trans-4,5-Dehydro-DL-lysine dihydrochloride

Introduction: Ulcerative colitis (UC) is an inflammatory bowel disease characterized by repeated remissions and relapses. Immunosuppressive drugs have facilitated the induction and maintenance of remission in many patients with UC. However, immunosuppressive drugs cannot directly repair impaired intestinal mucosa and are insufficient for preventing relapse. Therefore, new treatment approaches to repair the damaged epithelium in UC have been attempted through the transplantation of intestinal organoids, which can be differentiated into mucosa by embedding in Matrigel, generated from patient-derived intestinal stem cells. The method, however, poses the challenge of yielding sufficient cells for UC therapy, and patient-derived cells might already have acquired pathological changes. In contrast, human induced pluripotent stem (iPS) cells generated from healthy individuals are infinitely proliferated and can be differentiated into target cells. Recently developed human iPS cell-derived intestinal organoids (HIOs) aim to generate organoids that closely resemble the adult intestine. However, no study till date has reported HIOs injected into in vivo inflammatory models, and it remains unclear whether HIOs with cells that closely resemble the adult intestine or with intestinal stem cells retain the better ability to repair tissue in colitis. Methods: We generated two types of HIOs via suspension culture with and without small-molecule compounds: HIOs that include predominantly more intestinal stem cells [HIO (A)] and those that include predominantly more intestinal epithelial and secretory cells [HIO (B)]. We examined whether the generated HIOs engrafted in vivo and compared their ability to accelerate recovery of the damaged tissue. Results: Findings showed that the HIOs expressed intestinal-specific markers such as caudal-type homeobox 2 (CDX2) and villin, and HIOs engrafted under the kidney capsules of mice. We then injected HIOs into colitis-model mice and found that the weight and clinical score of the mice injected with HIO (A) recovered earlier than that of the mice in the sham group. Further, the production of mucus and the expression of cell proliferation markers and tight junction proteins in the colon tissues of the HIO (A) group were restored to levels similar to those observed in healthy mice. However, neither HIO (A) nor HIO (B) could be engrafted into the colon. Conclusions: Effective cell therapy should directly repair tissue by engraftment at the site of injury. However, the difference in organoid property impacting the rate of tissue repair in transplantation without engraftment observed in the current study should be considered a critical consideration in the development of regenerative medicine using iPS-derived organoids.

The title complex, [Zn(C(10)H(8)N(2))(2)(H(2)O)(4)](C(9)H(7)O(3))(2), was obtained by the hydro-thermal reaction of zinc sulfate with mixed 4-hydroxy-lcinnamic acid (H(2)L) and 4,4'-bipyridine (4,4'-bipy) ligands. The complex consists of a centrosymmetric [Zn(4,4'-bipy)(2)(H(2)O)(4)](2+) cation with the metal centre in a distorted ZnN(2)O(4) coordination, and of two HL(-) anions. Extensive O-H⋯O and O-H⋯N hydrogen-bonding inter-actions between the constituents lead to the formation of a three-dimensional network.

The effects of SB-772077-B [4-(7-((3-amino-1-pyrrolidinyl)carbonyl)-1-ethyl-1H-imidazo(4,5-c)pyridin-2-yl)-1,2,5-oxadiazol-3-amine], an aminofurazan-based Rho kinase inhibitor, on the pulmonary vascular bed and on monocrotaline-induced pulmonary hypertension were investigated in the rat. The intravenous injections of SB-772077-B decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressure were enhanced when pulmonary vascular resistance was increased by U46619 [9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha)], hypoxia, or N(omega)-nitro-L-arginine methyl ester. SB-772077-B was more potent than Y-27632 [trans-4-[(1R)-1-aminoethyl]-N-4-pyridinyl-cyclohexanecarboxamide dihydrochloride] or fasudil [5-(1,4-diazepane-1-sulfonyl)isoquinoline] in decreasing pulmonary and systemic arterial pressures. The results with SB-772077-B, fasudil, and Y-27632 suggest that Rho kinase is constitutively active and is involved in the regulation of baseline tone and vasoconstrictor responses. Chronic treatment with SB-772077-B attenuated the increase in pulmonary arterial pressure induced by monocrotaline. The intravenous injection of SB-772077-B decreased pulmonary and systemic arterial pressures in rats with monocrotaline-induced pulmonary hypertension. The decreases in pulmonary arterial pressure in response to SB-772077-B in monocrotaline-treated rats were smaller than responses in U46619-infused animals, and the analysis of responses suggests that approximately 60% of the pulmonary hypertensive response is mediated by a Rho kinase-sensitive mechanism. The observation that Rho kinase inhibitors decrease pulmonary arterial pressure when pulmonary vascular resistance is increased by interventions such as hypoxia, U46619, angiotensin II, nitric-oxide synthase inhibition, and Bay K 8644 [S-(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-[trifluoromethyl]phenyl)-3-pyridine carboxylic acid methyl ester] suggest that the vasodilatation is independent of the mechanisms used to increase intracellular calcium and promote vasoconstriction. The present results suggest that SB-772077-B would be beneficial in the treatment of pulmonary hypertensive disorders.