Vascular endothelial growth factor (VEGF) inhibition has been demonstrated to be an effective strategy in preserving the integrity of the blood-brain barrier (BBB) in patients with acute ischemic stroke. Loss of the BBB is the key event associated with morbidity and mortality in these patients. However, the underlying mechanisms remain poorly understood. In the present study, the effects of VEGF inhibition and the possible mechanism that underlies acute cerebral ischemia in rats was investigated. Following the induction of transient middle cerebral artery occlusion for a 90-min period, either an anti-VEGF neutralizing antibody (RB-222; 5 or 10 µg), or IgG (control), was administered by intracerebroventricular injection at 1 h following reperfusion. Functional outcomes, BBB leakage, brain edema, microvessel numbers and the relative protein levels of VEGF, matrix metalloproteinase (MMP)-2, MMP-9, occludin and collagen-IV were then determined using neurological assessments, Evans Blue staining, brain water content, CD31 staining and western blotting. Treatment with RB-222 at a dose of 5 and 10 µg significantly improved neurological functional outcomes and diminished infarct size, BBB leakage and brain edema compared with the MCAO and IgG groups at 24 h following reperfusion; 10 µg RB-222 was more effective than a 5 µg dose of the antibody. In addition, RB-222 reduced the number of immature microvessels, which subsequently attenuated BBB permeability. RB-222 significantly repressed VEGF expression as well as decreased MMP-2 and MMP-9 expression. However, it enhanced occludin and collagen-IV levels in the ischemic rat brain compared with the MCAO and IgG groups. Taken together, the results indicate that early inhibition of VEGF may have significant potential against cerebral ischemia, partly by regulating the expression of MMPs.
Aberrant hedgehog signaling contributes to the development of various malignancies, including glioblastoma (GBM). However, the potential mechanism of hedgehog signaling in GBM migration and invasion has remained to be elucidated. The present study showed that enhanced hedgehog signaling by recombinant human sonic hedgehog N-terminal peptide (rhSHH) promoted the adhesion, invasion and migration of GBM cells, accompanied by increases in mRNA and protein levels of matrix metalloproteinase-2 (MMP-2) and MMP-9. However, inhibition of hedgehog signaling with cyclopamine suppressed the adhesion, invasion and migration of GBM cells, accompanied by decreases in mRNA and protein levels of MMP-2 and -9. Furthermore, it was found that MMP-2- and MMP-9-neutralizing antibodies or GAM6001 reversed the inductive effects of rhSHH on cell migration and invasion. In addition, enhanced hedgehog signaling by rhSHH increased AKT phosphorylation, whereas blockade of hedgehog signaling decreased AKT phosphorylations. Further experiments showed that LY294002, an inhibitor of phosphoinositide-3 kinase (PI3K), decreased rhSHH-induced upregulation of MMP-2 and -9. Finally, the protein expression of glioblastoma-associated oncogene 1 was positively correlated with levels of phosphorylated AKT as well as protein expressions of MMP-2 and -9 in GBM tissue samples. In conclusion, the present study indicated that the hedgehog pathway regulates GBM-cell migration and invasion by increasing MMP-2 and MMP-9 production via the PI3K/AKT pathway.
pH-sensitive micelles are considered promising carriers for tumor targeted drug delivery. In this study, novel pH-sensitive star-shape copolymers of amphiphilic poly(epsilon-caprolactone)-b-poly(N, N-diethylaminoethyl methacrylate)-r-poly(N-(3-sulfopropyl)-N-methacryloxyethy-N, N-diethylammoniumbetaine) (4sPCLDEAS) are designed and synthesized with the combination of ring opening polymerization (ROP) and atom radical transferpolymerization (ATRP). The structure of the copolymers is characterized by proton nuclear magnetic resonance spectra (1HNMR). The poly(N-(3-sulfopropyl)-N-methacryloxyethy-N, N-diethylammoniumbetaine) segment is used instead of poly(ethylene glycol) (PEG) as hydrophilic block in the copolymers to form polymeric micelles. The micelles present spherical shape, narrow size distribution, and are reponsive to the acidity. The CMC of the micelles is as low as 1 x 10(-3) mg mL(-1). Doxorubin (DOX) is efficiently encapsulated in the micelles and the drug release is pH dependant. The cytotoxicity as well as the intracellular drug delivery of the micelles are investigated. The micelles are nontoxic to human cervical carcinoma (Hela) cells. The DOX-loaded micelles are internalized in Hela cells efficiently, which are better than that of hydrophilic doxorubicin hydrochloride (DOX x HCl). These pH-sensitive micelles are potential promising carriers for anti-cancer drug delivery.
Ring expansion of in situ generated cyclopropylmethyl cations via Wagner–Meerwein rearrangement to cyclobutanes is widely used in synthesis. However, the cyclopropylmethyl cations generated are planar, which would lead to loss of chiral information in the case of chiral precursors, making an asymmetric version of such ring expansion difficult. In the present work, a gold(I)-catalyzed asymmetric cyclopropanation/C–C cleavage/Wagner–Meerwein rearrangement of easily affordable yne-methylenecyclopropanes (1,6-yne-MCPs) has been developed to synthesize 3-azabicyclo[5.2.0]nonadiene, a bicyclic 7/4 ring (azepine fused with cyclobutane) with a bridgehead aryl substituent. This reaction overcomes the challenging loss of chirality from the Wagner–Meerwein rearrangement. Density functional theory calculations indicate that the chirality of the final product comes from the first cyclopropanation step in this reaction. The chirality in the resultant cyclopropane is lost in the following C–C cleavage step, generating rigid, planar cyclopropylmethyl carbocation intermediate. Then, only one carbon of the cyclopropyl group in the cyclopropylmethyl carbocation intermediate can migrate via ring expansion in the Wagner–Meerwein rearrangement process, and consequently, the chirality in the cyclopropane generated in the first step is transferred to the final product.
The polyene cyclization of E-polyenes has evolved into a reliable and widely used strategy for the construction of trans-decalin frameworks of terpene and steroid natural products. However, the polyene cyclization approach to cis-decalin framework is considerably challenging because such a reaction requires more difficult accessed Z-polyenes. Furthermore, polyene cyclization of Z-polyene to cis-decalin was usually accompanied by the formation of trans-isomer. We herein report a "universal" polyene cyclization approach to cis-decalin frameworks by employing ynamide-capped polyenes (YCPs), in which the central alkene can be either Z-or E-configuration. A broad range of YCPs are compatible to furnish the cis-decalin frameworks in good to excellent yields with excellent diastereoselectivity. No detectable trans-isomer has been observed for all the substrates used in this study. Both experimental and DFT calculation results revealed that the ynamide protonationinitiated polyene cyclization proceeds in a stepwise manner involving an unprecedented double protonation mechanism, wherein the steric repulsion between the iminium and the forming decalin
Abstract. Aberrant hedgehog signaling contributes to the development of various malignancies, including glioblastoma (GBM). However, the potential mechanism of hedgehog signaling in GBM migration and invasion has remained to be elucidated. The present study showed that enhanced hedgehog signaling by recombinant human sonic hedgehog N-terminal peptide (rhSHH) promoted the adhesion, invasion and migration of GBM cells, accompanied by increases in mRNA and protein levels of matrix metalloproteinase-2 (MMP-2) and MMP-9. However, inhibition of hedgehog signaling with cyclopamine suppressed the adhesion, invasion and migration of GBM cells, accompanied by decreases in mRNA and protein levels of MMP-2 and -9. Furthermore, it was found that MMP-2-and MMP-9-neutralizing antibodies or GAM6001 reversed the inductive effects of rhSHH on cell migration and invasion. In addition, enhanced hedgehog signaling by rhSHH increased AKT phosphorylation, whereas blockade of hedgehog signaling decreased AKT phosphorylations. Further experiments showed that LY294002, an inhibitor of phosphoinositide-3 kinase (PI3K), decreased rhSHH-induced upregulation of MMP-2 and -9. Finally, the protein expression of glioblastoma-associated oncogene 1 was positively correlated with levels of phosphorylated AKT as well as protein expressions of MMP-2 and -9 in GBM tissue samples. In conclusion, the present study indicated that the hedgehog pathway regulates GBM-cell migration and invasion by increasing MMP-2 and MMP-9 production via the PI3K/AKT pathway.
Transition metal-catalyzed [4 + 2 + 1] cycloaddition of in situ generated ene/yne–ene–allenes (from ene/yne–ene propargyl esters) and carbon monoxide (CO) gives the [4 + 2 + 1] cycloadducts rather than [2 + 2 + 1] cycloadducts. Investigating the mechanism of this [4 + 2 + 1] reaction and understanding why the [2 + 2 + 1] reaction does not compete and the role of the allene moiety in the substrates are important. This is also helpful to guide the future design of new [4 + 2 + 1] cycloadditions. Reported here are the kinetic and computed studies of the [4 + 2 + 1] reactions of ene–ene propargyl esters and CO. A quantum chemical study (at the DLPNO-CCSD(T)//BMK level) revealed that the [4 + 2 + 1] reaction includes four key steps, which are 1,3-acyloxy migration (rate-determining step), oxidative cyclization, CO migratory insertion, and reductive elimination. The allene moiety in the substrates is critical for providing additional coordination to the rhodium center in the final step of the catalytic cycle, which in turn favors the reductive elimination transition state in the [4 + 2 + 1] rather than in the [2 + 2 + 1] pathway. The CO insertion step in the [4 + 2 + 1] reaction, which could occur through either the UP (favored here) or DOWN CO insertion pathway, has also been deeply scrutinized, and some guidance from this analysis has been provided to help the future design of new [4 + 2 + 1] reactions. Quantum chemical calculations have also been applied to explain why [4 + 2] and [4 + 1] cycloadditions do not happen and how trienes as side products for some substrates are generated.
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