Vasodilator-stimulated phosphoprotein (VASP) controls actin dynamics associated with the malignant phenotype of colorectal tumors. Oncogenic VASP function, in turn, is finely regulated by cyclic nucleotide-dependent phosphorylation of serine (Ser) residues 157 and 239, whose differential expression determines cell survival behavior in colon cancer. However, the role of differential VASP Ser phosphorylation in colorectal carcinogenesis remains unclear. Specific VASP phosphomutant constructs were employed to selectively silence Ser157 or Ser239 phosphorylation in human colon carcinoma cells. Cyclic nucleotide-dependent manipulation of VASP Ser phosphorylation was performed with 8-bromoadenosine 3',5'-cyclic adenosine monophosphate (8-Br-cAMP) or 8-chlorophenylthio 3',5'-cyclic guanosine monophosphate (8-CPT-cGMP). Tumorigenic and locomotory phenotypes were examined in vitro with clonogenic and wound healing assays, respectively. Finally, tumor formation and growth were investigated in vivo employing two dis colon cancer. Fracture site is regionally hypoxic resulting from vasculature disruption. HIF-1αplays an essential role in fracture repair. This study aims to investigate the influence of FG4592 on the femur fracture of SD rats and the proliferation, migration of BMSCs. After the femoral fracture model was established, computed tomography imaging and histological analyses were used to quantify bone healing and the expression of CD90, HIF-1α, VEGF were observed by means of immunohistochemistry method on Day 10 and Day 20. In addition, CCK-8 assay, transwell, flow cytometric analysis, laser confocal microscopy assay, western blot and rT-PCR were performed to text the proliferation and migration of BMSCs using FG4592. In vivo, FG4592 facilitated the repair of bone fracture by increasing the number of BMSCs and cartilage formation. In vitro, FG4592 markedly improved the proliferation, migration of BMSCs via upregulation of intracellular Ca , NO and concomitant decrease of ROS. Gene silencing of HIF-1α resulted in the opposite phenomenon in BMSCs with the treatment of FG4592. The transplantation of BMSCs is the most promising candidate for the treatment of fracture non-union. We illustrated that FG4592 promoted the proliferation, migration of BMSCs via the HIF/Ca /NO/ROS pathway and further accelerated fracture healing. These results provide a deeper understanding for the mechanism of HIF in promoting fracture healing.The transplantation of BMSCs is the most promising candidate for the treatment of fracture non-union. We illustrated that FG4592 promoted the proliferation, migration of BMSCs via the HIF/Ca2+/NO/ROS pathway and further accelerated fracture healing. These results provide a deeper understanding for the mechanism of HIF in promoting fracture healing. Arginine depleting enzymes are found effective to treat arginine-auxotrophic cancers and therapy-resistant malignancies, alone or in combination with cytotoxic agents or immune checkpoint inhibitors. We aim to select and validate a long-lasting, safe and effective PEGylated and cobalt-chelated arginase conjugated at the selective cysteine residue as a therapeutic agent against cancers. Exploring pharmacokinetic and pharmacodynamic properties of the three arginase conjugates with different PEG modality (20kDa linear as A20L, 20kDa branched as A20Y, and 40kDa branched as A40Y) by cell-based and animal studies. Arginase conjugates showed comparable systemic half-lives, about 20h in rats and mice. The extended half-life of PEGylated arginase was concurrent with the integrity of conjugates of which PEG and protein moieties remain attached in bloodstream for 72h after drug administration. Arginase modified with a linear 20kDa PEG (A20L) was chosen as the lead candidate (PT01). In vitro assays confirmed the very potent cytotoxicity of PT01 against cancer cell lines of breast, prostate, and pancreas origin. Epalrestat In MIA PaCa-2 pancreatic and PC-3 prostate tumor xenograft models, weekly infusion of the PT01 at 5 and 10mg/kg induced significant tumor growth inhibition of 44-67%. All mice experienced dose-dependent but rapidly reversible weight loss following each weekly dose, suggesting tolerable toxicity. These non-clinical data support PT01 as the lead candidate for clinical development that may benefit cancer patients by providing an alternative cytotoxic mechanism.These non-clinical data support PT01 as the lead candidate for clinical development that may benefit cancer patients by providing an alternative cytotoxic mechanism. Interleukin (IL)-22 activates multiple signaling pathways to exert anti-inflammatory effects, but few studies have examined whether and how IL-22 may shift macrophage polarization between M (pro-inflammatory) and M (anti-inflammatory) states and thereby influence the progression of hepatic fibrosis. Utilized CCl to induce liver fibrosis in mice, detected the role of IL-22 in inhibiting liver fibrosis by regulating Kupffer cells (KCs) polarization in vivo and in vitro. U937 cells were used to confirm the mechanism of IL-22 regulating macrophage polarization via the STAT3/Erk/Akt pathways. Human liver specimens were collected to verify the correlation between the levels of IL-22 and KCs during liver fibrogenesis. During CCl -induced liver fibrosis progression in mice, adding exogenous IL-22 significantly inhibited pro-fibrogenic and macrophage phenotype-altering factors secreted by M -KCs, and it increased the number of M -KCs. In co-cultures of hepatic stellate cells and KCs from mice treated with IL-22, a high M /M -KCs ratio inhibited collagen production and stellate cell activation. These results suggest that IL-22 can increase the ratio of M -KCs to M -KCs and thereby attenuate the progression of liver fibrosis. Mechanistic studies in vitro showed that IL-22 promoted polarization of lipopolysaccharide-treated U937 macrophages from M to M . The cytokine exerted these effects by activating the STAT3 pathway while suppressing Erk1/2 and Akt pathways. Furthermore, immunofluorescent staining in human liver specimens confirmed that IL-22 levels positively correlated with the number of M -KCs during liver fibrogenesis. IL-22 regulates the STAT3/Erk/Akt to increase the M /M -KCs ratio and thereby slow liver fibrogenesis.IL-22 regulates the STAT3/Erk/Akt to increase the M2/M1-KCs ratio and thereby slow liver fibrogenesis.