It is a great challenge to fabricate self-healing hydrogels that simultaneously possess high mechanical strength and good elasticity, and are capable of rapidly and efficiently healing physical damage. In this work, such hydrogels are fabricated by grafting 4-carboxybenzaldehyde (CBA) onto poly(vinyl alcohol) (PVA) in dimethyl sulfoxide, followed by sequential dialysis in ethanol and water. The dialysis in ethanol generates hydrogen-bondcross-linked PVA-CBA organogels with homogeneous structures while the subsequent dialysis in water leads to PVA-CBA hydrogels uniformly dispersed with hydrogen-bond-cross-linked hydrophobic domains. The in-situ-formed hydrophobic domains with an average diameter of ∼13 nm can strengthen the PVA-CBA hydrogels to a tensile strength of ∼5.8 MPa and toughness of ∼14.9 MJ m −3 , and endow the hydrogels with good elasticity. Because of the presence of hydrogen bonds, the hydrophobic domains can reversibly break and reform to enable the rapid and efficient self-healing of fractured hydrogels at room temperature to restore their original mechanical strength. Meanwhile, the hydrogels have good biocompatibility and are potentially useful as post-operative antiadhesive films.
Glioblastoma, the most common human brain tumor, is highly invasive and difficult to cure using conventional cancer therapies. As an alternative, adenovirus-mediated virotherapies represent a popular and maturing technology. However, the cell surface coxsackievirus and adenovirus receptor (CAR)-dependent infection mechanism limits the infectivity and oncolytic effects of Adenovirus type 5. To address this limitation, in this study we aimed to develop a novel oncolytic adenovirus for enhanced infectivity and therapeutic efficacy toward glioblastoma. We developed a novel genetically modified oncolytic adenovirus vector with dual capsid modifications to facilitate infection and specific cytotoxicity toward glioma cells. Modification of the adenoviral capsid proteins involved the incorporation of a synthetic leucine zipper-like dimerization domain into the capsid protein IX (pIX) of human adenovirus serotype 5 (Ad5) and the exchange of the fiber knob from Ad37. The virus infection mechanism and anti-tumor efficacy of modified vectors were evaluated in both in vitro (cell) and in vivo (mouse) models. Ad37-knob exchange efficiently promoted the virus infection and replication-induced glioma cell lysis by oncolytic Ad5. We also found that gene therapy mediated by the dual-modified oncolytic Ad5 vector coupled with the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibited significantly enhanced anti-tumor efficacy in vitro and in vivo. This genetically modified oncolytic adenovirus provides a promising vector for future use in glioblastoma gene-viral-based therapies.
Methamphetamine (METH) exerts significant neurotoxicity in experimental animals and humans when taken at high doses or abused chronically. Long-term abusers have decreased dopamine levels, and they are more likely to develop Parkinson's disease (PD). To date, few medications are available to treat the METH-induced damage of neurons. Glial cell line-derived neurotrophic factor (GDNF) has been previously shown to reduce the dopamine-depleting effects of neurotoxic doses of METH. However, the effect of cerebral dopamine neurotrophic factor (CDNF), which has been reported to be more specific and efficient than GDNF in protecting dopaminergic neurons against 6-OHDA toxicity, in attenuating METH neurotoxicity has not been determined. Thus, the present study aimed to evaluate the neuroprotective effect of CDNF against METH-induced damage to the dopaminergic system in vitro and in vivo. In vitro, CDNF protein increased the survival rate and reduced the tyrosine hydroxylase (TH) loss of METH-treated PC12 cells. In vivo, METH was administered to rats following human CDNF overexpression mediated by the recombinant adeno-associated virus. Results demonstrated that CDNF overexpression in the brain could attenuate the METH-induced dopamine and TH loss in the striatum but could not lower METH-induced hyperthermia.
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