showed that BDKRB2, TRPM7 and MMP2 had higher overexpression proportions in 25 HCC cell lines. Some clinical specimens of HCC also indicated that BDKRB2 and MMP2 were overexpressed. In conclusion, BK promoted migration and invasion of HCC cells through TRPM7 and MMP2.

•Autophagy was activated in response to Ang II stimulation in vitro and in vivo.•Rapa suppressed Ang II-induced upregulation of ECM in rat CFs.•CQ or ATG5 knockdown aggravated Ang II-induced upregulation of ECM in rat CFs.•Rapa attenuated, while CQ exacerbated, Ang II-induced cardiac fibrosis in mice.Autophagy has been involved in numerous diseases processes. However, little is known about the role of autophagy in cardiac fibrosis. Thus, whether or not angiotensin II (Ang II)-induced autophagy has a regulatory function on cardiac fibrosis was detected in vitro and in vivo. In rat cardiac fibroblasts (CFs) stimulated with Ang II, activated autophagy was observed using transmission electron microscopic analysis (TEM), immunofluorescence and Western blot. In Ang II-infused mice, increased co-localization of LC3 puncta with vimentin was observed. In rat CFs, co-treated with rapamycin (Rapa), an autophagy inducer, Ang II-induced the upregulation of type I collagen (Col-I), fibronectin (FN) was decreased. Conversely, inhibition of autophagy by chloroquine (CQ), an autophagy inhibitor, or knockdown of ATG5, a key component of the autophagy pathway by specific siRNA, aggravated Ang II-mediated the accumulation of Col-I and FN. Furthermore, in C57 BL/6 mice with Ang II infusion, intraperitoneal administration of Rapa ameliorated Ang II-induced cardiac fibrosis and cardiac dysfunction, while CQ treatment not only exacerbated Ang II-mediated cardiac fibrosis and cardiac dysfunction, but also impaired cardiac function. These findings suggest that autophagy may exert a protective role to attenuate excess extracellular matrix (ECM) accumulation in the heart.