Near-infrared AIE-active phosphorescent iridium(III) complex for mitochondria-targeted photodynamic therapy.

Mitochondria-targeted photodynamic therapy (PDT) has recently been recognized as a promising strategy for effective cancer treatment. In this work, a mitochondria-targeted near-infrared (NIR) aggregation-induced emission (AIE)-active phosphorescent Ir(III) complex (Ir1) is reported with highly favourable mitochondria-targeted bioimaging and cancer PDT properties. Complex Ir1 has strong absorption in the visible light region (∼500 nm) and can effectively produce singlet oxygen (1O2) under green light (525 nm) irradiation. It preferentially accumulates in the mitochondria of human breast cancer MDA-MB-231 cells as revealed by colocalization analysis. Complex Ir1 displays high phototoxicity toward human breast cancer MDA-MB-231 cells and mouse breast cancer 4T1 cells. Complex Ir1 induces reactive oxygen species (ROS) production, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in MDA-MB-231 cells upon photoirradiation, leading to apoptotic cell death. The favorable PDT performance of Ir1in vivo has been further demonstrated in tumour-bearing mice. Together, the results suggest that Ir1 is a promising photosensitizer for mitochondria-targeted imaging and cancer phototherapy.

The Amomum tsao-ko Essential Oils Inhibited Inflammation and Apoptosis through p38/JNK MAPK Signaling Pathway and Alleviated Gentamicin-Induced Acute Kidney Injury.

The clinical application of gentamicin may lead to acute kidney injury (AKI), and the nephrotoxicity of gentamicin is related to the pathological mechanism of several oxidative and inflammatory cytokines. Plant-derived essential oils have good anti-inflammatory and antioxidant properties. This study aimed to clarify the protective effect of Amomum tsao-ko essential oils (AOs) on gentamicin-induced AKI in rats and its possible mechanism. The rat AKI model was induced by intraperitoneal injection of gentamicin. After 14 days of oral AO treatment, the renal function and pathological changes of the kidney tissues were evaluated, and the level of kidney tissue oxidative stress was detected. The content of inflammatory cytokines was measured by ELISA. The expression of ERK1/2, JNK1/2, p38, NF-κB, caspase-3, and Bax/Bcl-2 proteins were estimated by Western blot analysis. The results showed that taking AO reduced the contents of serum urea and creatinine in AKI rats and improve the pathological changes and oxidative stress of the kidney tissue in rats. At the same time, AO reduced inflammation and apoptosis during AKI by regulating the MAPK pathway. The data show that AO has a protective effect on the kidneys and may be a potential drug for treating kidney injury.

Three new tyrosol derivatives from Huangjing wine.

Phytochemical investigation on the concentrate of Huangjing wine, resulted in the isolation of three new tyrosol derivatives 4'''-hydroxyphenethyl 2-(R)-hydroxy-3-phenylpropionate (1), 4'''-hydroxyphenethyl(4'-hydroxy-3'-methoxyphenyl)propionate (2) and 4''-hydroxyphenethyl ethyl succinate (3), together with 5 known compounds, ferulic acid (4), L-phenyllactic acid (5), hydroxytyrosol (6), dihydroferulic acid (7), cyclo(L-Pro-D-Tyr) (8). Their structures were elucidated using spectroscopic analysis and by comparison with the literature data. All compounds displayed antioxidant effect in the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical. Among them, the new compound 2 exhibited obvious antioxidant effect, and new compounds 1 and 3 exhibited medium antioxidant effect.

A small-molecule activator of ULK1 that induces cytoprotective autophagy for Parkinson disease treatment / 中国药理学与毒理学杂志

OBJECTIVE To discover a small- molecule activator of ULK1 for Parkinson disease treatment and exploreits potential mechanisms. METHODS Candidate ULK1 activator was found by using structure-based design and high-through put screening, then modified by chemical synthesis and screened by kinase and autophgic activities.The amino acid residues that key to the activation site of the best candidate ULK1 activator (BL-918) were determined by site-directed mutagenesis, as well as in vitro kinase assay, ADP- Glo kinase assay and surface plasmon resonance (SPR) analysis. The mechanisms of BL- 918 induced cytoprotective autophagy were investigated by electron microscopy, fluorescence microscopy, Western blotting, co-immunoprecipitation assay, siRNA and GFP-LC3 plasmid transfections. The therapeutic effect of BL- 918 was determined by MPTP- mouse model, including behavioral tests, the levels of dopamine and its derivatives, as well as immunofluorescence and Western blotting. The toxicity of BL-918 was assessed by blood sample analysis and hematoxylin-eosin staining. RESULTS We discovered a small molecule (BL-918) as a potent activator of ULK1 by structure-based drug design. Subsequently, some key amino acid residues (Arg18, Lys50, Asn86 and Tyr89) were found to be crucial to the binding pocket between ULK1 and BL- 918, by site- directed mutagenesis. Moreover, we found that BL- 918 could induce autophagy via the ULK complex in neuroblastoma SH-SY5Y cells. Intriguingly, this activator displayed a cytoprotective effect on MPP +-treated SH-SY5Y cells, as well as protected against MPTP-induced motor dysfunction and loss of dopaminergic neurons by targeting ULK1- modulated autophagy in mouse models of PD. CONCLUSION We discovered a novel ULK1 activator (BL-918) that potently activated ULK1. This activator could induce cytoprotective autophagy via the ULK1 complex in SH- SY5Y cells, and also exerted its neuroprotective effects by targeting ULK1- modulated autophagy in a MPTP- induced PD mouse model, which may serve as a candidate drug for future PD therapy.