Extracellular
vesicles (EVs) released by mesenchymal stem cells
(MSCs) have exhibited regenerative capability in animal models of
ischemia–reperfusion (I/R) acute kidney injury (AKI) and are
considered as potential alternatives to direct MSC therapy. However,
real-time in vivo imaging of MSC-EVs in renal I/R
injury has yet to be established. Renal intracellular targets of MSC-EVs
responsible for their regenerative effects also remain elusive. Here,
we report that we real-time observed MSC-EVs specifically accumulated
in the injured kidney and were taken up by renal proximal tubular
epithelia cells (TECs) via DPA-SCP with aggregation-induced
emission (AIE) characteristics. DPA-SCP precisely tracked the fate
of MSC-EVs in a renal I/R injury mouse model for 72 h and exhibited
superior spatiotemporal resolution and tracking ability to popular
commercially available EV tracker PKH26. Further analysis revealed
that the accumulated MSC-EVs stimulated mitochondrial antioxidant
defense and ATP production via activating the Keap1-Nrf2
signaling pathway, which protected TECs against oxidative insult by
reducing mitochondrial fragmentation, normalizing mitochondrial membrane
potential, and increasing mitochondrial DNA copy number. Increased
microRNA-200a-3p expression in renal TECs induced by MSC-EVs was identified
as a regulatory mechanism contributing to the protective actions on
mitochondria as well as stimulating the renal signal transduction
pathways. In conclusion, MSC-EVs accumulated in the renal tubules
during renal I/R injury and promoted the recovery of kidney function via activating the Keap1-Nrf2 signaling pathway and enhancing
mitochondrial function of TECs. DPA-SCP with AIE characteristics allows
noninvasive and precise in vivo visualization of
MSC-EVs in kidney repair.
To explore the influence of the positions
of the two nitrogen atoms
on the thiazole ring and the isoxazoline ring on the activity, a series
of novel piperidyl thiazole derivatives containing oxime ether and
oxime ester moieties with two nitrogen atoms on the same or opposite
sides have been designed, synthesized, and first evaluated for their
fungicidal activities against Phytophthora capsici
in vitro. The bioassay results showed that the
target compounds possessed moderate to good fungicidal activities
against P. capsici, among which oxime
ether compound 11b shows the highest fungicidal activity in vitro (EC50 = 0.0104 μg/mL) which is
higher than dimethomorph (EC50 = 0.1148 μg/mL) and
diacetylenyl amide (EC50 = 0.040 μg/mL). Compared
with oxime ether compounds (the two nitrogen atoms are on the opposite
sides), the activities of oxime ester compounds were significantly
reduced. It is different from the commercial fungicide fluoxapiprolin,
and the activities of the compounds with the two nitrogen atoms on
the same side were significantly reduced compared to the compounds
with the two nitrogen atoms on the opposite sides. Moreover, compounds 11b, 11d, 11e, and 11g showed moderate to good antifungal activities in vivo against Phytophthora capsici, Pseudoperonospora cubensis, and Phytophthora
infestans. Scanning electron microscopy of compound 11b on the hyphae morphology showed that compound 11b might cause mycelial abnormalities of P. capsici.
Carboxylic acid amide (CAA) fungicides are an important class of agricultural fungicide with oomycete activity and low toxicity toward mammalian cells. To find CAA analogues with high activity against resistant pathogens, a series of substituted N-benzhydryl valinamide carbamate derivatives were designed and synthesized by introducing substituted aromatic rings into valinamide carbamate leads. Bioassays showed that some title compounds exhibited very good in vitro fungicidal activity against Phytophthora capsici and in vivo fungicidal activities against Pseudoperonospora cubensis. Topomer CoMFA was performed to explore the structure-activity relationship on the basis of the in vitro data. The dimethoxy substituted aromatic analogue 9e was found to display higher in vitro fungicidal activity against Phytophthora capsici than iprovalicarb but lower activity than mandipropamid, and higher in vivo fungicidal activity against Pseudoperonospora cubensis than dimethomorph at a dosage of 6.25 μg mL(-1).
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