Early blood immune molecular alterations in cynomolgus monkeys with a PSEN1 mutation causing familial Alzheimer's disease.

INTRODUCTION: More robust non-human primate models of Alzheimer's disease (AD) will provide new opportunities to better understand the pathogenesis and progression of AD. METHODS: We designed a CRISPR/Cas9 system to achieve precise genomic deletion of exon 9 in cynomolgus monkeys using two guide RNAs targeting the 3' and 5' intron sequences of PSEN1 exon 9. We performed biochemical, transcriptome, proteome, and biomarker analyses to characterize the cellular and molecular dysregulations of this non-human primate model. RESULTS: We observed early changes of AD-related pathological proteins (cerebrospinal fluid Aß42 and phosphorylated tau) in PSEN1 mutant (ie, PSEN1-ΔE9) monkeys. Blood transcriptome and proteome profiling revealed early changes in inflammatory and immune molecules in juvenile PSEN1-ΔE9 cynomolgus monkeys. DISCUSSION: PSEN1 mutant cynomolgus monkeys recapitulate AD-related pathological protein changes, and reveal early alterations in blood immune signaling. Thus, this model might mimic AD-associated pathogenesis and has potential utility for developing early diagnostic and therapeutic interventions. HIGHLIGHTS: A dual-guide CRISPR/Cas9 system successfully mimics AD PSEN1-ΔE9 mutation by genomic excision of exon 9. PSEN1 mutant cynomolgus monkey-derived fibroblasts exhibit disrupted PSEN1 endoproteolysis and increased Aß secretion. Blood transcriptome and proteome profiling implicate early inflammatory and immune molecular dysregulation in juvenile PSEN1 mutant cynomolgus monkeys. Cerebrospinal fluid from juvenile PSEN1 mutant monkeys recapitulates early changes of AD-related pathological proteins (increased Aß42 and phosphorylated tau).

A Supramolecular Nanovehicle Featuring a pH/Enzyme Co-Response for Targeted Delivery of the Antitumor Compound.

Triptolide (TPL) has gained much attention as an antitumor compound with potential applications. However, TPL suffers from low bioavailability, severe toxic side effects, and limited targeted uptake by tumor cells, thus restricting the conversion of its clinical application. Here, a supramolecular nanovehicle, named TSCD/MCC NPs, featuring pH/AChE co-response was designed and prepared for loading, delivery, and targeted release of TPL. The cumulative release rate of TPL from TPL@TSCD/MCC NPs reached ∼90 % within 60 h at pH 5.0 and AChE co-stimulation. Bhaskar model is used to study TPL release procedure. In cell experiments, TPL@TSCD/MCC NPs showed high toxicity to the four tumor cells lines A549, HL-60, MCF-7, and SW480, and favorable biosafety to normal cells BEAS-2B. Furthermore, TPL@TSCD/MCC NPs containing relatively small amounts of TPL presented similar apoptosis rates to those of intrinsic TPL. We anticipate that TPL@TSCD/MCC NPs may facilitate the conversion of TPL into clinical applications through further studies.

Hyaluronidase-trigger nanocarriers for targeted delivery of anti-liver cancer compound.

Chemotherapy is recognized as one of the significant treatment methods for liver cancer. The compound celastrol (CSL) could effectively inhibit the proliferation, migration, and invasion of liver cancer cells, which is regarded as a promising candidate to become a mainstream anti-liver cancer drug. However, the application of CSL in liver cancer chemotherapy is limited due to its systemic toxicity, poor water solubility, multidrug resistance, premature degradation, and lack of tumor targeting. Meanwhile, in order to comply with the current concept of precision medicine, precisely targeted delivery of the anti-liver compound CSL was desired. This paper takes into account that liver cancer cells were equipped with hyaluronic acid (HA) receptors (CD44) on their surface and overexpressed. Hyaluronidase (HAase) capable of degrading HA, HAase-responsive nanocarriers (NCs), named HA/(MI)7-ß-CD NCs, were prepared based on the electrostatic interaction between HA and imidazole moieties modified ß-cyclodextrin (MI)7-ß-CD. HA/(MI)7-ß-CD NCs showed disassembly properties under HAase stimuli, which was utilized to trap, deliver, and the controllable release of the anti-liver cancer compound CSL. Furthermore, cytotoxicity assay experiments revealed that CSL-trapped HA/(MI)7-ß-CD NCs not only reduced cytotoxicity for normal cells but also effectively inhibited the survival for five tumor cells, and even the apoptotic effect of CSL-trapped NCs with a concentration of 5 µg mL-1 on tumor cells (SMMC-7721) was consistent with free CSL. Cell uptake experiments demonstrated HA/(MI)7-ß-CD NCs possessed the capability of targeted drug delivery to cancerous cells. HA/(MI)7-ß-CD NCs exhibited site-specific and controllable release performance, which is anticipated to proceed further in precision-targeted drug delivery systems.

Phosphogermanate Crystal: A New Ultraviolet-Infrared Nonlinear Optical Crystal with Excellent Optical Performances.

The phase matching ability is a key factor for nonlinear optical crystals to realize coherent output. Herein, a new design strategy combining ultraviolet and infrared functional groups into a ferroelectric was put forward. Thus, a phosphogermanate crystal, KGeOPO4, was designed and studied. It exhibits a wide transparency window (0.22-9.70 µm), a strong second harmonic generation response (5× KH2PO4), a high laser-induced damage threshold (1.61 GW/cm2), and the typical ferroelectricity (coercive field ∼ 9.8 kV/cm and remnant polarization ∼7.6 µC/cm2). In the infrared region, it could realize coherent output by the birefringence phase matching method, while it could generate ultraviolet coherent lights by the quasi-phase matching technique. Therefore, this work designs a promising ultraviolet-infrared nonlinear optical crystal and provides a new perspective for exploring nonlinear optical crystals.