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Myocardial ischemia, while causing cardiomyocyte injury, can activate innate protective processes, enhancing myocardial tolerance to ischemia. Such processes are present in not only the heart, but also remote organs. In this investigation, we demonstrated a cardioprotective process involving FGF21 from the liver and adipose tissue. In response to myocardial ischemia/reperfusion injury in the mouse, FGF21 was upregulated and released from the hepatic cells and adipocytes into the circulation and interacted with FGFR1 in cardiomyocytes under the mediation of the cell membrane protein β-Klotho, inducing FGFR1 phosphorylation. This action caused phosphorylation of the signaling molecules PI3K p85, Akt1 and BAD, thereby reducing caspase 3 activity, cell death and myocardial infarction in association with improvement of myocardial function. These observations suggest that FGF21 is upregulated and released from the liver and adipose tissue in myocardial injury, contributing to myocardial protection by the mediation of the FGFR1/β-Klotho–PI3K–Akt1–BAD signaling network.

Cerebral ischemia, while causing neuronal injury, can activate innate neuroprotective mechanisms, minimizing neuronal death. In this report, we demonstrate that experimental cerebral ischemia/reperfusion injury in the mouse causes upregulation of the secretory protein trefoil factor 3 (TFF3) in the hepatocyte in association with an increase in serum TFF3. Partial hepatectomy (~60% liver resection) immediately following cerebral injury significantly lowered the serum level of TFF3, suggesting a contribution of the liver to the elevation of serum TFF3. Compared to wild-type mice, TFF3(-/-) mice exhibited a significantly higher activity of caspase 3 and level of cell death in the ischemic cerebral lesion, a larger fraction of cerebral infarcts, and a smaller fraction of the injured cerebral hemisphere, accompanied by severer forelimb motor deficits. Intravenous administration of recombinant TFF3 reversed changes in cerebral injury and forelimb motor function due to TFF3 deficiency. These observations suggest an endocrine neuroprotective mechanism involving TFF3 from the liver in experimental cerebral ischemia/reperfusion injury.

Myocardial ischemia induces cardiomyocyte injury and death, resulting in impairment of cardiac function. The adult cardiomyocytes possess a limited capacity of protection in myocardial ischemia, and nonmyocytic cells can be activated to support myocardial protection. We recently demonstrated that hepatic cells were able to upregulate genes encoding secreted proteins and were mobilized to the circulatory system, potentially contributing to myocardial protection against ischemic injury. In this investigation, we tested the potential mechanisms by which hepatic cells were mobilized in experimental myocardial ischemia. Following the induction of myocardial ischemia, hepatic cells, including hepatocytes and biliary epithelial cells, were mobilized to the circulatory system with a peak population 1.9 ± 0.4% at day 5. The cytokine IL-6 was upregulated in the ischemic myocardium as well as the serum. IL-6 promoted leukocyte retention in the liver as demonstrated by an increase in liver-retained leukocytes in myocardial ischemia in wild type mice, reduced leukocytes in IL-6 −/− mice, and restoration of leukocyte retention in response to IL-6 administration to IL-6 −/− mice. Liver-retained leukocytes exhibited upregulation of MMP-2, which in turn mediated hepatic cell mobilization by degrading extracellular matrix. These observations suggest that IL-6-stimulated leukocytes mediate the mobilization of hepatic cells via releasing MMP-2 in myocardial ischemia.

The activities of vascular cells, including adhesion, proliferation, and migration, are mediated by extracellular matrix components, including collagen matrix and elastic fibers or laminae. Whereas the collagen matrix stimulates vascular cell adhesion, proliferation, and migration, the elastic laminae inhibit these activities. Coordinated regulation of cell activities by these matrix components is an essential process for controlling the development and remodeling of the vascular system. This article summarizes recent development on the role of arterial elastic laminae in regulating the development of smooth muscle-like cells from bone marrow-derived progenitor cells as well as in mediating cell adhesion, proliferation, and migration with a focus on the molecular mechanisms and physiological significance.

Cerebral ischemia, while causing neuronal injury, can activate innate neuroprotective mechanisms, minimizing neuronal death. In this report, we demonstrate that experimental cerebral ischemia/reperfusion injury in the mouse causes upregulation of the secretory protein trefoil factor 3 (TFF3) in the hepatocyte in association with an increase in serum TFF3. Partial hepatectomy (~60% liver resection) immediately following cerebral injury significantly lowered the serum level of TFF3, suggesting a contribution of the liver to the elevation of serum TFF3. Compared to wild-type mice, TFF3-/- mice exhibited a significantly higher activity of caspase 3 and level of cell death in the ischemic cerebral lesion, a larger fraction of cerebral infarcts, and a smaller fraction of the injured cerebral hemisphere, accompanied by severer forelimb motor deficits. Intravenous administration of recombinant TFF3 reversed changes in cerebral injury and forelimb motor function due to TFF3 deficiency. These observations suggest an endocrine neuroprotective mechanism involving TFF3 from the liver in experimental cerebral ischemia/reperfusion injury.

Aim： To investigate the effects of （-）-epigallocatechin-3-gallate （EGCG）, an active compound in green tea, on prostaglandin E2 （PGE2）- induced proliferation and migration, and the expression of prostanoid EP1 receptors in hepatocellular carcinoma （HCC） cells. Methods： HCC cell line HepG2, human hepatoma cell lines MHCC-97L, MHCC-97H and human hepatocyte cell line L02 were used. Cell viability was analyzed using MTr assay. PGE2 production was determined with immunoassay. Wound healing assay and transwel filter assay were employed to assess the extent of HCC cell migration. The expression of EP1 receptor and Gq protein were examined using Western blot assay. Results： PGE2 （4-40000 nmol/L） or the EP1 receptor agonist ONO-DI-O04 （400-4000 nmol/L） increased the viability and migration of HepG2 cells in concentration-dependent manners. EGCG （100 pg/mL） significantly inhibited the viability and migration of HepG2 cells induced by PGE2 or ONO-DI-O04. HepG2 cells secreted an abundant amount of PGE2 into the medium, and EGCG （100 pg/mL） significantly inhibited the PGE2 production and EP1 receptor expression in HepG2 cells. EGCG （100 pg/mL） also inhibited the viability of MHCC-97L cells, but not that of MHCC-97H cells. Both EGCG （100 pg/mL） and EP1 receptor antagonist 0N0-8711 inhibited PGE2 4 pmol/L and ONO-DI-O04 400 nmol/L-induced growth and migration of HepG2 cells. Both EGCG （100 pg/mL） and 0N0-8711 210 nmol/L inhibited PGE2- and ONO-Dl-OO4-induced EP~ expression. EGCG and 0N0-8711 had synergistic effects in inhibiting EP1 receptor expression. PGE2, ONO-DI-004, 0N0-8711, and EGCG had no effects on Gq expression in HepG2 cells, respectively. Conclusion： These findings suggest that the anti-HCC effects of EGCG might be mediated, at least partially, through the suppressing EP1 receptor expression and PGE2 production.

Aim： To characterize the pharmacological profiles of a novel K-opioid receptor agonist MB-1C-OH. Methods： [3H]diprenorphine binding and [35S]GTPyS binding assays were performed to determine the agonistic properties of MB-lC-OH Hot plate, tail flick, acetic acid-induced writhing, and formalin tests were conducted in mice to evaluate the antinociceptive actions. Forced swimming and rotarod tests of mice were used to assess the sedation and depression actions. Results： In [3H]diprenorphine binding assay, MB-lC-OH did not bind to p- and 6-opioid receptors at the concentration of 100 μmol/L, but showed a high affinity for κ-opioid receptor （K1=35 nmol/L）. In [35S]GTPγS binding assay, the compound had an Emax of 98% and an ECso of 16.7 nmol/L for κ-opioid receptor. Subcutaneous injection of MB-lC-OH had no effects in both hot plate and tail flick tests, but produced potent antinociception in the acetic acid-induced writhing test （ED50=0.39 mg/kg）, which was antagonized by pretreatment with a selective κ-opioid receptor antagonist Nor-BNI. In the formalin test, subcutaneous injection of MB-lC-OH did not affect the flinching behavior in the first phase, but significantly inhibited that in the second phase （ED50=0.87 mg/kg）. In addition, the sedation or depression actions of MB-lC-OH were about 3-fold weaker than those of the classical K agonist （-）U50,488H. Conclusion： MB-1C-OH is a novel K-opioid receptor agonist that produces potent antinociception causing less sedation and depression.

Tree shrews have a close relationship to primates and have many advantages over rodents in biomedical research. However, the laek of gene manipulation methods has hindered the wider use of this animal. Spermatogonial stem cells （SSCs） have been successfully expanded in culture to permit sophisticated gene editing in the mouse and rat. Here, we describe a culture system for the long-term expansion of tree shrew SSCs without the loss of stem cell properties. In our study, thymus cell antigen 1 was used to enrich tree shrew SSCs. RNA-sequencing analysis revealed that the Wnt/β-catenin signaling pathway was active in undifferentiated SSCs, but was downregulated upon the initiation of SSC differentiation. Exposure of tree shrew primary SSCs to recombinant Wnt3a protein during the initial passages of culture enhanced the survival of SSCs. Use of tree shrew Sertoli cells, but not mouse embryonic fibroblasts, as feeder was found to be necessary for tree shrew SSC proliferation, leading to a robust cell expansion and long-term culture. The expanded tree shrew SSCs were transfected with enhanced green fluorescent protein （EGFP）-expressing lentiviral vectors. After transplantation into sterilized adult male tree shrew＇s testes, the EGFP-tagged SSCs were able to restore spermatogenesis and successfully generate transgenic offspring. Moreover, these SSCs were suitable for the CRISPR/Cas9-mediated gene modification. The development of a culture system to expand tree shrew SSCs in combination with a gene editing approach paves the way for precise genome manipulation using the tree shrew.

The activities of vascular cells, including adhesion, proliferation, and migration, are mediated by extracellular matrix components, including collagen matrix and elastic fibers or laminae. Whereas the collagen matrix stimulates vascular cell adhesion, proliferation, and migration, the elastic laminae inhibit these activities. Coordinated regulation of cell activities by these matrix components is an essential process for controlling the development and remodeling of the vascular system. This article summarizes recent development on the role of arterial elastic laminae in regulating the development of smooth muscle-like cells from bone marrow-derived progenitor cells as well as in mediating cell adhesion, proliferation, and migration with a focus on the molecular mechanisms and physiological significance.

Lung metastasis is the major cause of death in patients with triple negative breast cancer （TNBC）, an aggressive subtype of breast cancer with no effective therapy at present. It has been proposed that dual-targeted therapy, ie, targeting chemotherapeutic agents to both tumor vasculature and cancer ceils, may offer some advantages. The present work was aimed to develop a dual-targeted synergistic drug combination nanomedicine for the treatment of lung metastases of TNBC. Thus, Arg-Giy-Asp peptide （RGD）- conjugated, doxorubicin （DOX） and mitomycin C （MMC） co-loaded polymer-lipid hybrid nanoparticles （RGD-DMPLN） were prepared and characterized. The synergism between DOX and MMC and the effect of RGD-DMPLN on cell morphology and cell viability were evaluated in human MDA-MB-231 cells in vitro. The optimal RGD density on nanoparticles （NPs） was identified based on the biodistribution and tumor accumulation of the NPs in a murine lung metastatic model of MDA-MB-231 cells. The microscopic distribution of RGD-conjugated NPs in lung metastases was examined using confocal microscopy. The anticancer efficacy of RGD- DMPLN was investigated in the lung metastatic model. A synergistic ratio of DOX and MMC was found in the MDA-MB-231 human TNBC cells. RGD-DMPLN induced morphological changes and enhanced cytotoxicity in vitro. NPs with a median RGD density showed the highest accumulation in lung metastases by targeting both tumor vasculature and cancer cells. Compared to free drugs, RGD-DMPLN exhibited significantly low toxicity to the host, liver and heart. Compared to non-targeted DMPLN or free drugs, administration of RGD-DMPLN （10 mg/kg, iv） resulted in a 4.7-fold and 31-fold reduction in the burden of lung metastases measured by bioluminescence imaging, a 2.4-fold and 4.0-fold reduction in the lung metastasis area index, and a 35% and 57% longer median survival time, respectively. Dual-targeted RGD-DMPLN, with optimal RGD density, significantly inhibited the progression of lung metastasis and extended host survival.