Aagesenthisted6605

Temporal lobe epilepsy is the most common form of epilepsy, and current antiepileptic drugs are ineffective in many patients. The endocannabinoid system has been associated with an on-demand protective response to seizures. Blocking endocannabinoid catabolism would elicit antiepileptic effects, devoid of psychotropic effects. We herein report the discovery of selective anandamide catabolic enzyme fatty acid amide hydrolase (FAAH) inhibitors with promising antiepileptic efficacy, starting from a further investigation of our prototypical inhibitor 2a. When tested in two rodent models of epilepsy, 2a reduced the severity of the pilocarpine-induced status epilepticus and the elongation of the hippocampal maximal dentate activation. Notably, 2a did not affect hippocampal dentate gyrus long-term synaptic plasticity. These data prompted our further endeavor aiming at discovering new antiepileptic agents, developing a new set of FAAH inhibitors (3a-m). Biological studies highlighted 3h and 3m as the best performing analogues to be further investigated. In cell-based studies, using a neuroblastoma cell line, 3h and 3m could reduce the oxinflammation state by decreasing DNA-binding activity of NF-kB p65, devoid of cytotoxic effect. Unwanted cardiac effects were excluded for 3h (Langendorff perfused rat heart). Finally, the new analogue 3h reduced the severity of the pilocarpine-induced status epilepticus as observed for 2a.Aggregation-induced emission (AIE) active Pdots are attractive nanomaterials applied in electrochemiluminescence (ECL) fields, while the irreversible redox reaction of these Pdots is a prevailing problem, resulting in instability of ECL emission. Herein, we first designed and synthesized an AIE-active Pdot with reversible redox property, which contains a tetraphenylethene derivate and benzothiadiazole (BT) to achieve stable ECL emission. BT has a good rigid structure with excellent electrochemical behaviors, which is beneficial for avoiding the destruction of the conjugated structure as much as possible during the preparation of Pdots, thus maintaining good redox property. The tetraphenylethene derivate, as a typical AIE-active moiety, provides a channel for highly efficient luminescence in the aggregated states. The Pdots exhibited reversible and quasi-reversible electrochemical behaviors during cathodic and anodic scanning, respectively. The stable annihilation, reductive-oxidative, and oxidative-reductive ECL signals were observed. Subsequently, we constructed an ultrasensitive ECL biosensor based on the oxidative-reductive ECL mode for the detection of miRNA-21 with a detection limit of 32 aM. This work provides some inspiration for the future design of ECL materials featuring AIE-active property and stable ECL emission.The presence of intracellular signal transduction and its abnormal activities in many cancers has potential for medical and pharmaceutical applications. We recently developed a protein kinase C α (PKCα)-responsive gene carrier for cancer-specific gene delivery. Here, we demonstrate an in-depth analysis of cellular signal-responsive gene carrier and the impact of its selective transgene expression in response to malfunctioning intracellular signaling in cancer cells. We prepared a novel gene carrier consisting of a linear polyethylenimine (LPEI) main chain grafted to a cationic PKCα-specific substrate (FKKQGSFAKKK-NH2). The LPEI-peptide conjugate formed a nanosized polyplex with pDNA and mediated efficient cellular uptake and endosomal escape. This polyplex also led to successful transgene expression which responded to the target PKCα in various cancer cells and exhibited a 10-100-fold higher efficiency compared to the control group. In xenograft tumor models, the LPEI-peptide conjugate promoted transgene expression showing a clear-cut response to PKCα. Furthermore, when a plasmid containing a therapeutic gene, human caspase-8 (pcDNA-hcasp8), was used, the LPEI-peptide conjugate had significant cancer-suppressive effects and extended animal survival. Collectively, these results reveal that our method has great potential for cancer-specific gene delivery and therapy.Treatment resistance of the tumors to photodynamic therapy (PDT) owing to O2 deficiency largely compromised the therapeutic efficacy, which could be addressed via modulating oxygen levels by using O2 self-enriched nanosystems. Here, we report on augmenting the O2-evolving strategy based on a biomimetic, catalytic nanovehicle (named as N/P@MCC), constructed by the catalase-immobilized hollow mesoporous nanospheres by enveloping a cancer cell membrane (CCM), which acts as an efficient nanocontainer to accommodate nitrogen-doped graphene quantum dots (N-GQDs) and protoporphyrin IX (PpIX). Inheriting the virtues of biomimetic CCM cloaking, the CCM-derived shell conferred N/P@MCC nanovehicles with highly specific self-recognition and homotypic targeting toward cancerous cells, ensuring tumor-specific accumulation and superior circulation durations. N-GQDs, for the first time, have been evidenced as a new dual-functional nanoagents with PTT and PDT capacities, enabling the generation of 1O2 for PDT and inducing local low-temperature hyperthermia for thermally ablating cancer cells and infrared thermal imaging (IRT). Leveraging the intrinsic catalytic features of catalase, such N/P@MCC nanovehicles effectively scavenged the excessive H2O2 to sustainably evolve oxygen for a synchronous O2 self-supply and hypoxia alleviation, with an additional benefit because the resulting O2 bubbles could function as an echo amplifier, leading to the sufficient echogenic reflectivity for ultrasound imaging. Concurrently, the elevated O2 reacted with N-GQDs and PpIX to elicit a maximally increased 1O2 output for augmented PDT. Significantly, the ultrasound imaging coupled with fluorescence imaging, IRT, performs a tumor-modulated trimodal bioimaging effect. Overall, this offers a paradigm to rationally explore O2 self-supply strategies focused on versatile nanotheranostics for hypoxic tumor elimination.This study aims to push the frontier of the engineering of human cathelicidin LL-37, a critical antimicrobial innate immune peptide that wards off invading pathogens. By sequential truncation of the smallest antibacterial peptide (KR12) of LL-37 and conjugation with fatty acids, with varying chain lengths, a library of lipopeptides is generated. These peptides are subjected to antibacterial activity and hemolytic assays. Candidates (including both forms made of l- and d-amino acids) with the optimal cell selectivity are subsequently fed to the second layer of in vitro filters, including salts, pH, serum, and media. These practices lead to the identification of a miniature LL-37 like peptide (d-form) with selectivity, stability, and robust antimicrobial activity in vitro against both Gram-positive and negative bacteria. Proteomic studies reveal far fewer serum proteins that bind to the d-form than the l-form peptide. CC-885 chemical structure C10-KR8d targets bacterial membranes to become helical, making it difficult for bacteria to develop resistance in a multiple passage experiment.